1<html> 2<head> 3<title>MDMA / Ecstasy : Utopian Pharmacology</title> 4<META name="keywords" content="mdma, ecstasy, drugs, pharmacology, health, research, serotonin, dopamine, oxytocin, ecstacy"> 5<META name="description" content="Lifelong Ecstasy? Beyond MDMA. Mental Health in the Third Millennium; drugs and medications"> 6<meta name="alias" content="https://www.mdma.net/"> 7<meta name="owner" content="[email protected]"> 8<meta name="author" content="[email protected]"> 9<meta name="distribution" content="global"> 10<meta name="resource-type" content="document"> 11<style> 12a:hover{color:336699; } 13</style>
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15</head> 16<body bgcolor="#FFFFFF" link="#8897DB" vlink="#293A8B" alink="#cc0000"> 17<a href="https://www.bltc.com/index.html"><img src="50logo.gif" width="50" height="41" border="0" alt="mdma.net : BLTC logo"></a> 18<blockquote> <blockquote><blockquote><blockquote><font face="Verdana", "Arial", "Helvetica" size="-1"> 19<center> <h3><big> UTOPIAN PHARMACOLOGY</big><br> Mental Health in the Third Millennium<br> 20MDMA and Beyond<br> <br> <br> </h3><br> <h3><a href="mdma.html"><img src="structure/mdma.jpg" width="148" height="288" alt="3,4-methylenedioxy-n-methylamphetamine : MDMA - 'Ecstasy'" border="0"></a></h3></center><br><br> 21<OL><b> 22<LI><a href=#ecstasy>MDMA/Ecstasy</a><P> 23<LI><a href=#mdmahistory>A brief history of MDMA</a><br><P> 24<LI><a href=#ecstasyfeel>The MDMA Experience</a><P> 25<LI><a href=#mdmatox>MDMA : neurotoxicity</a><P> 26<LI><a href=#ecstasyprotect>MDMA : neuroprotection</a><P> 27<LI><a href=#mdmalife>Ecstasy for life?</a><P> 28<LI><a href=#ecstasymagic>The molecular machinery of magic</a><P> 29<LI><a href=#mdmadarwin>Post-Darwinian Medicine</a><P> 30<LI><a href=#ecstasymdma>Beyond MDMA : mental superhealth</a><P> 31<LI><a href=#update>Update (2024)</a> 32</ol></b> 33 34 35 36 37 38<a name=ecstasy></a><br> 39<h3>MDMA/Ecstasy</h3>Can safe, sustainable analogues of <a href="https://www.mdma.net/mdma.html">MDMA</a> 40be developed? There is an urgent need for non-neurotoxic <a href="http://www.maps.org/news-letters/v04n2/04247eed.html" target="_blank">empathogens</a> 41and <a href="https://www.mdma.net/entactogens/index.html">entactogens</a> suitable 42for lifelong use. Alas no single "magic bullet" yet exists that replicates the 43subjective effects of MDMA on a <a href="https://www.mdma.net/tolerance/index.html">long-term</a> basis. Hence most of us are doomed to 44display the quasi-psychopathic indifference to each other characteristic of the 45MDMA-naïve state.<P> 46<a name=mdmahistory></a><br> 47 <h3>A brief history of MDMA</h3> 48 <a href="https://www.mdma.net/refs/index.html">MDMA</A> was <a href="https://www.researchgate.net/publication/6875349_The_origin_of_MDMA_ecstasy_revisited_the_true_story_reconstructed_from_the_original_documents">first synthesized</A> at Merck in Darmstadt, Germany, in 1912. Imperial German Patent No. 274, 350 was applied for on 24 December, 1912; and officially issued on 16 May, 1914. Merck researchers were trying to synthesize hydrastinine and methylhydrastinine - substances used as haemostatics/styptics to reduce bleeding - specifically to bypass a patent held by their rival, Bayer. MDMA (referred to in Merck's internal lab notes as Methylsafrylamin) was created merely as an unstudied chemical precursor. Its psychoactive properties were completely unknown to the researchers at the time; and the compound was effectively shelved. 49 50 51 52<P> MDMA surfaced again briefly 53as one of a number of agents used in clandestine US military research during the 541950s. The <a href="https://www.cia.gov/index.html" target="_blank">CIA</a>'s Project <a href="https://www.mdma.net/mk-ultra/index.html">MK-Ultra</A> was investigating 55new techniques of brainwashing, espionage and mind-control. MDMA, code-named EA-1475, 56was tested at the US Army's Edgewood Arsenal in Maryland. However, unlike <a href="https://www.hallucinogens.org/hofmann/">LSD</a> 57or the ill-named "truth drug" <a href="https://www.biopsychiatry.com/scopolamine/index.html">scopolamine</a>, 58MDMA was used only on non-human animals: mice, rats, pigs, monkeys and dogs. Thankfully, 59MDMA's military potential was not realised. For although MDMA is no infallible truth-serum, 60its <a href="https://www.mdma.net/acute/review.html">effects</a> on the human user might indeed be abused for sinister purposes by 61skilled interrogators. The heightened emotional responsiveness, lowering of defensive 62barriers, openness and sense of closeness to others induced by MDMA can promote 63an <a href="https://www.mdma.net/ecstasy-honesty.html">honesty</a> of self-disclosure that might be manipulated for malign ends. Fortunately, 64this hasn't yet happened on an organised scale. 65 66 67<P> MDMA's
68parent and longer-acting metabolite, 3,4-methylenedioxyamphetamine [<a href="https://www.mdma.net/mda.html">MDA</a>] 69was first synthesized by Carl Mannich and Willy Jacobsohn synthesized MDA in 1912. MDMA differs structurally from MDA only in its additional 70methyl group attached to the nitrogen atom. MDA's own empathy-enhancing effect 71at low doses was explored by Chilean anthropologist-psychiatrist <a href="https://www.mdma.net/claudio-naranjo/index.html">Dr 72Claudio Naranjo</a> in his private practice. Dr Naranjo discusses MDA-assisted 73therapy in his classic <I>The Healing Journey</I> (1973). MDA was patented by 74drug company SmithKline French for use as a tranquilliser (1960) and appetite-inhibitor 75(1961). SmithKline were interested in MDA's potential as an antidepressant and 76a slimming-drug. In 1958 human trials were conducted; unfortunately the compound 77was to prove too psychedelic for licensed clinical use. But MDA was popular as 78"the love drug" in the counterculture of the 1960s. <P> 79 80 81 The 82identity of the first human being to take MDMA/Ecstasy isn't known. The drug 83 gained prominence only in the late 1970s. Tipped off by Merrie Kleinman, a graduate 84student in the medicinal chemistry group he advised at San Francisco State University, 85the legendary Californian <a href="https://www.mdma.net/alexander-shulgin/index.html">psychedelic 86chemist</a> Alexander ("Sasha") Shulgin (1925 - 2014) synthesized and taste-tested MDMA at incrementally 87ascending doses. Ironically, Dr Shulgin had himself synthesized MDMA in 1965, 88but hadn't tried it, an error of omission he later did much to <a href="https://www.mdma.net/alexander-shulgin/mdma.html">repair</a>. The effects of a 120mg dose of MDMA are recorded in Dr Shulgin's 89lab-notes (Sept 1976): <blockquote> <I>"I feel absolutely clean inside, and there 90is nothing but pure euphoria. I have never felt so great or believed this to be 91possible. The cleanliness, clarity, and marvelous feeling of solid inner strength 92continued throughout the rest of the day and evening. I am overcome by the profundity 93of the experience..."</I> </blockquote>In the first published scholarly paper 94[Shulgin,A.T. & Nichols,D.E.: Characterization of three new psychotomimetics. In: Stillman,R.C. & Willette,R.E. (Eds.) <I>The Pharmacology of hallucinogens</I>. New York: Pergamon, 1978] on MDMA use in humans, <a href="http://www.cognitiveliberty.org/shulgin/" target="_blank">Dr 95Shulgin</a> and <a href="http://www.mcmp.purdue.edu/Faculty/Nichols.shtml">Dr 96David Nichols</a> describe the effects of MDMA on the human psyche as "an easily 97controlled altered state of consciousness with emotional and sensual overtones." 98The well-connected stepfather of MDMA soon introduced the drug to the wider scientific 99community. Some of Dr Shulgin's friends, notably the "Johnny Appleseed of MDMA", 100<a href="https://www.mdma.net/leo-zeff/index.html">Leo Zeff</a>, were professional therapists. They in turn introduced MDMA to colleagues 101as a valuable adjunct to <a href="https://www.mdma.net/misc/liftingtheveil.html">psychotherapy</a>. 102 103 104<P> Later, in 1991, <a href="https://www.mdma.net/alexander-shulgin/dr-ecstasy.html">Dr Shulgin</a> 105and his wife <a href="https://www.mdma.net/alexander-shulgin/shulgins.html">Ann</a> 106published <I><a href="https://www.mdma.net/alexander-shulgin/pihkal-tihkal.html">PiHKAL</a></I> 107[Phenethylamines I Have Known And Loved]: A Chemical Love Story. <i>PiHKAL</i> 108describes the synthesis and systematic testing on human subjects of a range of 109novel or neglected <a href="https://www.mdma.net/pea.html">phenethylamine</a> research drugs.<i> PiHKAL</i> also offers a 110uniquely sophisticated methodology for human psychopharmacology and the scientific 111study of mind as an experimental discipline. <P> 112 113 114 By 115the early 1980s, over a thousand private <a href="https://www.mdma.net/mda/therapy.html">psychotherapists</a> 116in the USA were using MDMA in their clinical practice. MDMA was commonly known 117as "Adam", an allusion to "being returned to the natural state of innocence before 118guilt, shame and unworthiness arose". MDMA was used discreetly; no one wanted 119a re-run of the 60s. <a href="https://www.mdma.net/alexander-shulgin/professor-x.html">Dr 120Shulgin</a> himself reportedly felt MDMA came closest to fulfilling his ambition 121of finding the perfect <a href="https://www.mdma.net/therapy/ptsd-treat.html">psychotherapeutic</A> drug. 122 123 124 <P> Inevitably 125word leaked out. MDMA was profiled by the <I>San Francisco Chronicle</I> as "The 126Yuppie Psychedelic" (10 June 1984). In <I>Newsweek</I>, J Adler ["High on 'Ecstasy", 127April 15 1985] likened his MDMA experience to "a year of therapy in two hours". 128<I>Harpers Bazaar</I> described MDMA as "the hottest thing in the continuing search 129for happiness through chemistry". Unsurprisingly, MDMA use soon spread beyond 130the couch and clinic to the wider world. MDMA's now universal brand-name, "Ecstasy", 131was coined in 1981 by a member of a Los Angeles distribution network. The unnamed 132distributor, quoted in <a href="https://en.wikipedia.org/wiki/Bruce_Eisner" target="_blank">Bruce 133Eisner</a>'s <I>Ecstasy:The MDMA Story</I> (1989), apparently chose the name "Ecstasy" 134because "it would sell better than calling it 'Empathy'. 'Empathy' would be more 135appropriate, but how many people know what it means?" Condemned by purists as 136a cynical marketing ploy, the brand-name "Ecstasy" isn't wholly misleading [ecstasy: 137<I>"an overpowering emotion or exaltation; a state of sudden intense feeling.
138Rapturous delight. The frenzy of poetic inspiration. Mental transport or rapture 139from the contemplation of divine things"</I>]. Many first-time MDMA users do indeed 140become ecstatic. Some people report feeling truly well for the first time in their lives. 141 142 143 144<P> In the early 1980s, American production 145of MDMA beyond the research laboratory was effectively controlled by chemists 146known as the "Boston Group". Somewhat incongruously, MDMA was especially popular 147in Texas, where the Southwest distributor for the Boston Group launched his own 148commercial operation. Mass-production of MDMA by the so-called "Texas Group" began 149in 1983; supply (and demand) soon mushroomed. Ecstasy was distributed openly in 150bars and nightclubs in Dallas and Fort Worth. It could be purchased via toll-free 151800-numbers by credit card. The drug was even marketed via pyramid-style selling-schemes. 152Ecstasy could be bought in little bottles at convenience stores under the label 153"Sassyfras", a tongue-in-cheek allusion to the botanical origins of its precursor. 154 155 156<P> The <a href="http://www.dea.gov/" target="_blank">DEA</a> 157reacted by petitioning to have MDMA banned altogether. In 1985 the drug-warriors 158succeeded in having MDMA made Schedule One. Schedule One is the most restricted 159of all drug categories i.e. MDMA had allegedly "no legitimate medical use or manufacturer" 160in the USA; it lacked safety for use even under medical supervision; and it carried 161a "high potential for abuse". But by then MDMA's fame had spread across the Atlantic. 162MDMA had metamorphosed from "Adam", the psychotherapeutic tool, to "Ecstasy", 163the <a href="https://www.mdma.net/club-drugs/partying-hard.html">party</a> drug. <P> 164 165 166 MDMA was first 167introduced to Europe via the sannyasins, disciples of the Bhagwan Shree Rajneesh. 168"<i>Sannyasa</I>" is a Sanskrit word meaning complete or perfect renunciation. 169Cult members slipped MDMA into the drinks of rich sympathisers to open up their 170hearts and their wallets. <P> 171 172 173 Ecstasy 174became associated with the birth of <a href="https://www.mdma.net/acidhouse/index.html">Acid 175House</a> music in the Spanish tourist resort of <a href="https://www.mdma.net/misc/ibiza.html">Ibiza</A>. By the summer of '86, 176Ibiza was popularly known as "XTC Island". Returning tourists and disc-jockeys 177took the message back home. The UK's rave scene was born. Hundreds of thousands 178of tablets were consumed each weekend in the famous "Summer of Love" (1988). The 179Conservative Government and its allies in the British press were aghast. A moral 180panic set in at the threat to the nation's youth. <a href="https://www.mdma.net/mda.html">MDA</a>, <a href="https://www.mdma.net/mde.html">MDEA</a>, <a href="https://www.mdma.net/mdma.html">MDMA</a> and assorted 181psychedelic amphetamines had been outlawed in the <a href="https://www.mdma.net/club-drugs/uk.html">UK</A> since 1977. Yet the Criminal 182Justice and Public Order Act 1994 sought to <a href="http://www.uk-legislation.hmso.gov.uk/acts/acts1994/Ukpga_19940033_en_6.htm#mdiv63" target="_blank">criminalize</a> an entire youth-culture 183by suppressing music played publicly with "sounds wholly or predominantly characterised 184by the emission of a succession of repetitive beats". <P> 185 186 187 Soon 188production and distribution of the world's leading empathogen-entactogen fell 189into the hands of organised <a href="https://www.mdma.net/club-drugs/global-ecstasy.html">crime</a>. By the turn of the millennium, perhaps 80-90% 190of the world's MDMA was manufactured in Belgium and the <a href="https://www.mdma.net/law/index.html">Netherlands</a>. Russian-Israeli 191syndicates and Eastern European chemists are now increasingly active too. The 192<a href="https://www.mdma.net/accidental-ecstasy.html">expertise</a> needed in 193MDMA production varies according to the route of synthesis. Over twenty recipes
194have been described in the literature. Only seven are common. Clandestine production 195is easiest starting with MDP2P. MDP2P (3,4-methylenedioxyphenyl-2-propanone) is 196a commercial product used by the flavouring and fragrance industry. Groups with 197access to MDP2P can make MDMA via a simple conversion process. Otherwise, MDMA 198must be <a href="https://www.designer-drug.com/pte/12.162.180.114/dcd/chemistry/brightstar.mdma.html">synthesized</a> 199from piperonal, isosafrole, or <a href="https://www.mdma.net/safrole/index.html">safrole</a>. 200These primary <a href="https://www.mdma.net/misc/impurities.html">precursor</a> chemicals of MDMA are produced in India, China, Poland, 201Germany, and increasingly elsewhere. Typically, safrole or isosafrole are first 202converted to MDP2P. The essential oil safrole occurs naturally as the primary 203constituent of oil of sassafras. Oil of sassafras is found in the root-bark of 204US East Coast tree <I>Sassafras albidum</I> and from the above-ground woody parts 205of the South American tree <I>Ocotea pretiosa</I>. Safrole is also present in 206<a href="https://www.moodfoods.com/nutmeg/index.html">nutmeg</a> (<I>Myristica 207fragrans</I>), dill, parsley seed, crocus, saffron, vanilla beans, and calamus. 208If MDMA were on-patent, then today it might be marketed as "natural" or "naturally-inspired"; 209but Nature has not been so kind. <P> 210 211 212 Early 213in the twenty-first century, an estimated several million people worldwide were 214taking Ecstasy and allied <a href="https://www.mdma.net/uk/index.html">research chemicals</A> each month on college campuses, in high schools and on dance-floors. 215Purity varies; perhaps 10%-15% of tablets consumed contain MDMA as the sole active 216ingredient. Illicit knowledge of the "penicillin of the soul" is <a href="https://www.mdma.net/misc/ecstasy.html">spreading</a> 217rapidly around the world, but in corrupt and contaminated form. <P> 218 219 220<a name=ecstasyfeel></a><br> 221<h3>The 222MDMA Experience</h3>Pure MDMA salt is a white crystalline solid. It looks white 223and tastes bitter. The compound is chemically stable. MDMA does not readily decompose 224in heat, air or light. The optimal adult dose of racemic MDMA is probably around 225120-130mg [around 2mg/kg of body weight i.e. about 125mg] but optimal dose ranges from perhaps 22675mg to as much as 250mg. Pills sold in clubs often contain less. There are gender 227differences in response; proportionately to body-weight, <a href="https://www.mdma.net/women/index.html">women</a> 228are normally more sensitive than <a href="https://www.mdma.net/men/index.html">men</a> to the sub-acute and longer-term effects of MDMA, so their optimal dosage may be lower. The 229preferentially metabolised (+)-<a href="https://www.mdma.net/enantiomers/cpp.html">enantiomer</a> 230("mirror image") of MDMA is more active, more stimulating, more dopaminergic, more subjectively <a href="https://www.mdma.net/isomers/index.html">rewarding</a>, and more neurotoxic 231than the (-)-<a href="https://www.mdma.net/enantiomers/index.html">enantiomer</a>. 232MDMA is usually taken orally as a tablet, a capsule, or a powder. MDMA is readily 233absorbed from the gastrointestinal tract into the bloodstream. More rarely, the 234drug is snorted, smoked or injected. 235 236 237 <P> Onset 238of action is normally within twenty to sixty minutes or so after administration. 239When MDMA is administered by the oral route, "coming up" is naturally faster on 240an empty stomach. Taking MDMA causes both an increased neuronal reuptake inhibition 241of the neurotransmitter <a href="https://www.mdma.net/review/index.html">serotonin</a> 242(5-hydroxytryptamine, 5-HT) and also, critically, its increased synaptic <a href="https://www.mdma.net/misc/vamph.html">release</a>. 243The MDMA molecule is small enough to be taken up via the membrane-bound serotonin 244transporter into the presynaptic serotonin axon terminals. Here MDMA acts to reverse 245the normal direction of the so-called serotonin reuptake pump. Inside the nerve 246cell, MDMA alters the configuration of the transporter protein so it binds to
247cytoplasmic serotonin, after which the transporter dumps serotonin outside the 248cell, reversing the normal inward-bound direction of the transporter channel i.e. 249MDMA increases the rate of transporter-mediated serotonin outflow. The consequent 250additional flood of serotonin in the user's synapses is soon followed by an increased 251release of <a href="https://www.mdma.net/misc/serodop.html">dopamine</a> especially 252in the reward centres of the striatum and <a href="https://www.biopsychiatry.com/nucleus-accumbens.htm">nucleus 253accumbens</a>. Release of oxytocin, the "<a href="https://www.oxytocin.wiki/oxytoc/love-science.html">cuddle hormone</a>", surges too via stimulation of the serotonin <a href="https://www.mdma.net/oxytocin-release/index.html">5-HT(1A)</a> receptors. 254 255<P> 256 257 258 First-time 259MDMA users occasionally feel confused or anxious before the dose-dependent dopamine-release 260kicks in. A transient hint of nausea is common when coming up. Most of the body's 261serotonin is found outside the brain, notably in neurons of the enteric nervous 262system, our "little brain" inside the smooth muscles of the gut. The user's peak 263experience or plateau phase after the exhilarating dopaminergic "rush" doesn't 264last much more than ninety minutes to two hours. MDMA's primary effects wear off 265after some 3-4 hours. MDMA is more fat-soluble than its structural parent, so 266its speed of onset is slightly faster and its duration of action shorter. With oral MDMA dosing, peak concentration in the plasma follows after around two hours. <a href="https://www.mdma.net/therapy/method.html">Therapists</a> then 267sometimes add(ed) a final 50mg booster-dose. <a href="https://www.mdma.net/pharmacology/repeated.html">Heavy</A> recreational users are not 268always so restrained either in dosage ["stacking"] or <a href="https://www.mdma.net/misc/binge.html">top-up</a> schedule ["piggybacking"]. 269 270 271<P> The clarity and unique psychological 272effects of MDMA can be impaired by ethyl alcohol. Thus MDMA is best taken while 273completely sober, though a modest drink later to ease any comedown may be useful. 274 275 276<P> MDMA has a complex <a href="https://www.mdma.net/mdma/pharmacokinetics.html">nonlinear</a> 277pharmacokinetics. Taking higher and/or more frequent doses of the drug disproportionately 278increases levels of plasma MDMA. Higher levels substantially increase <a href="https://www.mdma.net/misc/oxidative-stress.html">oxidative 279stress</a> and magnify the risk of toxicity. MDMA is <a href="https://www.mdma.net/enantiomers/enant.html">metabolised</a> 280via N-demethylation to the active metabolite MDA; MDA can itself induce a state 281of sensual euphoria, though in humans the conversion rate from MDMA in the body 282is low. At least four other metabolites have been identified. MDMA is broken down 283mainly in the <a href="https://www.mdma.net/liver/index.html">liver</A>, primarily by the polymorphic <a href="https://www.mdma.net/metabolism/cyp2d6.html">cytochrome 284P450</a> enzyme <a href="https://www.mdma.net/metabolism/cyp2d6.html">CYP2D6</a>. However, other enzymes are involved in its degradation 285beside CYP2D6; some of them, like CYP2D6 itself, are saturated at relatively low 286MDMA concentrations. MDMA metabolism seems to run up against such a metabolic 287saturation-point somewhere between 120 and 150mg. When the high-affinity enzymes 288are saturated, a disproportionately large increase in blood- and brain MDMA-concentrations 289may occur if the user then takes more of the drug. A large but variable quantity 290of the parent compound is excreted unchanged, especially when the drug is taken 291at higher doses; but the opportunities for MDMA recycling by the cost-conscious 292are normally wasted. 293 294 295<P> MDMA 296is sometimes described as a cross between a psychostimulant and a mild hallucinogen. 297Since it's a methoxylated amphetamine, MDMA is indeed structurally related to 298<a href="https://www.mescaline.com/synth/">mescaline</a>. MDMA's methylenedioxy 299(O-CH<sub>2</sub>-O-) group is attached to positions 3 and 4 of the aromatic ring 300of the amphetamine molecule. But hallucinations on MDMA taken at therapeutic dosages 301are extremely rare; and <a href="https://www.amphetamines.org/refs/">psychostimulants</a>, unlike MDMA, don't typically induce 302a profound sense of inner peace. Thus MDMA exhibits a different profile both from 303the prototypical "serotonergic" 2,5-dimethoxy-4-methylamphetime (<a href="https://www.mdma.net/dom-stp.html">DOM</a>),
304with its psychedelic <a href="https://www.biopsychiatry.com/5ht2hal.htm">5-HT2A</a>-mediated 305mechanism of action, and also from the prototypical "dopaminergic" stimulant (+)-amphetamine. 306 307 308<P> MDMA is perhaps best characterised 309as belonging to a functionally unique class of "empathogen-entactogen". These 310words don't mean a great deal in the MDMA-naïve state. The term "empathogen" 311to describe MDMA and other closely related phenethylamine "empathy drugs" [MDA, 312MDEA, MBDB] was proposed by <a href="http://www.rmetzner-greenearth.org/index.html#ralph" target="_blank">Ralph 313Metzner</a>, Dean of the California Institute of Integral Studies, at a 1983 conference 314at the University of California at Santa Barbara. The term "<a href="https://www.mdma.net/entactogens/index.html">entactogen</a>" 315was coined in 1986 by Dr David Nichols, Professor of Medicinal Chemistry and Pharmacology 316at Purdue University and co-founder of the <a href="http://www.heffter.org/" target="_blank">Heffter 317Research Institute</a>, to refer to substances that generate a sense of "touching 318within" or "produce a feeling in one's innermost being". Both terms are quite 319apt, though neither will win any marketing awards. MDMA can promote an extraordinary 320clarity of introspective self-insight, together with a deep love of self and a 321no less emotionally intense empathetic love of others. MDMA also acts as a <a href="https://www.mdma.net/euphoria/index.html">euphoriant</a>. 322The euphoria is usually gentle and subtle; but sometimes profound. 323 324 <P> Culture, 325set and setting inevitably shape the MDMA experience. Idiosyncratic responses 326to MDMA aren't rare. MDMA has even been described as a drug that "could be all 327things to all people" (Dr Shulgin). Even so, MDMA's primary effects on the user 328are surprisingly consistent, unlike the wilder psychedelics such as <a href="https://www.hallucinogens.org/lsd/index.html">LSD</a>, 329<a href="https://www.biopsychiatry.com/psilocybin/index.html">psilocybin</a>, or 330<a href="http://www.dimethyltryptamine.com/synthesis.html">DMT</a>. MDMA may feel mystical, 331magical or sublime; but it doesn't feel <I>weird</I>. The drug's influence feels 332highly controllable. MDMA tends to enrich the user's sense of self-identity, not 333diminish it. MDMA "provides a centering experience, rather than an ego diffusing 334experience" (Dr. Philip Wolfson), though it may also cause a "softening of the 335ego-boundaries". Sometimes a degree of derealisation on MDMA may occur, but rarely 336depersonalisation in the <a href="https://www.biopsychiatry.com/depersonalisation.htm">ordinary</a> 337sense of the term. On the <a href="https://www.entactogens.com/">contrary</a>, 338users feel they can introspectively "touch inside" to their ideal authentic self 339with total emotional self-honesty. <P> 340 341 As 342well as acting as a "gateway to the soul", MDMA "opens up the heart". Taking MDMA 343induces an amazing feeling of closeness and connectedness to one's fellow human 344beings. MDMA triggers intense emotional release beyond the bounds of everyday 345experience. The drug also enhances the felt intensity of the senses - most exquisitely 346perhaps the sense of touch. The body-image looks and feels wonderful. Other people 347look and feel wonderful too. Minutes after dropping a pill, a lifetime of Judaeo-Christian 348guilt, shame or disgust at the flesh melt away to oblivion. <P> 349 350 When 351MDMA is taken outdoors, the natural world seems vibrant and awe-inspiring, perhaps 352even enchanted. The experience of colour is gorgeously intensified. On MDMA, Dr 353Shulgin reported how mountains he'd observed many times before appeared to be 354so beautiful that he could barely stand looking at them. MDMA is not normally 355classed as an <a href="https://www.entheogens.com/">entheogen</a>. "Entheogen" 356is a term proposed in 1979 by the scholars R. Gordon Wasson, Carl A.P. Ruck, Jonathan 357Ott, Jeremy Bigwood and Danny Staples for agents "generating the god or the divine 358within", shorn of any speculative metaphysics. Yet MDMA is used by a variety of 359<a href="https://www.mdma.net/spirituality/index.html">spiritual</a> practitioners 360of widely diverse beliefs as a gateway to the divine. Some MDMA users undergo 361life-changing spiritual experiences. <a href="http://www.ecstasy.org/" target="_blank">Nicholas 362Saunders</a>, author of the book <I>E for Ecstasy</I> (1993), cites a Benedictine 363monk who finds MDMA "opens up a direct channel to God". MDMA may
363not be "Christ 364in (al)chemical form", but if it had been present in the Eucharist, then we would 365all still be devout Christians, possibly for ever. A minority of first-time MDMA 366users undergo what the inventor of the <a href="https://www.mdma.net/alexander-shulgin/shulginscale.html">Shulgin scale</a> christened a Plus Four... 367<blockquote> <I>"PLUS FOUR, n. (++++) A rare and precious transcendental state, 368which has been called a "peak experience," a "religious experience," "divine transformation," 369a "state of Samadhi" and many other names in other cultures. It is not connected 370to the +1, +2 and +3 of the measuring of a drug's intensity. It is a state of 371bliss, a participation mystique, a connectedness with both the interior and exterior 372universes, which has come about after the ingestion of a psychedelic drug, but 373which is not necessarily repeatable with a subsequent ingestion of the same drug. 374If a drug (or technique or process) were ever to be discovered which would consistently 375produce a plus four experience in all human beings, it is conceivable that it 376would signal the ultimate evolution, and perhaps the end of, the human experiment. 377(PiHKAL, pages 964-965)"</I> </blockquote>Plus Fours are rare, today. But on MDMA, 378even the most jaded and world-weary soul with a tin-ear for <a href="https://www.paradise-engineering.com/quotation/">poetry</a> 379may "see a world in a grain of sand, And a heaven in a wild flower, Hold infinity 380in the palm of your hand, And eternity in an hour." <P> 381 382 MDMA 383is sensuous and <a href="https://www.mdma.net/sex/index.html">sensual</a> in its 384effects without being distinctively pro-sexual. Although once dubbed "lover's 385speed", MDMA is proverbially more of a hugdrug than a lovedrug: "I kissed someone 386I was in love with and almost felt as if I was going to pass out from the intensity", 387recalls one American clubber. However, MDMA's capacity to dissolve a lifetime's 388social inhibitions, prudery and sexual hang-ups means that lovemaking while under 389its spell is not uncommon. Superfluous clothes tend to get shed. In men, orgasm 390is more intense than normal but delayed: MDMA retains a residual sympathomimetic 391activity, triggering a detumescence of the male organ. To ease MDMA-induced performance 392difficulties, flagging Romeos increasingly combine Ecstasy with <a href="https://www.biopsychiatry.com/sildenafil/index.html">Viagra</a> 393('<a href="https://www.mdma.net/sexstasy/index.html">Sexstasy</a>'). Unless carefully premeditated, this is not a recipe for <a href="https://www.mdma.net/sex/sexuality-ecstasy.html">safe sex</a>. 394MDMA may sometimes cause "inappropriate bonding". Prudence should be exercised 395before taking it with ex-girlfriends, boyfriends or culturally inappropriate love-objects. 396The effects of MDMA on <a href="https://www.primates.com/bonobos/bonobosexsoc.html">bonobos</a> 397("pygmy chimpanzees"), our sexually uninhibited primate cousins, are unknown. 398 399 400<P> On pure MDMA, subjects feel 401at peace with themselves and the world. They discover an enhanced sense of self-worth, 402self-forgiveness and complete self-acceptance. Cynical thoughts and negative feelings 403disappear. Aspects of life normally too sensitive to talk about can be explored 404freely. Heightened feeling allows long-forgotten and repressed emotional memories 405from childhood to be retrieved with unusual ease. In some settings, painful, 406highly-charged and even hitherto unmentionable problems may be discussed with 407(rose-tinted) candour. On MDMA, a lifetime of accumulated psychological barriers 408and defence-mechanisms go down, somehow magicked out of existence with a pill. Anger, irritability 409and ingrained fear dissolve; the hostile <a href="https://www.biopsychiatry.com/amygdala.htm">amygdala</a> 410is subdued, if only for a few hours. Ecstasy users tell each other affectionately 411what beautiful people they are; and they do so from the depths of their hearts. 412 413 414<P> Before the Orwellian-sounding 415Drug Enforcement Administration [<a href="http://www.usdoj.gov/dea/" target="_blank">DEA</a>] 416placed MDMA on Schedule 1 of controlled substances, professional <a href="https://www.mdma.net/therapy/index.html">therapists</a> 417in the USA found MDMA a valuable tool for counselling and marriage-guidance sessions. 418MDMA's capacity to induce empathetic bliss, heightened introspection and an increased 419ability and desire to communicate feelings can create a rapport with the therapist
420and accelerate a successful outcome. MDMA acts to boost self-esteem and self-confidence, 421while paradoxically diminishing egotism. The user's sense of social isolation 422vanishes. "I love the world and the world loves me", affirmed one beneficiary 423of MDMA-assisted therapy. 424 425<P> On 426a more sceptical note, it's hard scientifically to validate claims of long-lasting 427therapeutic success. For MDMA's stunning short-term results make double-blind, 428placebo-controlled trials effectively impossible. Such a problem doesn't always 429bedevil today's <a href="https://www.biopsychiatry.com/antidepressants/antidepressant.html">lame</a> 430"<a href="https://www.biopsychiatry.com/refs/">antidepressants</a>", the results 431of whose trials often struggle to reach statistical significance. Investigational 432drugs are lab-tested by Big Pharma to discover whether or not non-human animals will self-administer 433them. Candidate compounds are normally discarded if the animals do so, arguably a perverse route 434to uncovering antidepressants with good clinical <a href="https://www.biopsychiatry.com/bigpharma/">efficacy</a> and high patient compliance. By contrast, MDMA is 435a warm, fast-acting, non-sedating mood-enricher that banishes social anxiety and 436physical pain alike. Unlike <a href="https://www.opioids.wiki/">opioids</a> or the 437anxiolytic <a href="https://www.biopsychiatry.com/diazepam/index.html">benzodiazepines</a>, 438MDMA doesn't cloud consciousness even at relatively high doses. This doesn't stop 439less cerebrally-inclined ravers from getting "<a href="https://www.mdma.net/club-drugs/sorted.html">cabbaged</a>" by swallowing pills all weekend. 440 441 442<P> Explored in a <a href="https://www.mdma.net/therapy/traumatic-anxiety.html">controlled</A> setting, 443MDMA can be <a href="https://www.mdma.net/therapy/ptsd.html">therapeutic</a> for victims of Post-Traumatic Stress Disorder (<a href="http://maps.org/research/mdmaplan.html" target="_blank">PTSD</a>). 444A minority of subjects find they enjoy the experience too much to focus on the 445emotional baggage of the past. Sessions are most likely to be productive with 446an experienced MDMA therapist. In the Prohibitionist era, MDMA-assisted therapy-sessions 447are rare. <P> 448 449 Dr David Nichols 450suspects that the related phenethylamine entactogen <a href="https://www.mdma.net/mbdb.html">MBDB</a> 451("Eden": 2-Methylamino-1-(3,4-Methylenedioxyphenyl)Butane), formed by extending 452the 3-carbon chain of MDMA to a 4-carbon chain, might prove superior to MDMA as 453an adjunct to psychotherapy. This is because Dr Nichols' creation lacks significant 454dopaminergic activity. It's thus less likely to induce a distracting euphoria. 455On the other hand, if and when the substrates of blissful self-insight can be 456sustained indefinitely, then who'll need therapy? Perhaps some inner demons are better 457left to die of neglect, not awakened for exorcism. Either way, a case can be made 458that MBDB is indeed a "purer" entactogen than MDMA. Yet as an empathogen, MDMA 459is unsurpassed and possibly unmatched. MDMA's residual <a href="https://www.mdma.net/mbdb/entactogen.html">dopaminergic</a> amphetamine-like 460action contributes a euphoric warmth to the user's intensified feelings and also 461the desire and ability to express them freely. MBDB's chemical cousin beta-keto-MBDB (bk-MBDB, "<a href="https://en.wikipedia.org/wiki/Bk-MBDB" target="_blank">Butylone</a>") is a more enjoyable and stimulating empathogen than MBDB. As of 2014, its human use is still extremely limited. 462 463 464 465 <P> Against 466formidable odds, the Multidisciplinary Association for Psychedelic Studies (<a href="http://www.maps.org/" target="_blank">MAPS</a>) 467has been seeking funding and <a href="https://www.mdma.net/therapy/trial.html">FDA-approval</a> for controlled <a href="http://www.maps.org/research/mdmaplan.html" target="_blank">trials</a> 468of MDMA-assisted therapy for PTSD. If these trials are successful, then MAPS hopes 469that MDMA could eventually become a prescription-medicine. For on MDMA, many traumatized 470or seemingly emotionally frigid people who can never otherwise speak about their 471innermost fears and feelings find they can spontaneously open up. There is no 472compulsion to talk - just a dissipation of the social anxieties that make us normally 473tight-lipped. 474 475<P> Functional 476analogues of MDMA may one day be employed in other kinds of insight-oriented therapy 477as well. Safe, long-acting MDMA analogues may prove therapeutic in the treatment
478of <a href="https://www.biopsychiatry.com/socphob.htm">social phobia</a>, eating 479disorders and obsessive-compulsive disorder (<a href="https://www.biopsychiatry.com/ocd.html">OCD</a>). 480 481<P> 482In <a href="https://www.mdma.net/terminally-ill/index.html">December 2004</a>, the FDA granted permission for <a href="http://www.maps.org/research/mdma/canceranxiety/fda-protocol/" target="_blank">Dr John Halpern</a>'s proposed study of MDMA-assisted psychotherapy for patients diagnosed with severe anxiety related to advanced cancer. The likelihood of <a href="http://www.usdoj.gov/dea/" target="_blank">DEA</a> approval of the protocol is unknown. If the magic of MDMA could be replicated safely and sustainably, then the fear of death and dying could in principle be banished in the population at large. This would be a substantial payoff, though the fear of personal mortality is probably the prime mover of scientific progress in <a href="https://www.supercentenarian.com/archive/treatments.html">anti-aging</a> research. 483 484 485<P> <a href="http://www.naturalmood.com/" target="_blank">Dr Julie Holland</a>, editor of the invaluable <I><a href="https://www.mdma.net/ecstasy/ecstasy-guide.html">Ecstasy:The 486Complete Guide</a></I> (2001), tentatively endorses "the judicious, supervised 487and single oral doses of MDMA as a psychiatric medicine..." In her introduction 488to the guide, Dr Holland notes that "Like any powerful tool, it should be used 489by people who are properly trained, educated and supervised. And like any powerful 490tool, it should come with an instruction manual. This book, I hope, will serve 491as that manual". It may be testimony to the <I>comparative</I> safety of MDMA 492that millions of young people use MDMA in the absence of a manual or any training, 493education and supervision at all. Alas Prohibitionism puts the 494<a href="https://www.mdma.net/raves/chemi-kids.html">young</a> and vulnerable 495at unnecessary risk; and squanders the therapeutic opportunities. In defiance 496of scepticism from medical orthodoxy, Dr Holland also provides supporting evidence 497to back up anecdotal reports that MDMA can induce temporary remission of symptoms in victims 498of otherwise intractable <a href="https://www.biopsychiatry.com/schizophrenia.htm">schizophrenia</a>. 499Less controversially, it's possible for victims of body dysmorphic disorder (<a href="https://www.biopsychiatry.com/bdd.htm">BDD</a>), 500or simply anyone with a negative body self-image, to view themselves in the mirror 501while euphorically loved-up on MDMA. The transformation can be magical, though 502it would be imprudent to repeat the experiment two days later. 503 504 505<P> MDMA 506can also be used just to have fun. Most commonly today, teenagers and young adults 507take Ecstasy to <a href="http://www.dancesafe.org/" target="_blank">rave</a>. Mozart sounds great
508on Ecstasy, but high-energy all-night dance parties celebrated with techno-pop 509house music are more standard. <a href="https://www.mdma.net/raves.html">Raves</a> 510are held in clubs, warehouses or more exotic outdoor settings and open fields. 511Often raves last a whole weekend. The music may be techno, hardcore, jungle, trance 512or form an improvised, eclectic mix of styles harder to categorise. The atmosphere 513is astonishingly friendly, the mood and ethos is well captured by the ravers' 514motto <a href="https://www.mdma.net/plur/index.html">P.L.U.R.</a> ["Peace, Love, 515Understanding and Respect"]. In darkened clubs, the intoxicating atmosphere of 516the rave is enhanced with artificial fog, lasers, strobe lights, glow sticks, 517whistles and Vicks inhalers [on MDMA, aromas are fragrantly enriched]. In many 518cases, the product now passed off as "Ecstasy" is adulterated with other agents. 519Individual pills bought by the end-user typically cost between US$7 and US$25. 520The worldwide street price is falling. Tablets can be mass-manufactured for as 521little as 50 cents. Professionally-made tablets of MDMA are stamped with distinctive 522<a href="https://www.mdma.net/ecstasy.html">logos</a>. This is because MDMA manufacturers and merchants seek to promote brand-awareness 523and customer loyalty. Alas counterfeit goods are still rife. 524 525<P> Sometimes 526"Ecstasy" doesn't contain MDMA at all, but <a href="https://www.mdma.net/mda/index.html">MDA</a>; 527<a href="https://www.mdma.net/mde.html">MDEA</a> (3,4-methylenedioxyethylamphetamine: 528"Eve"); <a href="https://www.2c-b.com/index.html">2C-B</a> (4-Bromo-2,5 Dimethoxyphenethylamine: 529''Nexus", "Venus", "Bromo"); <a href="https://www.mdma.net/club-drugs/2c-i.html">2C-I</a>; <a href="https://www.mdma.net/pma.html">PMA</a> 530(paramethoxyamphetamine); <a href="https://www.amphetamines.org/resource/">amphetamine</a> 531("speed"); ephedrine; pseudoephedrine; <a href="https://www.biopsychiatry.com/caffsui.htm">caffeine</a>; 532the dissociative anaesthetic <a href="https://www.biopsychiatry.com/ketaminedep.htm">ketamine</a> 533("Special K"); <a href="https://www.biopsychiatry.com/misc/dextromethorphan.html">DXM</a> 534(dextromethorphan); <a href="https://www.biopsychiatry.com/ghb/index.html">GHB</a> 535(gamma-hydroxybutyrate: "liquid ecstasy"); or some combination thereof. This list 536is far from exhaustive. A minority of psychologically robust or reckless clubbers 537purposely <a href="https://www.mdma.net/club-drugs/mixing.html">mix</a> MDMA with <a href="https://www.hallucinogens.org/hofmann/childf.htm">LSD</a> 538("<a href="https://www.mdma.net/candyflip.htm">candyflipping</a>") to impart a 539"warm, loving glow" to their acid trips. Or they "<a href="https://www.mdma.net/ecstasy-mdma.html">hippieflip</a>" with <a href="https://www.psychedelics.org/psilocybe/index.html">psilocybin</a> 540mushrooms; or "kittyflip" with <a href="https://www.ketamine.co.uk/">ketamine</a>. 541<a href="https://www.cannabis-marijuana.com/weblife.html">Cannabis</a> is widely smoked as 542well. Ravers who want to dance all night may prefer Ecstasy laced with speed; 543a sub-neurotoxic dose of MDMA can be made toxic by adding (+)-amphetamine. To 544outsiders, Ecstasy-fuelled raving might seem mindless <a href="https://www.utilitarianism.com/hedonism.html">hedonism</a>; 545its devotees have likened it to group-therapy or meditation. But either way, chronic 546heavy use of the methoxylated amphetamines or any other "<a href="https://www.mdma.net/club-drugs/index.html">club-drug</a>" 547poses risks to the user's health. 548 549<a name=mdmatox></a><br> 550 551<h3>MDMA: neurotoxicity </h3><P> No 552compelling evidence exists that taking a single c.125mg dose of MDMA a few times 553or so a year is likely to cause any <a href="https://www.mdma.net/longterm/intravenous.html">long-term</A> harm to the user's mental or physical 554health. Nevertheless, even pharmaceutical-grade MDMA taken at moderate doses in 555optimal conditions is <a href="https://www.mdma.net/serotonin/serotonin-syndrome.html">not</a> 556a wholly benign drug. The problem isn't (just) the toxic adulterants used by dance-floor 557pharmacologists or the botched syntheses of bathtub chemists. Deceptively, and 558in contrast to most other recreationally used drugs, ingesting pure MDMA can sometimes 559leave the user feeling better than normal the next day, albeit tired and slightly 560spaced-out. Beyond warm memories, this afterglow may in part be explained by MDMA's 561residual amphetamine metabolic by-products: MDMA itself has a long, c.8-9 hour 562elimination half-life from the blood; and its main metabolite's longer-acting, 563less stimulating 564<a href="https://www.mdma.net/mda/discrimprop.html">(-)-MDA</a>
564 enantiomer has <a href="https://www.biopsychiatry.com/5ht2hal.htm">5-HT2A</a> 565activating effects resembling low-grade LSD. But two days or so after taking MDMA, 566most users experience the <a href="https://www.mdma.net/toxicity/serotonin.html">serotonin 567dip</a>. The dip ranges from the almost imperceptible to the markedly <a href="https://www.mdma.net/women/gender.html">unpleasant</a>. 568The functional deficit the dip reflects may last ten days or more - in some cases possibly 569weeks or months. A biphasic post-E serotonin profile in the user has been reported: 570users' serotonin levels - though hard to measure and interpret - apparently fall 5713-6 hours after taking the drug, then recover to nearly normal levels after around 57224 hours, and then decline again. <P> 573 574 575 576Excessive MDMA intake triggers oxidative damage to the user's 577serotonergic nerve cell <a href="https://www.mdma.net/mda/fineaxon.html">fine axon terminal</a> 578 lipids and proteins via the production of toxic free radicals. 579However, the threshold dose for any lasting MDMA-induced toxicity is unknown; 580and the identity and precise mechanism of the chemical(s) causing the oxidative 581stress is unclear. The issue is also controversial. Currently the three leading 582candidates for guilty agent are:<blockquote>
582 1] toxic metabolites of <a href="https://www.mdma.net/toxicity/toxmetab.html">MDMA</a><P> 583 584 5852] toxic metabolites of <a href="https://www.mdma.net/mdma.htm">dopamine</a><P> 3] 586impaired <a href="https://www.mdma.net/glucose/">cellular energetics</a><P> </blockquote>An 587excellent <a href="http://www.erowid.org/chemicals/mdma/mdma_neurotoxicity1.shtml " target="_blank">review</a> 588of the published scientific evidence on neurotoxicity is offered by Matthew Baggott 589and John Mendelson on the indispensable <a href="http://www.erowid.com/" target="_blank">Erowid</a>. 590A role has also been proposed for <a href="https://www.mdma.net/toxicity/no.html">nitric 591oxide</a>; increased <a href="https://www.mdma.net/toxicity/no.html">Ca2(+)</a>; and 592a toxic intraneuronal metabolite of <a href="https://www.mdma.net/toxicity/toxmet.html">serotonin</a>. 593Elevation of <a href="https://www.mdma.net/hyperthermia/ambient.html">body temperature</a> 594can seriously worsen possible MDMA-induced toxicity; and the <a href="https://www.mdma.net/hyperthermia/ucp-3.html">thermogenic</a> effect of MDMA is 595magnified in a <a href="https://www.mdma.net/thermoregulation/heat.html">hot</a> environment like an indoor rave. Certainly, <i>hypo</I>thermia-inducing agents are (partially) neuroprotective against Ecstasy damage; and the primary role of <a href="https://www.mdma.net/toxicity/dopamine.html">dopamine</a> in MDMA-induced toxicity may actually be to elevate body temperature via its increased action on the <a href="https://www.mdma.net/hyperthermia/mechanisms.html">dopamine D1</a> receptors rather than its uptake into the depleted serotonergic axon terminals. But consensus on the molecular 596mechanisms behind MDMA megadose-induced damage remains elusive. <P> 597 598 599 MDMA 600itself (probably) isn't the culprit. Experimental <a href="https://www.mdma.net/toxicity/intracerebral.html">microinjection</a> of MDMA, MDA or other 601amphetamine analogues directly into the cerebrum doesn't produce the toxicity 602to the serotonergic axons ascending from the dorsal 603<a href="https://www.mdma.net/serotonin/raphe.html">raphé nucleus</a> that follows 604high and/or frequent doses of the peripherally administered drug. MDMA can be 605centrally injected to induce the release of just as much serotonin as the <a href="https://www.mdma.net/toxicity/serotonin.html">toxic</a> 606peripherally-administered dose; but there's still no sign of neurotoxicity. Nor 607does experimental central MDMA perfusion trigger the toxicity-enhancing higher 608body temperatures likely from the peripheral route. When MDMA is centrally administered 609in animal experiments, not even artificially inducing <a href="https://www.mdma.net/hyperthermia/mechanisms.html">hyperthermia</a> 610in the victim is enough to produce serotonergic damage. If systemic metabolism 611of MDMA is indeed necessary for neurotoxicity, the nature of any such possible 612toxic <a href="https://www.mdma.net/toxicity/toxmetab.html">metabolite</a>(s) is 613unknown: <a href="https://www.mdma.net/toxicity/toxmetab.htm">thioether conjugates</a> 614of alpha-methyl dopamine have been mooted; and in 2009 neurotoxic thioether adducts of MDMA were <a href="https://www.mdma.net/metabolites/thioether.html">detected</A> in humans. 615 Since drug metabolites are normally 616more hydrophilic than their parent drug, specific transporters are presumably 617needed to take up the neurotoxic metabolite into the brain; but their identity 618or even existence isn't known either. If they do exist, then presumably they are monoamines; otherwise <a href="https://www.selegiline.com/">selegiline</a> wouldn't be <a href="https://www.mdma.net/depsave.htm">protective</a> against MDMA-induced neurotoxicity.<P> 619 620 621 622Whatever the mechanism at work, most users eventually <a href="https://www.mdma.net/quitting/index.html">stop</A> taking MDMA. They do so after 623 either they find the E-magic wears off, or the unwanted side-effects of heavy E-use 624begin to outweigh its joys. Doctors report that one Englishman consumed an estimated <a href="https://www.mdma.net/ecstasy/excess.html">40,000</a> tablets of MDMA over a nine year period. Such cases are exceptional. Even so, some heavy MDMA users claim they don't experience 625any long-term adverse effects. Prolonged MDMA administration can even cause a 626long-lasting <a href="https://www.mdma.net/misc/opposite.html">increase</a> in 627the dopamine content of the nucleus accumbens, possibly indicating its disinhibition 628from normal serotonergic control. The persistent elevation of dopamine function 629reported in the nucleus accumbens of some MDMA veterans might otherwise be expected 630to enhance mood, not darken it. Likewise, MDMA users may be <I>less</I> anxious 631or panic-stricken in response to the normally anxiogenic challenge of a 5-HT2C 632agonist such as m-chlorophenylpiperazine (<a href="https://www.mdma.net/mdma/mdma5ht.html">m-CPP</a>). 633Depending on one's ideological agenda, this diminished response to m-CPP
633can be described 634as evidence either of serotonergic "toxicity", or alternatively as a pointer to 635the substrate of a long-lasting "therapeutic" effect. Again, MDMA use increases 636<a href="https://www.mdma.net/misc/cokesense.html">sensitisation</a> to the rewarding 637effects of euphoriant dopaminergics such as <a href="https://www.erythroxylum-coca.com/refs/">cocaine</a>; 638and once more, this is not inherently a sign of "brain damage". However, reports 639of real and serious health problems from excess E-use are <I>not</I> all prohibitionist 640propaganda or part of a government-inspired conspiracy to stop young people having a good 641time. Among heavy "recreational" MDMA users, self-medicating or otherwise, the 642incidence of <a href="https://www.mdma.net/longterm/depression.html">depression</a> 643seems to be more common than healed minds or any enduring 644<a href="https://www.mdma.net/therapy/agony-ecstasy.html">therapeutic</a> benefit. 645The prospect of serotonergic axon terminal degeneration doesn't sound much fun, 646even if the axons <a href="https://www.mdma.net/serotonin/resprout.html">re-sprout</a> 647- one way or another. Worryingly, the MDMA-induced pruning of the serotonergic 648axon tree seen at high-dosage regimens leads to altered patterns of reinnervation 649by ascending axons projecting especially to forebrain sites. In the process of recovery from 650a prolonged MDMA-binge, the <a href="https://www.mdma.net/memory/hippocampus.html">hippocampus</a>, a brain structure critical for episodic 651memory formation, may actually be hyperinnervated, but reinnervation of the dorsal 652cortex is sparser. It has been suggested that the heavy MDMA user who discerns 653no long-lasting ill effects, and who displays minimal functional impairment, may 654still be subtly damaging his or her serotonergic "functional reserve". The disturbing 655parallel drawn here is with neurodegenerative disorders: clinical signs of <a href="https://www.biopsychiatry.com/l-dopa.html">Parkinson's 656disease</a>, a progressive disorder caused by outright dopaminergic cell death 657and frequently prefigured by depression, only become apparent after 70-80% of 658dopamine cells have been lost. It is fiendishly hard to demonstrate MDMA-induced 659dopaminergic cell damage without virtually killing 660the victim; in contrived 661circumstances it can be done. Yet the most <a href="https://www.mdma.net/toxicity/ricaurte.htm">notorious</a> attempt to show MDMA-induced dopaminergic neurotoxicity, <a href="https://www.mdma.net/toxicity/george-ricaurte.htm">Ricaurte</a>'s September 2002 <a href="https://www.mdma.net/toxicity/ricaurte.html">paper</a> <I>Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA ("Ecstasy")</I> in <I>Science</I>, actually demonstrated <a href="https://www.methamphetamine.co.uk/">methamphetamine</a>-induced dopaminergic neurotoxicity instead. This unfortunate study, its publication timed to coincide with debate in US Congress over the "Anti-Rave Act", was <a href="https://www.mdma.net/toxicity/retraction.html">retracted</a> in September 2003; but the spectre it raised of a post-E generation of Parkinsonian zombies may prove harder to dispel.<P> 662 663 664 Not 665even heroic doses of MDMA are likely to kill off serotonergic brain cells, though 666there have been unconfirmed reports of MDMA-induced <a href="https://www.mdma.net/toxicity/apoptosis.html">apoptosis</a> 667in mega-dosed rats. Only the most alarmist commentators anticipate a delayed epidemic 668of demented depressives as a result of serotonergic carnage caused by MDMA abuse. 669But equally, no alien anthropologist in his right mind who merely read the gruesome 670<a href="https://www.mdma.net/refs/">scientific literature</a> on MDMA would want 671to self-experiment with such a deadly <a href="https://www.mdma.net/longterm/damage.html">neurotoxin</a>. 672Taking weed-killer, glue sniffing or swallowing rat poison sounds marginally less 673dangerous. Calling it 674<a href="https://www.mdma.net/toxicity/damage.html">dystopian</a> pharmacology might seem more apposite. Even listening 675to glowing, first-person accounts of the MDMA experience is curiously uninspiring 676when refracted through the lens of our normal <a href="https://www.general-anaesthesia.c
676om/images/charles-darwin.html">Darwinian</a> consciousness. The prospect 677of love, peace and empathy seems less exciting than a round of <I>Quake 3</I>. 678We are all prone to mood-congruent thoughts. <P> 679 680 681 In 682any case, MDMA users themselves may find the magic of the initial drug-induced 683epiphany tends to fade with frequent use. For many but not all users, a magical 684drug becomes just a feel-good drug. Adverse side-effects tend to become more troublesome. 685Higher doses are needed to gain the same effect. Users lament that "the E isn't 686as pure as it used to be"; and that the tablets are weaker. Often indeed this 687is true; but a physiological explanation for so-called "cumulative tolerance" 688must be sought as well. Enzyme-induction plays a role, though the phenomenon isn't 689fully understood. Pharmacodynamic <a href="https://www.mdma.net/tolerance/index.html">tolerance</a> to a drug is normally reversible, 690yet some users of MDMA report they never quite recapture the initial ecstatic 691glory even if they abstain for a year or more. Researchers are still unsure if 692this fade-off is a symptom of long-term neuroadaptation or serotonergic damage. 693 694 695<P> Perhaps we shouldn't be so 696surprised at the "loss of magic". The liver (and the brain) is adapted to life 697on the African savannah. Our vital organs can't know the difference between the 698elixir of life and a poison. MDMA has the attributes of both, and in the African 699bush, the latter is a more realistic outcome. Yet we won't be trapped in brutish 700states of consciousness for ever. In the near future, functional analogues of MDMA promise 701to enhance mental health, add perpetual magic to our lives, and beautify our troubled 702minds. Empathetic bliss isn't inherently toxic; though its <a href="https://www.mdma.net/toxicity/toxmetab.html">reactive 703metabolites</a> may be. In principle, the psychopathologies of everyday life can 704all be cured. MDMA offers a foretaste of life in <a href="https://www.hedweb.com/object26.htm">post-Darwinian</a> 705paradise; but it delivers, at best, only a fleeting hint of the magic to come. 706<P> 707 708<a name=ecstasyprotect><br></a><h3>MDMA: neuroprotection </h3>No safe, indefinitely sustainable entactogens-empathogens 709yet exist. Drugs that consistently induce the opposite syndrome are legion. Some 710such drugs are billion-dollar moneyspinners for <a href="https://www.pharmapolitics.com/" target="_blank">Big 711Pharma</a>. They are clinically licensed and widely prescribed in the guise of 712psychiatric medicines. Other psychoactive drugs are used mainly for "unrecognised" 713and non-medical purposes. Psychostimulants like <a href="https://www.erythroxylum-coca.com/">cocaine</a> 714and <a href="https://www.amphetamines.org/">amphetamine</a> notoriously promote egotism 715and aggression. Drinking ethyl alcohol tends to make the user relaxed, disinhibited 716and stupid. <P> 717 718 So is MDMA itself 719best reserved as a sacrament for special occasions? Or can it be safely taken 720"recreationally" and socially? What dosage, if any, is prudent? Is the MDMA experience 721so tantalising that it's best avoided altogether lest the rest of one's life pall 722in contrast? Would one want one's sixteen year-old daughter to take it; and with 723whom? <P> 724 725 Currently the risk-benefit 726analysis of taking - or missing out on - MDMA is unclear. Probably the gravest 727threat to the long-term emotional and physical health of the user is getting caught 728up in the criminal justice system. Victims of the law-enforcement agencies frequently 729suffer long-term neuropathological changes. Lowered serotonin levels, elevated 730cortisol, confusion, depression, sleep problems, severe anxiety, and paranoia 731are common. In some cases, the neurological damage may be permanent. Currently 732around <a href="https://www.cannabis-marijuana.com/drugterrorist.html">500,000</a> "drug-offenders" 733languish in American jails alone; and millions more young people throughout the 734world are at risk. Yet repealing ill-conceived drug laws is only part of the answer 735in protecting mental health. 736 737 738<P> 739Ever more <a href="https://www.mdma.net/serotonin/">alarming</a> animal studies conducted 740over a decade by <a href="https://www.mdma.net/toxicity/george-ricaurte.htm">George Ricaurte</a>, a neurotoxicologist at John Hopkins University 741School of Medicine, suggest that taking high and/or frequent doses of MDMA causes 742damage to the terminals of serotonin axons in the brain. Cerebrospinal fluid 5-hydroxyindoleacetic 743acid (<a href="https://www.mdma.net/serotonin/5-hiaa.html">5-HIAA</a>), serotonin's 744major metabolite which serves as a marker of central serotonin (5-hydroxytryptamine, 7455-HT) neural function, may be lower in human MDMA users than in putatively matched
746controls. The number of serotonin transporter sites, structural protein elements 747on the presynaptic outer axonal membrane that recycle the released neurotransmitter, 748may be reduced too. Long-term MDMA-induced changes in the availability of the serotonin transporter <I>may</I> be <a href="https://www.mdma.net/serotonin/sert.html">reversible</a>; but it is unclear whether recovery is complete. Currently the balance of neurochemical and neuroanatomical 749evidence, and functional measures of serotonin neurons, suggests that it is <a href="https://www.mdma.net/mdmacog.htm">imprudent</a> 750to take MDMA or other ring-substituted methamphetamine derivatives without also 751taking <a href="https://www.mdma.net/protect.htm">neuroprotective</a> precautions. 752Arguably, it is best to take MDMA infrequently and reverently or not at all - 753<a href="https://www.mdma.net/alexander-shulgin/psychedelic-chemist.html">Dr Shulgin</a> once suggested a maximum of four times a year. <P> 754 755 MDMA's 756apologists aren't convinced that the neurotoxicity <a href="https://www.mdma.net/toxicity/polydrug.html">evidence</a> is persuasive - except 757for MDMA taken at unrealistically high doses. As <a href="https://www.opioids.wiki/opium/paracelsus.html">Paracelsus</a> 758(1493-1541) noted centuries ago, "All substances are poisons: there is none which 759is not a poison. The right dose differentiates a poison and a remedy." Most early 760studies of the possible long-term adverse effects of MDMA use in humans have been 761<a href="https://www.mdma.net/toxicity/methodological.html">methodologically</a> flawed - inadequately controlled, retrospective rather than <a href="https://www.mdma.net/toxicity/longitudinal.html">prospective</a>, 762and marred by a failure adequately to exclude <a href="https://www.mdma.net/longterm/mental-disorders.html">confounding</A> 763variables - e.g. the so-called <a href="https://www.mdma.net/toxicity/stereotype-threat.html">stereotype threat</a>. Some published toxicity studies include a large percentage of self-reported 764"Ecstasy" users who've never even taken MDMA. Other studies rely on a small minority 765of users whose drug-taking methodology owes more to Hunter S. Thompson than Sasha 766Shulgin. <P> 767 768 Yet the biggest problem 769in evaluating the published evidence isn't so much sloppy science or value-judgements 770masquerading as statements of fact. It's rather that just as the strongest predictive 771factor in the outcome of a published clinical trial of any psychiatric drug is 772the identity of the funding body, likewise the investigation of MDMA isn't a disinterested 773search for scientific truth. <a href="https://www.mdma.net/refs/">Published</a> 774papers that examine possible confounding variables in MDMA "toxicity studies" 775omit to mention the greatest biasing factor of all. Independent funding is critical 776to the integrity of biomedical research; but MDMA is now a Schedule One drug. 777Studies of MDMA can be lawfully conducted only under government license by ideologically-vetted 778researchers. Authors and licensed researchers are implicitly paid to show how 779prohibited drugs are harmful, not that they can be potentially therapeutic. Researchers 780certainly <I>aren't</I> paid to report that some illegal drugs are potentially 781life-enhancing agents. Nor do their paymasters expect them to investigate the 782design of safer, more sustainable analogues to improve the user experience. <P> 783 784 785 786 Intuitively, at least, it might 787seem axiomatic that in a democratic free society every person should have "the 788license to explore the nature of his own soul" (Dr Shulgin). Yet this license 789has lately been revoked in the name of the <a href="https://www.cannabis-marijuana.com/justsayno/">War 790Against Drugs</a>. Every law-abiding citizen is now locked into traditional modes 791of consciousness on pain of criminal prosecution and imprisonment. The chemical 792keys to the locks themselves have been outlawed. Most natural scientists are scornful 793of social constructivists who think that power structures underwrite the way
793we see 794the world. But in a daring extension of the Papacy's <I>Index Librorum Prohibitorum</I>, 795knowledge of entire state-spaces of potential experience has been outlawed following 796passage of the USA's Controlled Substance Analogue Enforcement Act of 1986. The 797UN's World Health Organization and foreign governments have been leaned on, bribed 798or dragooned into the War On Drugs too. In the USA itself, the world's most celebrated 799psychedelic chemist and leading authority on MDMA has been stymied from conducting 800human research on Schedule One compounds after publishing his trailblazing autobiography-cum-cookery 801book. Worried that his life's work might be quite literally destroyed by the drug-warriors, 802Dr Shulgin acted to thwart the obscurantists before it was too late. "I can see 803having maybe two or three people in the higher echelons of the government who 804may not like what I do, and I did not want particularly to have all of this be 805seizable and burnable, So I published it. Now you cannot get rid of it." Dr Shulgin 806had a DEA analytical license - a "Faustian bargain" according to MAPS's <a href="http://www.maps.org/staff.html" target="_blank">Rick 807Doblin</a>. But in 1994, Dr Shulgin fell victim to a DEA <a href="https://www.biopsychiatry.com/interview/index.html">raid</a> 808on his research lab. Under the transparent pretext of "health-and-safety" infractions, 809Dr Shulgin's license to work with scheduled drugs was withdrawn. <P> 810 811 Suppression 812of "illicit" knowledge in academia and the overground research community isn't 813normally so melodramatic or heavy-handed. But systemic bias and the habit of internalised 814self-censorship extends throughout the apparatus of peer-reviewed journals, sponsored 815conferences, and mainstream clinical medicine. On the one hand, negative results and non-results 816from toxicity studies are difficult to publish or publicise. Conversely, "positive" toxicity 817results from studies run by primate vivisectionists using chronic or <a href="https://www.mdma.net/toxicity/ricaurte.html">near-fatal</a> 818MDMA doses are newsworthy and fundable. Such publication bias is insidious and 819endemic; it's underestimated because prospective authors are broadly aware of 820what can - and can't - get published; and so they don't bother to submit what 821they know can't be accepted. Even this biasing factor massively understates the 822problem. This is because most potential psychedelic research projects can't get 823official permission or funding in the first place. As <a href="https://www.mdma.net/misc/ecstasy-mdma.html">noted</a> 824by <I>New Scientist</I> in Ecstasy on the Brain (April 2002): "'It's an open secret 825that some teams have failed to find deficits in ecstasy users and had trouble 826publishing the findings...The journals are very conservative,' says [Andrew] Parrott. 827'It's a source of bias.' Parrott himself has had two papers of this sort turned 828down." <P> 829 830 Of course bias cuts 831both ways. MDMA enthusiasts find it hard to write even-handedly too. Among MDMA's 832"unlicensed" and independent researchers, there is a natural tendency to believe 833any agent that triggers such sublime states must essentially be good for you. 834MDMA can indeed be life-transforming; but unless it's used sparingly and at conservative 835doses, it is still a potentially 836<a href="https://www.mdma.net/longterm/problems.html">toxic</a> drug. MDMA's defenders would say that the 837same is true of lithium, penicillin or paracetamol, none of which are banned. 838 839 840<P> Some studies suggest that 841possible MDMA-induced neurotoxicity to the serotonin system can be largely prevented 842by taking a double dose of <a href="https://www.mdma.net/protect/prozac.html">fluoxetine</a> 843(Prozac) or another <a href="https://www.biopsychiatry.com/ssris.htm">SSRI</a> 844shortly after starting to "come down". Post-E Prozac in particular mitigates the 845oxidative stress and consequent risk of serotonergic axon damage caused by reactive 846products of dopamine deamination. The long-acting SSRI Prozac/fluoxetine, and 847its even longer-acting metabolite norfluoxetine, apparently prevents the uptake 848of dopamine (and any toxic metabolite(s)?) into the serotonergic nerve terminals 849by binding to the serotonin reuptake transporter with higher affinity than MDMA 850or serotonin. Unfortunately, although liquid refreshment is now freely available 851at most MDMA-propelled raves, most chill-out rooms don't offer Prozac. Two days 852and more after taking MDMA, heavy recreational users are typically more irritable, 853subdued, unsociable and subtly <I><a href="https://www.mdma.net/empathy/index.html">less</a></I> empathetic than before their weekend 854binge: the "Terrible Tuesday's" syndrome of midweek blues. So with cruel irony, two or three days after communing on Ecstasy and declaring their undying 855love, couples are more likely to have rows and split up. Other heavy regular MDMA 856users, even those who aren't self-medicating for a pre-existing <a href="https://www.hedweb.com/bgcharlton/depression.html" target="_blank">malaise</a>, 857may experience depression, <a href="https://www.mdma.net/mice/anxiety.html">anxiety</a>, 858emotional burnout, rejection-sensitivity, fatigue, insomnia, aching limbs, subtle 859<a href="https://www.mdma.net/memory/index.html">cognitive</a> deficits, <a href="https://www.mdma.net/immune/immunosuppressant.html">immune</a> 860system dysfunction, body <a href="https://www.mdma.net/thermoregulation/index.html">temperature</a> 861dysregulation, and a sense of derealisation or depersonalisation for several weeks 862or months afterwards. This litany of woe sounds a high price to pay even for the 863peak experience of a lifetime. <P> 864 865 866 Alas, 867adopting a prophylactic SSRI regimen isn't a realistic long-term option for frequent 868MDMA users either, or at least not if they intend to continue using their hugdrug 869of choice. This is because a sustained regimen of SSRIs largely <a href="https://www.mdma.net/mdma/citalo
869pram.html">blunts</a> 870MDMA's empathogenic and entactogenic effects. SSRIs inhibit the binding of MDMA 871to the serotonin transporter. Thus pre-treatment with SSRIs prevents MDMA-triggered 872serotonin-release; and this in turn reduces dopamine-release in the striatum. 873Some SSRI users who like to rave nonetheless continue to take MDMA. They consume abnormally 874high quantities of pills to gain the desired E-like effect. At this dosage range, 875the persistence of metabolite-induced 876<a href="https://www.mdma.net/mda/dualstim.html">MDA-like</a> states of consciousness the next 877day is not unexpected. In practice, the after-effects are often modulated by <a href="https://www.mdma.net/memory/cannabis.html">cannabis</a> 878and alcohol. <P> 879 880 881 <a href="https://www.mdma.net/tolerance/index.html">Tolerance</a> to 882MDMA itself develops quite rapidly with steady use. If MDMA is taken several days 883in a row, amphetamine-like and eventually dysphoric effects start to predominate. 884<a href="https://www.biopsychiatry.com/monohypo.htm">Monoamine</a> neurotransmitters, 885most drastically serotonin, are <a href="https://www.mdma.net/serotonin/effects.html">depleted</a> from the axon terminals; serotonin <a href="https://www.mdma.net/serosynth.html">synthesis</a> 886is choked off following oxidative inactivation of <a href="https://www.biopsychiatry.com/trysa.htm">tryptophan 887hydroxylase</a>; and the nerve-cell receptors re-regulate. Thus MDMA is not addictive 888in the conventional sense. Taken chronically, it soon ceases to be rewarding. 889Even dedicated ravers typically don't binge more than once a week. Wiser heads 890save the drug for "special occasions". Yet MDMA's non-addictive profile is no 891guarantee that (as was once fondly hoped), "once you get the message you hang 892up the phone." The mind/brain isn't built like that. If you really like a drug-delivered 893message, you want to hear it again and again. But with MDMA, the message can subtly 894<a href="https://www.mdma.net/longterm/social.html">change</a> with time; and its primal magic gets sullied or forgotten. <P> 895 896 897 There 898are other options for neuroprotection besides taking post-Ecstasy Prozac. On one 899<a href="https://www.mdma.net/dopamine/tox.html">hypothesis</A> of MDMA-induced serotonergic neurotoxicity, the extra <I><a href="https://www.mdma.net/mdma.htm">dopamine</a>
899</I> 900released into the synapses is transported into the depleted serotonin axonal terminals 901where it is deaminated by the enzyme monoamine oxidase type-B present in the terminal. 902MAO has two isoforms, <a href="https://www.biopsychiatry.com/mao.html">MAO-A</a> 903and <a href="https://www.mdma.net/toxicity/moa-b.html">MAO-B</a>. These differ 904in their substrate affinities and inhibitor sensitivities: the MAO-A isoenzyme 905has a greater affinity than the MAO-B isoenzyme for serotonin, but mainly MAO-B 906is present in the serotonergic axonal terminals, where it breaks down "foreign" 907neurotransmitters. However, after a subject has taken a high dose of MDMA, excess 908dopamine is taken up by the so-called serotonin transporters into the depleted 909serotonin terminals. Here its oxidation produces a glut of toxic <a href="https://www.mdma.net/misc/oxidative-stress.html">free 910radicals</a> - highly reactive chemicals with one or more unpaired electrons - 911such as hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>). These toxic free radicals 912are liable to exhaust or overwhelm the free radical scavenging systems of the 913cell. In consequence, the serotonin fine axonal terminals are broken down by lipid 914peroxidation. Why exactly the serotonin reuptake transporters lose their normal 915selectivity for serotonin and take up dopamine isn't known for certain. Possibly 916it's because by this time there's far less serotonin around for the reuptake pump 917to use. After the directionality of the reuptake pump is reversed by MDMA, serotonin 918released into the synapse can't be recycled back into the cell; and so it diffuses 919away. In any event, the monoamine oxidase inhibitor <a href="https://www.selegiline.com/">selegiline</a> 920[l-deprenyl/<a href="https://www.selegiline.com/prescribe/">Eldepryl</a>] appears to be <a href="https://www.mdma.net/depsave.htm">neuroprotective</a> 921at monoamine oxidase type-B-selective dosages i.e. 2 x 5mg daily or less. Selegiline 922also protects against MDMA-induced inhibition of <a href="https://www.mdma.net/tryptophan-hydroxylase/post-e.html">tryptophan hydroxylase</a>. Interestingly, 923Prozac too has MAO-B inhibiting properties; and these may contribute to its neuroprotective 924effect. Selegiline itself has additional free radical scavenging properties that 925may exert a neuroprotective action. It will be instructive to compare the neuroprotective 926efficacy of selegiline with <a href="https://www.rasagiline.com/">rasagiline</a> (Azilect, Agilect) for E-users. Rasagiline is a selective 927MAO-B inhibitor licensed from mid-2005 in the EC for the treatment of <a href="https://www.rasagiline.com/resource/index.html">Parkinson's disease</a>; 928rasagiline lacks selegiline's trace amphetamine metabolic by-products. Whatever 929the older compound's neuroprotective efficacy compared to rasagiline, 930selegiline is potentially valuable too because, unlike taking a SSRI, adopting a long-term 931selegiline regimen doesn't impair MDMA's subjective effects. Even so, no controlled 932clinical trials of their co-administration are currently planned. 933 934 935<P> One 936reason for such caution beyond a reflex Just-Say-No dogmatism is that it's potentially 937<a href="https://www.mdma.net/toxicity/maointeract.html">dangerous</a> to tamper with the MAO enzyme. Selegiline has <a href="https://www.selegiline.com/deplong.html">lifespan-extending</a> properties 938in "animal models", and possibly in humans too; but if used recklessly, then it 939could abruptly shorten life instead: selegiline is an irreversible MAO-B inhibitor. 940Prohibitionism and a consequent absence of quality-control means that the "Ecstasy" 941sold in clubs often contains liberal quantities of amphetamine. Amphetamine and 942MAO inhibitors should not be combined. Both enantiomers of MDMA itself have <a href="https://www.biopsychiatry.com/mdmamao.htm">MAO-inhibiting</a> 943effects, preferentially for isoenzyme type-A. Taken at dosages of above 2 x 5mg 944per day, selegiline loses its selectivity for MAO-B. Individual variation in MAO 945status makes it imprudent for the MDMA user to take selegiline even at 10mg daily; 946and selegiline itself, like MDMA, is a weak inhibitor of MAO-A. MAO-A deaminates 947serotonin; and the <a href="https://www.mdma.net/serotonin/serotonin-syndrome.html">serotonin 948syndrome</a>, characterised <I>inter alia</I> by hyperthermia, autonomic instability 949and altered muscle tone, is potentially lethal. Serotonin 5-HT2A antagonists like 950<a href="https://www.mdma.net/ketanserin/index.html">ketanserin</a> (Sulfrexal) 951can inhibit the syndrome; but they aren't widely available on the street or average 952dance-floor. 953 954 955 <P> Milder cases 956of the serotonin syndrome are not uncommon among the hard-rolling stackers and piggybackers dancing all night at crowded <a href="https://www.mdma.net/thermoregulation/index.html">ill-ventilated</a> 957raves. Dehydration and overcrowding tend to worsen drug-induced toxicity. Heat 958exhaustion and severe <a href="https://www.mdma.net/hyperthermia/carvedilol.html">hyperthermia</a> are probably the gravest risk to the raver's 959<a href="https://www.mdma.net/misc/x.html">health</a>. MDMA tends to raise 960body temperature by a degree or so, sometimes by quite a bit more if the user dances 961all night without rest ["Saturday night fever"]. MDMA also increases the body's 962secretion of antidiuretic hormone, <a href="https://www.mdma.net/misc/argininevasopressin.html">arginine-vasopressin</a>. 963Ravers sometimes overcompensate for the risk of dehydration by gulping down too 964much pure water. This can cause <a href="https://www.mdma.net/hyponatraemia/index.html">hyponatraemia</a> 965(literally "low salt": "water intoxication"). Sipping a couple of sports-drinks 966every hour or so instead is a prudent way to maintain electrolyte balance. Indeed it 967would be safer if sports drinks were distributed with each E-tablet sold as a matter 968of course, perhaps accompanied with a neuroprotectant mix and a health-tips sheet thrown in 969for good measure. <P> 970 971 Unfortunately, 972<a href="https://www.mdma.net/misc/information.html">tips</A> found on the Net are no substitute for systematic, well-planned health-education 973programs. Organisations like the Berkeley-based <a href="http://www.dancesafe.org/" target=_blank">Dancesafe</a>, funded by Microsoft 974millionaire the late Bob Wallace and founded to promote safe raving, are rare; 975their activities are also <a href="https://www.mdma.net/toxicity/clubdrugs.html">controversial</a>. 976Until <a href="https://www.hedweb.com/bgcharlton/psychopharm.html" target="_blank">psychopharmacology</a> 977becomes part of the educational core curriculum, any responsibly designed drug 978cocktail, and any <a href="https://www.mdma.net/harm-reduction/index.html">harm-reduction</a> program, must be formulated with the recklessness 979of a minority of sensation-seekers in mind, not just risk-averse research scientists. 980Such a revolution in mental healthcare for young people is sorely needed. An examination 981system akin to ritualised child-abuse wreaks terrible damage on the young minds 982incarcerated in our educational institutions. Critics of exam-culture claim an 983"education" based around competitive testing screws kids up far more than empathetic 984drugs. Unfortunately, what's tested in these rituals of abuse isn't our children's 985emotional well-being, levels of reflective self-insight, capacity for loving empathy 986or social intelligence. Nor do schools and colleges offer courses in effective 987technologies to promote them. 988 989 990<P> A 991healthcare revolution of this magnitude isn't going to happen tomorrow. So more
992realistically for now, clubbers seeking neuroprotection against MDMA-induced toxicity 993may do well to use humble antioxidants such as <a href="https://www.mdma.net/protect/index.html">ascorbic 994acid</a> (Vitamin C), <a href="https://www.mdma.net/protect/vitamin-e.html">alpha-tocopheryl-acetate</a> 995(Vitamin E), <a href="https://www.mdma.net/zinc/index.html">zinc</a>, <a href="https://www.mdma.net/alphalip.html">alpha-lipoic 996acid</a>, and <a href="https://www.mdma.net/protect/l-cysteine.html">L-cysteine</a>. 997The optimal mix and dosage before, during, and after dropping an E to maximise 998their respective neuroprotective action, and minimise any post-ecstatic hangover, 999hasn't yet been established. Even at high dosage, the neuroprotection such antioxidants 1000offer may be inadequate for heavy MDMA users. More encouragingly, antioxidants 1001also reduce tolerance between exposures. Clearly a lot more research is needed, 1002hopefully without the usual animal holocaust that accompanies drug testing today. <P> 1003 1004 The 1005serotonin <a href="https://www.mdma.net/mdmatryp.html">precursors</a> L-tryptophan 1006and 5-hydroxytryptophan (<a href="https://www.biopsychiatry.com/5-htp.htm">5-HTP</a>) 1007are also neuroprotective against MDMA-induced toxicity, possibly in part because 1008of their antioxidant effect but mainly because of their precursor role. 5-HTP 1009is the metabolite of <a href="https://www.biopsychiatry.com/tryptophan/index.html">L-tryptophan</a>. 1010It's the direct metabolic precursor to serotonin (5-HT). In contrast to the catecholamine neurotransmitters dopamine and noradrenaline, the synthesis of serotonin 1011isn't subject to strong end-product inhibition. Like L-tryptophan, 5-HTP is sometimes used as an <a href="https://www.biopsychiatry.com/5-htp.html">antidepressant</a> 1012and antianxiety agent; it seems to have a relatively narrow therapeutic window. 1013Unlike SSRIs, L-tryptophan and 5-HTP can be taken chronically without 1014blunting MDMA's effects. Indeed some clubbers pre-load with L-tryptophan or 5-HTP to <a href="https://www.mdma.net/l-tryptophan/index.html">intensify</a> 1015and enrich the MDMA experience and prevent serotonin depletion. Serotonin depletion 1016increases the vulnerability of the axon terminals to damage. Though such a tactic 1017is sensible enough in theory, excess <a href="https://www.mdma.net/preloading-postloading/index.html">preloading</A> with 5-HTP may potentially precipitate 1018or exacerbate the serotonin syndrome. So care is in order. 1019 1020 1021<P> With 1022or without 5-HTP supplementation, an idealised stone-age <a href="https://www.moodfoods.com/">diet</a> 1023can be especially valuable for heavy MDMA users. Contrary to a once widely-propagated 1024but now discredited <a href="https://www.mdma.net/merck/index.html">myth</a>, Merck 1025never planned to develop MDMA as an <a href="https://www.mdma.net/misc/appetite.html">appetite-suppressant</a>. Yet the company might 1026well have done so: MDMA's appetite-suppressing effect is quite strong. Drugs that 1027directly or indirectly activate the serotonin 5-HT1B and 5-HT2 receptors tend to 1028be anorexiants. Lazy and reluctant eaters who regularly take Ecstasy are at greater 1029risk of vitamin and mineral deficiencies, and more vulnerable to MDMA-induced 1030serotonergic damage, than matched controls. 1031 1032 1033<P> One novel and unlikely-sounding proposal to minimise MDMA-induced neurotoxicity is pretreatment with <a href="https://www.mdma.net/aspirin/index.html">aspirin</a>. Aspirin inhibits the enzyme prostaglandin H synthase (<a href="https://www.mdma.net/aspirin/phs.html">PHS</a>). PHS catalyses the transformation of amphetamines into toxic free radical products. Therefore taking aspirin before MDMA use may also indirectly block the conversion of amphetamines into reactive oxygen species responsible for long-term neurotoxicity. As of 2014, no controlled trials of aspirin have yet been conducted with MDMA-using humans. But if aspirin pretreatment does prove an effective harm-reduction strategy, then this is potentially a godsend - not least because other candidate neuroprotectants (SSRIs, selegiline, etc) carry hazards of their own in conjunction with E-use. Aspirin
1033itself cannot strictly be described as risk-free; but the risk/benefit ratio of its use is both favourable and well-known. 1034 1035 1036 1037<P> However, 1038the biggest long-term obstacles to preventing neurotoxicity and 1039<a href="https://www.mdma.net/longterm/psychiatric.html">drug-related</a> mental 1040health problems are ideological, not pharmacological. The discovery that MDMA 1041is not always the harmless fun-drug that a number of its <a href="https://www.mdma.net/misc/recreationals.html">recreational</a> users (understandably) 1042first supposed has caused the medical establishment to demonise MDMA or dismiss 1043its psychotherapeutic potential completely. Critics of the drug-warrior mentality 1044claim that MDMA's possible neurotoxicity served only as a pretext for banning 1045it. The case for making, say, <a href="https://www.biopsychiatry.com/tobacco/">tobacco</a> 1046a schedule-one drug isn't notably less compelling, nor would any rush to judgement 1047on the safety, medical use or addictive potential of tobacco-products seem so 1048premature. The size of the cumulative death toll in the tobacco epidemic almost 1049defies comprehension: yet we continue energetically to market a lethal drug to 1050hundreds of millions of youngsters in the Third World. The contrast between the 1051treatment of dealers in tobacco products and MDMA distributors couldn't be much 1052starker. Instead of aiming to prevent possible MDMA-induced neurotoxicity by tweaking 1053or enhancing the agent in question, or designing better functional analogues, 1054or seeking ways to antagonise possible <a href="https://www.mdma.net/toxicity/toxicmetab.html">toxic metabolites</a>, or running health campaigns promoting 1055the co-administration of free radical scavengers or other neuroprotectants, the 1056authorities opted simply to outlaw MDMA altogether. Users and independent researchers 1057alike were criminalised. Scientific investigation was crippled. MDMA was driven 1058underground, where it could mix with innumerable contaminants and <a href="https://www.mdma.net/usa/index.html">organised crime</A>. 1059 1060 1061<P> Fortunately, scientific research 1062on MDMA has lately <a href="https://www.mdma.net/mdma/controversies.html">revived</a>, 1063albeit under license and mainly on <a href="https://www.mdma.net/mdma/animal-ecstasy.html">non-humans</a>. Rats and <a href="https://www.mdma.net/misc/rhesus.html">monkeys</a> 1064are in some ways uncannily similar - genetically, behaviourally and biochemically 1065- to human beings. Both the electrical-signalling properties and molecular machinery 1066of neurons are widely conserved across the animal kingdom. There are interspecies 1067differences e.g. MDMA is <a href="https://www.mdma.net/mice/index.html">anxiogenic</a> 1068rather than anxiolytic in some mouse strains at low doses; MDMA administered to <a href="https://www.mdma.net/hyperthermia/body-temperature.html">rats</a> in cold ambient temperatures induces <I>hypo</I>thermia; and MDMA causes opposing 1069<a href="https://www.mdma.net/5-ht2/sensorimotor.html">sensorimotor gating</a> 1070effects in rats and humans. Yet the fundamental similarity of "animal models" 1071to human beings is precisely why we use, vivisect and then "<a href="https://www.mdma.net/fmri/index.html">sacrifice</a>" our fellow creatures 1072in drug discrimination studies and medical research. Using principles of interspecies 1073scaling, it is possible to estimate the crude physical effects of comparable MDMA 1074doses on people after conducting animal experiments, although species differences 1075in MDMA's pharmacokinetics and active metabolites make the details of such scaling 1076controversial. If oxidative metabolites, not MDMA itself, are responsible for 1077neurotoxicity, then investigation of the particular ways MDMA is metabolised in 1078humans will be critical in determining safe dosages. But beyond the narrow physical 1079effects of MDMA on the brain, it's hard enough for articulate humans who take 1080insight-and-empathy drugs to verbalise their processes of introspection. What 1081can we learn about <a href="https://www.entactogens.com/">entactogenesis</a> by 1082mega-dosing a rhesus monkey? All sorts of intellectually fascinating physiological 1083data can be gleaned from experimenting on live animals - and even more data from 1084experiments on live humans. Yet ethically, how can we humanely experiment on members 1085of other species when we can't "predict whether a particular molecule will open 1086the gates of heaven or stoke up the fires of hell" (Dr David Nichols). Clearly 1087<a href="https://www.animal-rights.com/">non-humans</a> can't describe the effects 1088on their consciousness of psychoactives, even though they can be taught to "discriminate" 1089them - the so-called "animal model" of subjective drug effects. So members of 1090other species can't describe the illegal knowledge drug-naïve humans are 1091missing out on - or the horrors we inflict on their minds and bodies. 1092 1093 1094<P> Even 1095if animal research throws up a true wonderdrug ideal for human use - a safe, sustainable 1096miracle-pill with a well-defined therapeutic window, life-enriching subjective 1097profile, and no significant adverse side-effects - then under today's regulatory 1098regime, the potential wonderdrug couldn't get a product-license. In law, only 1099<a href="https://www.psychedelics.org/medicine/">medicines</a> to treat well-defined clinical disorders can be licensed, not investigational 1100agents designed to enhance our quality of life or enrich "normal" human mental 1101(ill-)health. Short of labelling the agent as a "food supplement" - which might 1102be stretching it a bit for MDMA and its analogues - true pharmacological life-enrichers 1103will be condemned to legal limbo. Even if this perverse restriction on legal drug 1104availability were lifted, then any prospective blockbuster most likely still wouldn't 1105get regulatory approval in practice. Human <a href="https://www.mdma.net/therapy/clinical.html">clinical</a> trials cost tens of millions 1106of dollars to run. MDMA itself has long been off-patent. So <a href="https://www.bi
1106opsychiatry.com/drugcompanies/index.html">profit-driven</a> 1107pharmaceutical companies aren't interested in funding pilot studies. Empathy-And-Insight 1108Deficiency-Disorder isn't covered in <a href="http://www.dr-bob.org/tips/dsm4n.html" target="_blank">DSM-IV</a>, 1109the psychiatrists' bible. A condition that isn't medically acknowledged can't 1110be treated by state-licensed pharmacotherapy. <P> 1111 1112 1113 The 1114gloom-and-doom shouldn't be overdone. Eventually, safe long-lasting E-like super-cocktails 1115and enhanced functional analogues of MDMA may indeed be both patentable and judged 1116therapeutic for "officially" sanctioned medical conditions such as anti-social 1117personality disorder, refractory depression, PTSD, <a href="https://www.biopsychiatry.com/asperger.htm">Asperger 1118syndrome</a> and autism. These super-cocktails and sustainable MDMA analogues 1119should prove life-enhancing for "normal" self-regarding people who would like 1120to improve themselves too. Such usage may or may not stay "off-label"; but it 1121needn't be illegal. <P> 1122 1123 1124 In the 1125meantime, bitter experience of the hedonic treadmill of Darwinian life instils 1126a reluctance to believe anything so magical as the MDMA experience could be sustained 1127and enriched indefinitely. [<I>"You can't have the sweet without the sour"; "You 1128need pain to appreciate pleasure"</I>, etc.] But such superstition is pre-scientific; 1129it may soon seem quaint. As intracranial <a href="https://www.wireheading.com/delgado/index.html">self-stimulation</a> 1130studies attest, pure <a href="https://www.paradise-engineering.com/brain/">pleasure</a> 1131induced by electrical stimulation of the ancient mesolimbic <a href="https://www.wireheading.com/james-olds.html">pleasure 1132centres</a> of the brain shows no <a href="https://www.opioids.wiki/proglumide/index.html">tolerance</a>. 1133Response- and remission-rates are 100%. In the present era, depression, self-ignorance 1134and sociopathy are demonstrably sustainable over a lifetime; but so, in theory, 1135are the biochemical substrates of happiness, lucid self-insight and even saintly 1136empathetic bliss. The hedonic treadmill can be dismantled, its inhibitory feedback 1137mechanisms redesigned, and its neurogenetics rewritten. In principle, and perhaps 1138one day in practice, we can be <a href="https://www.empathogens.com/">nicer</a>, <a href="https://www.biopsychiatry.com/">happier</a> 1139and <a href="https://www.nootropic.com/">smarter</a> indefinitely. Unfortunately this 1140<a href="https://www.huxley.net/pauln/">utopian</a> outcome won't result from a 1141<a href="https://www.mdma.net/tolerance/index.html">chronic</a> regimen of MDMA. <P> 1142 1143<a name=mdmalife></a> <br><h3>Ecstasy for life?</h3> What 1144are the presently available options for enhancing and extending the MDMA experience? 1145Two separate questions need to be distinguished. First, what if any drug or drug-cocktail 1146can safely replicate the <a href="https://www.mdma.net/acute/index.html">acute</a> subjective effects of MDMA? Second, what if any 1147drug or drug-cocktail or gene-therapy can best induce E-like consciousness over 1148the long-term? <P> 1149 1150 1151 The holy grail 1152of safe, sustainable entactogen-empathogens almost certainly won't be found in 1153the guise of structurally-tweaked chemical <a href="https://www.mdma.net/pmma/deriv.html">homologues</a> 1154of MDMA. A long-term regimen doesn't seem feasible even if the exact structural 1155requirements needed to reproduce MDMA's acute stimulus effects were understood. 1156To make the magic last for ever, or at least to induce it at will over several 1157decades, only a long-lasting <a href="https://www.wireheading.com/homeostasis.html">
1157homeostatic</a> 1158re-regulation of the central nervous system will work. Thus the substrates of 1159a lifelong capacity for E-like consciousness can't be engineered via, say, a mechanism 1160akin to the MDMA-induced reversal of the serotonin reuptake pump. Depleting the 1161brain's serotonin or, even worse, inhibiting the molecular machinery needed for 1162its renewed synthesis, is a recipe for clinical depression, not Heaven-on-Earth. 1163Nor can the substrates of perpetual empathetic bliss be delivered by tonic stimulation 1164of the <I>same</I> pre- and post-synaptic <a href="https://www.mdma.net/5-ht2/receptors.html">receptors</a> 1165activated by an acute flood of extra serotonin/dopamine in the synapses - or at 1166least not in the same way. Prolonged receptor activation typically leads to receptor 1167desensitisation and/or down-regulation. The inhibitory feedback mechanisms that 1168keep our Darwinian brains so mean-spirited need to be sabotaged, not kicked into 1169gear. 1170 1171 1172<P> Such a profound homeostatic 1173shift in normal waking consciousness might conceivably be delivered by functional 1174analogues of MDMA. The idea here would be to reproduce E-like euphoric and empathogenic-entactogenic 1175effects, not acutely, but via delayed receptor <a href="https://www.mdma.net/brain/receptors.html">subtype-specific</a> re-regulation. 1176MDMA itself rapidly depletes serotonin from the axon terminals and inactivates 1177the enzyme <a href="https://www.mdma.net/protect/fluoxetine.html">tryptophan hydroxylase</a> 1178needed for its renewed biosynthesis. By contrast, altering the density and signal-transduction 1179efficiencies of the mission-critical receptor subtypes [<a href="https://www.mdma.net/5-ht1b/index.html">5-HT1B</a>(?), 1180<a href="https://www.mdma.net/dopamine/potentiation.html">5-HT2A</a>(?), dopamine 1181<a href="https://www.mdma.net/dopamine/haloperidol.html">D2</a>(?)], could, ideally, 1182deliver sustained ecstasy without emotional burnout. Such receptor re-regulation 1183might involve a <a href="https://www.biopsychiatry.com/delay.htm">time-lag</a> 1184of one-to-three weeks, as is normal with conventional "antidepressants". <I>Delayed-onset</I> 1185magic, if achievable, would offer an immense social and therapeutic advantage. 1186This is not just because the magic should be sustainable without limit, but because 1187postponing the onset of drug-induced reward minimises a medicine's "abuse-potential" 1188without compromising its efficacy. The practice of tobacco-smoking, for instance, 1189is so <a href="https://www.biopsychiatry.com/nicotine.html">addictive</a> not because 1190of the surpassing joys of inhaling a cigarette, but because a tobacco abuser need 1191wait only seven seconds or so between taking a puff and the miniscule hit. The 1192reward from oral MDMA takes somewhat longer; but the delight of E-like consciousness 1193needs to be divorced from its intimate association with <a href="https://www.mdma.net/soulmed.htm">pill-popping</a>. 1194 1195 1196<P> Alas the brain's <a href="https://www.mdma.net/misc/pkc.html">post-synaptic</a> 1197signal-transduction mechanisms aren't yet sufficiently understood to bring about 1198a magical E-like re-regulation of waking consciousness indefinitely. Inducing 1199lifelong <I>egoistic</I> bliss is less of a technical challenge. <a href="https://www.wireheading.com/index.html">Wireheading</a> 1200is uniquely effective, though most of us might prefer the services of a molecular 1201psychiatrist to a neurosurgeon. Fortunately, our options may soon extend beyond 1202the crudely hedonistic. Indeed within a few decades, taking a controlled-release 1203<a href="https://www.mdma.net/poster-advert.html">maintenance dose</a> of functional 1204analogues of MDMA may seem as natural as swallowing a multivitamin pill; and just 1205what the doctor ordered. 1206 1207 1208<P> Alternatively, 1209the neurochemical substrates of MDMA-like magic may be preserved, or continually 1210re-created as desired, via a cocktail of agents rather than monotherapy. On this 1211approach, each individually designed ligand would be targeted selectively at the 1212potentially magic-signalling receptor subtypes [or at second-messenger pathways 1213coupled to the G-protein-linked signal-transduction system, or in theory direct 1214mechanisms of gene regulation and expression]. This may be feasible; but its orchestration
1215will be much harder than it sounds. As the catalogue of serotonin receptor subtypes 1216has grown, so has our library of serotonergic molecular probes; yet so too has 1217a realisation that agents previously reckoned to be selective for a particular 1218class of serotonin receptor are less selective than originally claimed. Hence 1219there is a need for novel agonists, antagonists and inverse agonists with far 1220greater selectivity for each receptor subpopulation. This multiple targeting strategy 1221is technically challenging, but it's probably more promising than relying on a 1222single "dirty" non-specific indirect serotonin agonist like MDMA. Although there 1223are indeed <a href="https://www.mdma.net/toxicity/mechanisms.html">other</a>, non-neurotoxic 1224amphetamine derivatives that acutely induce transporter-mediated serotonin release, 1225achieving the all-important goal of sustainability may entail the use of drug 1226cocktails. Thus one might explore combining e.g. 1] new synthetic <a href="https://www.biopsychiatry.com/5htmoduline.htm">allosteric</a> 1227modulators of the serotonin <a href="https://www.mdma.net/5-ht1b/1b.html">5-HT1B</a> autoreceptors that regulate the evoked release 1228and synthesis of serotonin; 2] agents acting selectively on the 5-HT1B-autoreceptors 1229and heteroreceptors; 3] the right 5-HT2C receptor <a href="https://www.biopsychiatry.com/agomelatine.htm">antagonist</a> or <a href="https://www.biopsychiatry.com/sb-243213.htm">inverse agonist</a> to make the E-like state more ecstatic; 4] the right dopaminergic(s) 1230or, ideally, agents targeting the medium spiny GABAergic projection <a href="https://www.biopsychiatry.com/nucleus-accumbens.html">neurons</a> 1231in the rostromedial <a href="https://www.mdma.net/dopamine/mesolimbic.html">shell</a> of the <a href="https://www.biopsychiatry.com/nacc.htm">nucleus accumbens</a> directly. This is all still very speculative and unfunded. 1232 1233<P> Alternatively, 1234and perhaps more plausibly, locking in the neural substrates of empathetic bliss 1235as a default-state of consciousness may be achievable only via gene therapy, or 1236perhaps a hybrid gene-and-drug combination treatment. One option here would be 1237inserting "good" variants of the <a href="https://www.biopsychiatry.com/tryptophan-hydroxylase.htm">tryptophan 1238hydroxylase</a> gene, which codes for the rate-limiting enzyme of serotonin biosynthesis, 1239and then once again co-administering receptor subtype-selective ligands and/or 1240serotonin releasers. Our immediate options are limited. Pharmaceutical interventions 1241aimed at extending, for example, profound emotional depth over many decades rather 1242than a few hours may entail, not flooding the synapses with extra serotonin followed 1243by extra dopamine release as in acute dosing with MDMA, but instead using e.g. 1244serotonin reuptake <I>accelerators</I> analogous to the memory-enhancing antidepressant 1245<a href="https://www.tianeptine.com/index.html">tianeptine</a> (Stablon); 1246or perhaps enhancing the love-and-nurturance-promoting <a href="https://www.oxytocin.wiki/oxytoc/index.html">oxytocin</a> 1247system; or perhaps using better designed analogues of the <a href="https://www.biopsychiatry.com/ghb/authentic.html">emotion-deepening</a> 1248agent Gamma-HydroxyButyrate (<a href="https://www.mdma.net/misc/ecstasy-ghb.html">GHB</a>). 1249 1250<P> 1251A brief comparison of GHB and MDMA may be instructive because one therapeutic 1252challenge ahead will be to design agents that reverse SSRI-like <a href="https://www.biopsychiatry.com/emotionalblunting.htm">flattening</a> 1253of affect without inducing mawkish sentimentalism (cf. ethyl alcohol). In contrast 1254to mainstream psychiatric drug therapies, both GHB and MDMA deliver a rare emotional 1255intensity of experience, albeit an intensity different both in texture and molecular 1256mechanism. GHB is known by clubbers if not structural chemists as "liquid ecstasy". 1257GHB and MDMA are indeed sometimes mixed at raves; but the two drugs are chemically
1258unrelated. GHB is an <a href="https://www.biopsychiatry.com/ghbbrain.htm">endogenous</a> 1259neuromodulator derived from <a href="https://www.biopsychiatry.com/gaba/index.html">GABA</a>, 1260the main inhibitory neurotransmitter of the brain. A naturally-occurring fatty 1261acid derivative, GHB is a metabolite of normal human metabolism. GHB has its own 1262G protein-coupled presynaptic <a href="https://www.biopsychiatry.com/ghbrecep.htm">receptor</a> 1263in the brain. Sold as a medicine, GHB is licensed as an oral solution under the 1264brand name <a href="https://www.biopsychiatry.com/gamma-hydroxybutyrate.html">Xyrem</a> 1265for the treatment of cataplexy associated with <a href="https://www.modafinil.com/narcolepsyrev.html">narcolepsy</a>. 1266Unlike MDMA, GHB stimulates tissue serotonin turnover. GHB increases both the 1267transport of tryptophan to the brain and its <a href="https://www.biopsychiatry.com/ghb.html">uptake</a> 1268by serotonergic cells. Taking GHB stimulates <a href="https://www.biopsychiatry.com/ghbgh.htm">growth 1269hormone</a> secretion; hence its popularity with bodybuilders. GHB offers cellular 1270protection against cerebral hypoxia, and deep sleep without inducing a hangover. 1271GHB also stimulates tyrosine hydroxylase. Tyrosine hydroxylase converts L-tyrosine 1272to <a href="https://www.biopsychiatry.com/l-dopa.html">L-dopa</a>, subsequently 1273metabolised to dopamine. Unlike MDMA, the acute effects of GHB involve first inhibiting 1274the dopamine system, followed the next day by a refreshing dopamine rebound. GHB 1275induces mild euphoria in many users. In general, the neurotransmitter GABA acts 1276to reduce the firing of the dopaminergic neurons in the tegmentum and substantia 1277nigra. The sedative/hypnotic effect of GHB is mediated by its stimulation of <a href="https://www.biopsychiatry.com/gamma-hydroxybutyrate.htm">GABA(B)</a> 1278receptors, though GHB also modulates the <a href="https://www.biopsychiatry.com/ghbgaba.htm">GABA(A)</a> 1279receptor complex too. The main effect of GABA(B) agonism is normally muscle relaxation, though interestingly, pretreatment with the GABA(B) agonist <a href="https://www.mdma.net/baclofen/index.html">baclofen</A> also prevents an MDMA-induced rise in core body temperature. 1280Whatever the exact GABA(A), GABA(B), and GHB-specific mechanisms by which GHB works, 1281when taken at optimal dosage GHB typically acts as a "sociabiliser". This is a term 1282popularised by the late Claude Rifat (Claude de Contrecoeur), author of <I>GHB: 1283The First Authentic Antidepressant</I> (1999). Rifat was GHB's most celebrated 1284advocate and an outspoken critic of Anglo-American psychiatry. Similar therapeutic 1285claims have been made for GHB as for MDMA, despite their pharmacological differences. 1286GHB swiftly banishes depression and replaces low mood with an exhilarating feeling 1287of joy; GHB has anxiolytic properties; it's useful against panic attacks; it suppresses 1288suicidal ideation; it inhibits hostility, paranoia and aggression; it enhances 1289the recall of long-forgotten memories and dreams; and it promotes enhanced feelings 1290of love. Like MDMA, and on slightly firmer grounds, GHB has been touted as an 1291aphrodisiac: GHB heightens and prolongs the experience of orgasm. GHB disinhibits 1292the user, and deeply relaxes his or her body. Inevitably, GHB has been demonised 1293as a date-rape drug [<I>"I was at this party, and this guy gave me a drink. Next 1294thing I know, it's morning and I'm in someone's bed. I've no idea what happened 1295in between..."</I>]. GHB has a steep dose-response curve. Higher doses will cause 1296anterograde amnesia i.e. users forget what they did under the influence of the 1297drug. It's dangerous to combine GHB with other depressants. So despite GHB's therapeutic 1298and pro-social potential, GHB is probably <a href="https://www.biopsychiatry.com/gammahydroxybutyrate.htm">unsafe</a> 1299to commend to clubbers. This is because a significant percentage of the population 1300will combine any drug whatsoever with <a href="https://www.biopsychiatry.com/ghb-alcohol.htm">alcohol</a> 1301regardless of the consequences to health. If used wisely, sparingly, and in a 1302different cultural milieu, then GHB could be a valuable addition to the bathroom 1303pharmacopoeia. But even then, it's still flawed. GHB may intensify emotion and 1304affection, but not introspective depth or intellectual acuity. Unlike taking too 1305much MDMA, overdoing GHB makes the user fall profoundly asleep. If our consciousness 1306is to be durably enhanced, then sedative-hypnotics have only a limited role to 1307play in the transition ahead. 1308 1309<P> So 1310what are the prospects for richer, intenser, sustainable insight-and-empathy drugs 1311from MDMA's phenethylamine sisters and cousins? <P> 1312 1313 1314 Post-Shulgin, 1315the quantified structure-activity relationships of MDMA and related compounds 1316(<a href="https://www.mdma.net/mde.html">MDEA</a>, <a href="https://www.mdma.net/mda.html">MDA</a>, <a href="https://www.mdma.net/mbdb.html">MBDB</a>, <a href="https://www.mdma.net/mmda.html">MMDA,</a>, etc) have been investigated, even though systematic overground 1317exploration of their effects on the human psyche has been strangled at birth. Research chemists have designed a host of ring-substituted amphetamine derivatives with one or more substituents attached at different positions to the phenyl ring
1318of the amphetamine or <a href="https://www.biopsychiatry.com/methamphetamine/index.html">methamphetamine</a> 1319structure. Other such derivatives have been devised by entrepreneurs whose synthesis 1320of <a href="https://www.designer-drug.com/">designer drugs</a> aims more at circumventing 1321legal restrictions than pushing back the frontiers of knowledge. In general, different monoamine-releasing amphetamine analogues become less subjectively rewarding as their serotonin-releasing potency is increased relative to dopamine-releasing potency. 1322 1323<P> Whatever 1324their parentage, the phenethylamines as a whole exert a <a href="https://www.mdma.net/pmma/phenylalkylamine.htm">spectrum</a> 1325of action from the purely stimulant activity shown by "noradrenergic/dopaminergic" 1326amphetamine to the almost entirely psychedelic activity of the "serotonergic" 1327DOM - distributed at ultra-high doses in Haight-Ashbury San Francisco 1967 under 1328the name of 'STP': Serenity, Tranquillity, and Peace. In <a href="http://www.dd-database.org/" target="_blank">drug 1329discrimination</a> studies, MDMA's subjective effects only partially cross-generalise 1330to DOM and amphetamine. Indeed MDMA only partially cross-generalises to the other 1331two hypothetical family prototypes currently identified, <a href="https://www.mdma.net/pmma/index.html">PMMA</a> 1332[N-methyl-1-(4-methoxyphenyl)-2-aminopropane] and <a href="https://www.mdma.net/tdiq/index.html">TDIQ</a> 1333[5,6,7,8-tetrahydro-1,3-dioxolo[4,5-g]isoquinoline] from the "fourth dimension". 1334MDMA itself is truly "one of kind" (Dr Shulgin), both structurally (i.e. the effects 1335of the N-methylation of its primary amine, exclusive 3-4 di-substitution on the 1336aromatic ring, its anomalously potent (+)-enantiomer) and subjectively. There's 1337no obvious new tweak of its molecular structure, or to structurally related agents, 1338that promises to deliver SuperEcstasy Mark 2, or even if there were, to suppose 1339the supermagic would be truly sustainable. Thus MDMA's immediate homologue and 1340closest relative, <a href="https://www.mdma.net/mdmamde.htm">MDEA</a> (3,4-methylenedioxyethylamphetamine: 1341"Eve"), formed by swapping the 1 carbon methyl group for a 2 carbon ethyl group, 1342is an interesting agent in its own right, but it's not going to deliver lifelong 1343empathetic bliss. Indeed MDEA is actually less warm and empathetic, and more <a href="https://www.mdma.net/mde/mde.html">introverted</a> 1344in its typical subjective effects, than its sister molecule. Instead of taking 1345MDEA as the racemate, one option is administering only <a href="https://www.mdma.net/mde/enantiomer.html">(+)-MDEA</a>, 1346the optical isomer responsible for racemic MDEA's <a href="https://www.mdma.net/mde/enantiomers.html">entactogenic</a> 1347quality. Yet pure preparations of individual enantiomers are not always readily 1348to hand, nor a route to lifelong wisdom if they were. 1349 1350 1351<P> Curiously, the beta-ketone analogue of MDMA, <a href="https://www.mdma.net/methylone/mechneuro.html">methylone</a> (3,4-methylenedioxymethcathinone, MDMCAT), is poorly researched. Only a handful of papers appear in the published scientific literature. Methylone is another creation of Dr Shulgin. The drug is sold (expensively) as a "<a href="https://www.mdma.net/uk/index.html">research chemical</a>" over the Net. Branded rather unsubtly as "Explosion", methylone is also available in several <a href="https://www.mdma.net/methylone/index.html">Dutch</a> smartshops. Recently it has become very popular in the scientific counterculture. The DEA issued an emergency ban on methylone on October 21, 2011. The drug is not as potent as MDMA; and it has a higher dosage range. Methylone causes less inhibition of <a href="https://www.mdma.net/methylone/serotonin.html">serotonin</a> reuptake and triggers less serotonin release than MDMA; but its potency in promoting the synaptic accumulation of the <a href="https://www.mdma.net/methylone/catechol.html">catecholamine</a> neurotranmitters noradrenaline and dopamine is similar. Thus methylone has activating and empathetic effects while inducing less emotional outpouring. Many subjects experience an E-like "magic", though the two drugs can readily be distinguished by experienced users. It should be stressed that the comparative safety of methylone has not yet been well established, even at relatively low dosage levels of 120-150mg. This is still a new drug. Methylone is mood-elevating; higher doses induce a clear-minded and serene euphoria. Reputedly there is less serotonergic toxicity than MDMA; but there can still be a very noticeable comedown. If methylone is taken chronically, its stimulant effects become more pronounced. Its empathogenic qualities diminish. Tolerance soon sets in: a sad and familiar story. Likewise, the empathetic euphoriant <a href="https://www.mephedrone.org/index.html">mephedrone</a> (4-Methylmethcathinone; 2-Methylamino-1-p-tolylpropan-1-one) can be acutely rewarding; but it is a short-acting stimulant whose pharmacokinetics and toxicology are unknown. Alas our knowledge (2014) of its properties comes wholly from <a href="https://www.mephedrone.org/experiences/index.html">user reports</a>
1351 rather than peer-reviewed scientific journals. 1352 1353 1354 1355 1356<P> 1357From a theoretical perspective, <a href="https://www.mdma.net/pmma/index.html">PMMA</a> 1358[N-methyl-1-(4-methoxyphenyl)-2-aminopropane] a structural hybrid of paramethoxyamphetamine 1359and methamphetamine, is interesting. PMMA arguably better represents a pure <a href="https://www.mdma.net/pmma/pmma.htm">entactogenic</a> 1360[inward-looking, self-accepting, peaceful] family prototype than MDMA. However, 1361the warm self-acceptance and empathetic love of others experienced on MDMA feels 1362so clean and pure precisely because its mechanism is so messy. PMMA, on the other 1363hand, lacks MDMA's residual psychedelic or speedy effects: PMMA is thus clearly 1364distinct from the other hypothetical family <a href="https://www.mdma.net/pmma/phenylalkylamine.htm">prototypes</a>, 1365DOM or amphetamine, and also from <a href="https://www.mdma.net/tdiq/index.html">TDIQ</a>, about whose psychotropic effects <a href="https://www.mdma.net/tdiq/properties.html">rats</a> 1366currently know more than <I>Homo sapiens</I>. Unfortunately PMMA, like most methoxylated 1367amphetamines, is potentially neurotoxic. In any case, it's completely unsustainable 1368in regular use, though its ortho-isomer, methoxyphenamine, was once UK-licensed 1369in tablet form as the bronchodilator Othoxine. PMMA itself is a potent drug with 1370a very low therapeutic index: the combination of serotonin-release and MAO-A inhibition 1371integral to its entactogenic profile makes it hazardous in overdose. In general, 1372taking MAO-inhibiting agents with anything serotonergic is normally contraindicated 1373because of the <a href="https://www.mdma.net/toxicity/moclobemide.html">risk</a> of the <a href="https://www.mdma.net/serotonin/serotonin-syndrome.html">serotonin 1374syndrome</a>. <P> 1375 1376 1377 PMMA's reduced 1378dopamine-releasing action makes it less "abusable" than other family members with 1379overlapping psychostimulant effects. Yet rather than scorning the <a href="https://www.utilitarianism.com/pleasureprinciple.htm">pleasure 1380principle</a> by seeking to minimise drug-induced reward, it might instead be 1381more rational to design safer, benignly addictive lead compounds that maximise 1382the user's well-being in lastingly empathetic, entactogenic and socially responsible 1383ways. Well-designed (or serendipitously rediscovered) empathetic euphoriants can 1384trigger socially responsible happiness. This is the distinctively E-like happiness 1385that inspires love, nurturance and understanding rather than egotism and dominance 1386behaviour. It's hard to imagine that any such futuristic love-drugs won't be "abusable" 1387too. But if a drug isn't remotely rewarding or habit-forming, then it probably 1388isn't any good. In the immortal words of <a href="https://www.utilitarianism.com/bentham.htm">Jeremy 1389Bentham</a>... <blockquote> <I>"Nature has placed mankind under the government 1390of two sovereign masters, pain and pleasure...they govern us in all we do, in 1391all we say, in all we think: every effort we can make to throw off our subjection, 1392will serve but to demonstrate and confirm it."</I><br> <br></blockquote>Alas application 1393of means-ends rationality is rarely the norm in drug-policy debate or in psychiatric 1394medicine. Nor is the pursuit of happiness undertaken much more rationally elsewhere. 1395Thus we continue with Rube-Goldbergish efforts to improve our well-being via environmental 1396scene-shifting - with mixed success. <P> 1397 1398 1399 Of 1400course the biological route to nirvana has its share of pitfalls too; and MDMA 1401is merely one of its most alluring seductions. Seekers of sustainable ecstasy 1402would be rash to fetishise any particular drug or family of pharmacological tools 1403- however magnificent their acute action on the user. For what matters, presumably, 1404is the otherwise inaccessible modes of experience such agents can unlock in the 1405mind/brain - and ways to sustain them - not the chemical structure of the agent
1406that happens first to disclose their existence. "All science is either physics 1407or stamp-collecting", Rutherford provocatively once proclaimed; and if some organic 1408compounds didn't have the potential to unlock the doors to the kingdom of heaven, 1409then Rutherford might have been right. As it is, school chemistry-lessons and 1410standard textbooks rarely set young imaginations ablaze. They might conceivably 1411do so if the <I>PiHKAL</I>-inspired compounds they ought to contain evoked the 1412magical experiences their structures should ignite. Yet even the most astonishing 1413centrally active compounds are only research tools or therapies, not sacraments. 1414At least until we can <a href="https://www.wireheading.com/riley-day/index.html">genetically</a> enrich the human mind/brain, no drug or research 1415chemical, nor indeed any irritation of the body's surface sensory transducers 1416by the environment, can do more than <i><a href="https://www.huxley.net/organic.htm">select</a></I> 1417from a pre-existing menu of brain-states composing the subject's mind/virtual 1418world. In this sense, we're trapped. <P> 1419 1420 Fortunately 1421there is an escape-route; the false prison can be transcended. Within a few decades, 1422the insertion of entirely new genes and variant alleles into our genome promises 1423to revolutionise our stunted Darwinian minds. Novel neurally-expressed polypeptide 1424sequences should disclose modes of experience hitherto unknown. The creation of 1425genetically enriched neurons should allow the exploration of multidimensional 1426search-spaces of consciousness which we presently lack the molecular wetware to 1427imagine or even name. No psychoactive drug currently gives access to these hypothetical 1428state-spaces. Such modes of consciousness have been barred to us by natural selection. 1429They either diminished their user's Darwinian fitness or would have entailed crossing 1430gaps in the evolutionary fitness landscape to get there. Whereas merely E-like 1431states are normally inaccessible because their owners would get eaten or outbred, 1432these unDarwinian modes of consciousness are quite possibly orthogonal to anything 1433accessible today within our existing mental architecture. Each new state-space 1434may be as different from the others as is sound from vision, or volition from 1435cognition or emotion. The differences in gene-expression profile between neurons 1436mediating the experience of, say, colour, or disgust, or humour (or being loved-up) 1437may strike us as subtle. Yet the subjective differences in texture ("what it feels 1438like") that their respective post-synaptic intracellular cascades generate are 1439clearly spectacular. Who knows what else is accessible from Nature's psychoactive 1440library by means of even "trivial" molecular genetic tweaks to our nerve cells? 1441Disparate new categories of experience, and hopefully revolutionary conceptual 1442schemes to navigate them, are presumably waiting to be unlocked just by inserting 1443new sets of neurological instructions. Unfortunately we lack any God's-eye taxonomy 1444of consciousness that might let us act like physicists and "carve Nature at the 1445joints". The lack of an overall map, or even the ghost of a theory of consciousness 1446to guide us, makes it impossible to place MDMA, or the spectrum of altered experience 1447disclosed by psychedelic amphetamines, within any adequate scheme of classification. 1448"Empathogen", "entactogen", "entheogen", and "psychedelic" are provisional and 1449theoretically ill-motivated terms. A mature psychoactive taxonomy will need to 1450be formulated relative to the architecture of particular phenotypes of mind, not 1451the structure and pharmacology of the molecular probe alone. Alas the results 1452of animal "drug discrimination studies" are no substitute for explanatory depth. 1453In practice, today's psychonauts are reduced to describing the subjective effects 1454of psychoactive drugs by contrasting them with their "normal" states of being. 1455Inevitably this is all a bit lame. In retrospect, today's entire dreaming and 1456waking consciousness may prove to be only minor variants on a theme whose motif 1457can't be grasped from within. <P> 1458 1459 1460 Needless 1461to say, the genetic choices, varieties of drug habit and modes of consciousness 1462of our <a href="http://www.transhumanism.com/" target="_blank">post-human</a>
1462 descendants are 1463a matter for <a href="https://www.mdma.net/alexander-shulgin/21stc.html">conjecture</a>. 1464We've barely begun to ring the changes within the state-space of consciousness 1465we've got. In order to replicate and sustain the family of MDMA-like magical states 1466safely and reliably, it's necessary first to find the specific neurochemical signature 1467of the family of enchanted states we're targeting. Thus by using, for example, 1468transgenic receptor-knockout "animal models", SPECT (Single-Photon Computed Tomography), 1469<a href="https://www.mdma.net/brain/index.html">PET</a> (Positron Emission Tomography) 1470and MRI (Magnetic Resonance Imaging) scans, quantitative EEG with dense-mapping 1471electrode arrays, antisense regulation of protein expression, and pre-treatment 1472with other pharmacological ligands that activate or antagonise or act as inverse 1473agonists at particular subtypes of receptor in the brain, it should be possible 1474for <a href="https://www.bltc.com/">ideologically</a> committed bioscientists to discover 1475what is crucial - and what's unwanted or inessential - to MDMA's psychological 1476and physiological effects. Once the E-like signature is established, neuroscientists 1477can then work how to mimic, refine and extend its magic, even if sustainable ecstasy 1478is only a staging-post on the route to a richer biochemistry ahead. <P> 1479 1480 1481 First,
1482however, MDMA's acute adverse side-effects i.e. teeth-grinding ["<a href="https://www.mdma.net/bruxism/index.html">bruxism</A>"], jaw-tension 1483["trismus"], loss of coordination ["ataxia"], eye-wiggling ["nystagmus"], profuse 1484sweating ["diaphoresis"], nausea, appetite-suppression, tachycardia, dry mouth, 1485<a href="https://www.mdma.net/hyperthermia/mechanisms.html">hyperthermia</a> or 1486idiosyncratic reactions to MDMA need to be eliminated and not just minimised. 1487The really nasty stuff - <a href="https://www.mdma.net/toxicity/liver.html">hepatotoxicity</a>, 1488<a href="https://www.mdma.net/cardiovascular/heart.html">cardiac</a> arrhythmias, 1489<a href="https://www.mdma.net/hyponatraemia/index.html">hyponatremia</a>-induced 1490cerebral and pulmonary edema (caused by drinking too much water), rhabdomyolysis 1491(the breakdown of skeletal muscle), and disseminated intravascular coagulation 1492(inappropriate blood-coagulation leading to severe bleeding) are statistically 1493very rare. MDMA-induced incidence of these syndromes was apparently unknown in clinical practice prior to the drug's legal proscription. However, not all the problems of MDMA use can be blamed 1494on Prohibition and the lethal mix of ignorance and <a href="https://www.opioids.wiki/heroin/heroin-inc.html">criminality</a> 1495it spawns. Even <a href="https://www.mdma.net/ecstasy/purity.html">pure</a>, low-dose MDMA does not suit everybody. In the era of pre-<a href="https://www.biopsychiatry.com/genegenome.htm">genomic</a> 1496medicine, atypical reactions to any drug at all should be expected. Conversely, 1497with adequate medical research the mildest bad experience on MDMA should be preventable. 1498<P> 1499 1500 Much more speculatively, 1501the use of personalized somatic gene-therapy may enable future scientists of the 1502mind, or unabashed hedonists, to sustain an otherwise neurotoxic drug regimen 1503in safety. For instance, <a href="https://www.mdma.net/zinc/index.html">transgenic</a> 1504mice carrying the sequence of the human CuZn superoxide dismutase enzyme are resistant 1505to MDMA-induced serotonergic damage. Ideology aside, humans can benefit from genetically 1506enhanced neuroprotection no less than intoxicated rodents. If ever we wish to 1507adopt a potentially life-enhancing but otherwise hazardous drug-regimen indefinitely, 1508then one option may be to protect ourselves by inserting new genes or new alleles 1509into our legacy genome. Or we may simply induce the overexpression of endogenous 1510antioxidant enzymes already coded for. We're already on the brink of tailoring 1511our <a href="https://www.biopsychiatry.com/pharmacogenomics.htm">drugs</a> to our 1512genes, but in principle we can tailor our genes to our drugs. Or we may choose 1513to design, insert, and switch on and off as desired a suite of structural and 1514regulatory genes for whatever life-enriching chemical exotica (or <a href="https://www.mescaline.com/misc/index.html">old 1515favourites</a>) we seek to enjoy. The modes of experience they generate may thereby 1516become available, as it were, on tap. Nature uses lateral gene transfer; and rationally, 1517so can we. Or by contrast, it's possible some or all genetically enriched post-humans 1518may shun adulterants of their beautiful forms of consciousness altogether. If 1519one's soul has been purified, why defile it? 1520 1521 1522<P> To 1523suppose that we might opt deliberately to micromanage even a subset of the thousands 1524of neurally active genes of one's genome, and intervene to regulate their complex 1525post-transcriptional editing, sounds far-fetched, even as the <a href="https://www.paradise-engineering.com/biotechnology/index.html">biotech revolution</a> 1526gathers pace. The prospect that we might personally choose to enrich our genetic 1527repertoire from an ever-expanding library of newly-created DNA sequences, and 1528an ever vaster neuroactive <a href="https://www.biopsychiatry.com/proteomics.htm">proteome</a>, sounds still more remote. Could we really 1529cope with such an enlarged freedom of choice? In practical terms, and perhaps 1530surprisingly, yes. Sustainable E-like consciousness is just one option among myriad flavours of sentient existence. Radical enhancements of, say, the sorts of user-friendly visual interface 1531we rely upon to interact with our PCs today can potentially be exploited to manage 1532the neuroactive expression and regulation of one's individual genotype. End-user 1533ignorance of the low-level molecular machinery is fully compatible with everyday 1534expertise acquired in managing the kinds of consciousness one's genes code for 1535- and mastering the types of mind/virtual-world these genes express. Thus the 1536non-specialist user of genetic management software could, in principle, be shielded 1537from the complex chemical minutiae of what is happening many virtual layers of 1538complexity below, just as most PC users today wouldn't recognise machine code 1539if it bit them on the nose. <P> 1540 1541 1542 Pessimists 1543might argue that the opportunity for such life-transforming manipulations will 1544be solely the privilege of a rich elite. This anxiety is (probably) misplaced. For the 1545time-lag between the introduction of a new technology and its diffusion to the 1546population at large has been progressively shrinking. It took perhaps 50 years 1547to democratise the radio; some 20 years for the TV; around 10 years in the case 1548of the PC; and even less for the mobile phone. With information-based products, 1549the time-lag effectively collapses. Thus the gap between an expensive software 1550release in <a href="http://www.microsoft.com/" target="_blank">Redmond</a> and its availability 1551to the population of Thailand is perhaps a few hours. Irritating bottlenecks notwithstanding, 1552information is cheap. Technically, the "counterfeit" generic version is in no way inferior 1553to the brand-name product. In a mature information-based society, "scarcity" is 1554a far more elusive concept than in the era of material commodities. On this analysis, 1555the resources of, for instance, tomorrow's domestic quantum computers may be harnessed 1556anywhere and everywhere to more humanly empowering pursuits than the factoring 1557of thousand-digit numbers that so excites contemporary cryptographic theorists. 1558A good place to start will be simultaneously screening an unimaginable multitude 1559of alternate histories of gene- and drug-combos in search of promising leads for
1560one's personal development program. The friendliest, voice-activated, most visually 1561compelling user-interfaces that creative designers can build may make seizing 1562control of one's destiny from a legacy genome a less daunting challenge than it 1563seems today. This doesn't mean we won't need all the help we can get in mastering 1564the awesome software tools soon available to personalise our own genome and drug-regimen 1565of choice. But choosing who and what we want to be should <i>feel</I> exhilarating 1566rather than intimidating. 1567 1568 <P> In 1569this optimistic scenario, a product-pipeline of better, faster, cheaper and safer 1570designer-drugs and drug-and-gene-combos should in principle be accessible to everyone 1571within 15-20 years. Sustainable E-like empathogen-entactogens may become as familiar 1572as <a href="https://www.opioids.wiki/heroin/heroinhistory.html">aspirin</a>; much safer 1573in overdose; and far more ubiquitous. The design of E-like hugdrugs, lovedrugs 1574and euphoriants, and perhaps later the genetic programming of E-like waking consciousness, 1575could be just the beginning of a whole new genetic and chemical cornucopia for 1576mature post-Darwinian life. For now, certainly, the prospect of a loved-up world 1577reads like overheated science-fantasy. In practice, such predictions may prove 1578too tame to be realistic. <P> 1579 1580<a name=ecstasymagic></a> <br><h3>The molecular machinery of magic</h3> 1581 1582<P> 1583 Lifelong ecstatic wonderpills 1584and genetic self-mastery are at best some way off. So which ingredients of MDMA's 1585primal magic are most worth mimicking pharmacologically in the near-term future? Preventing 1586tolerance, promoting safety, and indefinitely extending duration are vital. Yet 1587how desirable is inducing more or less euphoria, more or less calmness or behavioural 1588activation, purer empathogenic or entactogenic action, and a greater or lesser 1589hint of trippiness? 1590 1591<P> Pre-treatment 1592studies with receptor antagonists indicate that dopamine D2 antagonists such as 1593<a href="https://www.mdma.net/mdma/dopamine.html">haloperidol</a> (Haldol) attenuate 1594MDMA's positive hedonic effects; <a href="https://www.biopsychiatry.com/5ht2a.html">5-HT2A 1595antagonists</a> like <a href="https://www.mdma.net/ketanserin/index.html">ketanserin</a> 1596suppress MDMA's residual psychedelic activity; and <a href="https://www.biopsychiatry.com/ssris.html">SSRIs</a> like <a href="https://www.mdma.net/mdma/citalopram.html">citalopram</a> (Celexa / Cipramil, 1597the most selective of the SSRIs) diminish if not abolish the full spectrum of 1598MDMA's psychoactivity. Drug discrimination studies performed on captive rodents 1599may overlook certain subtleties of the MDMA experience. Intriguingly, in mice at least, the behavioural and physiological effects of MDMA are selectively antagonised by 1600the plant alkaloid <a href="https://www.mdma.net/nantenine/index.html">nantenine</A> (9,10-methylenedioxy-1,2 dimethoxyaporphine). Nantenine is "antiserotonergic" and an alpha1-adrenoceptor antagonist; the effects of nantenine on ecstatic human subjects are unknown. But on present evidence, 1601it's primarily a combination of enhanced <a href="https://www.mdma.net/oxytocin-release/oxytocin.html">oxytocin</A> release and the <a href="https://www.mdma.net/euphoria/comparisons.html">interplay</a> between the serotonergic and dopaminergic systems that underlies MDMA's discriminative stimulus effects/sublime magic. 1602 1603<P> The 1604full story is complex and still poorly understood. As the user "comes up", serotonin 1605released into the synaptic cleft activates multiple serotonin receptor <a href="https://www.biopsychiatry.com/5-ht.html">subtypes</a> 1606(5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7), and subpopulations (most 1607notably, 5-HT1B, 5-HT2A and 5-HT2C). The hierarchy of their relative contributions 1608to the <a href="https://www.mdma.net/misc/subjective.html">subjective</a> and behavioural effects of MDMA use may shift with increasing 1609dosage and the course of the trip. Several of these serotonin receptor subtypes 1610have functionally opposing roles, notably the effects of <a href="https://www.mdma.net/5-ht1a/index.html">5-HT1A</a> 1611and <a href="https://www.mdma.net/5-ht2/receptors.html">5-HT2C</a> receptor agonism 1612on anxiety. As well as inducing a synaptic flood of serotonin, taking MDMA <a href="https://www.mdma.net/dopamsero.htm">indirectly</a> 1613induces the release of extra dopamine in the mesolimbic reward centres. Activation 1614of the serotonin 5-HT1B and 5-HT2A receptors leads to an increase in the vesicular 1615release of dopamine. Dopamine levels are also increased by reuptake inhibition. 1616In addition, dopamine synthesis is increased and turnover reduced. Increased synaptic 1617availability of dopamine in turn inhibits glutamate-evoked firing in the nucleus 1618accumbens. Dopamine released in the shell of the nucleus accumbens inhibits the
1619firing of <a href="https://www.biopsychiatry.com/gaba/index.html">GABA</a>ergic 1620medium <a href="https://www.biopsychiatry.com/medium-spiny.htm">spiny</a> projection 1621neurons. Inhibited excitability of the spiny projection neurons in the <a href="https://www.biopsychiatry.com/rostralshell.htm">rostral</a> shell of the <a href="https://www.biopsychiatry.com/nucleus-accumbens.htm">nucleus accumbens</a> - whether it's mediated by dopamine, glutamate antagonists or mu opioid agonists - is the neurological signature of euphoric bliss, whatever its guise. 1622 1623 1624<P> On MDMA, there's 1625much more going on as well. MDMA induces the release of <a href="https://www.mdma.net/toxicity/noradrenaline.html">noradrenaline</a> (norepinephrine), 1626and inhibits its reuptake. MDMA also triggers the enhanced release of <a href="https://www.mdma.net/mdma/mdmaacety.html">acetylcholine</a> in the striatum and prefrontal <a href="https://www.mdma.net/acetylcholine/index.html">cortex</a> via serotonin 5-HT4 and dopamine D(1) receptor mechanisms. Taking MDMA activates the poorly understood <a href="https://www.mdma.net/sigma-receptors/index.html">sigma(1) receptors</A>, contributing to its locomotor stimulant action. The role of MDMA in activation the cannabinoid <a href="https://www.mdma.net/cannabis/cb1-receptors.html">CB1</a> receptors to modulate its rewarding action is poorly understood. MDMA exerts (weak) binding to the alpha-2 adrenergic and histamine H1 receptors; 1627this binding contributes in <a href="https://www.mdma.net/tdiq/index.html">unknown</a> 1628degree to behavioural stimulation. Activation of the noradrenaline system causes 1629an acute elevation of <a href="https://www.mdma.net/cardiovascular/index.html">blood 1630pressure</a>. Additionally, taking MDMA increases plasma cortisol, <a href="https://www.mdma.net/prolactin/index.html">prolactin</a>, 1631and <a href="https://www.mdma.net/dhea/index.html">dehydroepiandrosterone</a> (<a href="https://www.biopsychiatry.com/dhearev.htm">DHEA</a>) and <a href="https://www.mdma.net/aldosterone/index.html">aldosterone</a> secretion. MDMA use alters the expression of several proteins involved in <a href="https://www.mdma.net/pharmacology/neuropharmacology.html">GABA</a> transmission. 1632To thicken the plot further, MDMA triggers the release of hypothalamic <a href="https://www.mdma.net/misc/argininevasopressin.html">arginine-vasopressin</a> 1633and <a href="https://www.oxytocin.wiki/cuddle-hormone/index.html">oxytocin</a> 1634(the "cuddle hormone"). These hormonal changes may influence some of MDMA's psychological 1635effects. But the current consensus is that enhanced serotonin and dopamine release 1636are crucial to the magic, even though they don't explain it. 1637 1638 1639<P> 1640The serotonin system is uniquely complex. A whistlestop tour can't do it justice. 1641The existence of the serotonin <a href="https://www.biopsychiatry.com/serotonin/">molecule</a> 1642in Nature long predates the brain; serotonin is found in both the plant and animal kingdoms. 1643However, the effects exerted by a neurotransmitter on the post-synaptic membrane 1644aren't determined by the chemical itself, but rather by the structure of the post-synaptic 1645receptor subtypes to which it binds. Our serotonin-producing neurons belong to 1646a phylogenetically ancient neurotransmitter system. In the vertebrate CNS, serotonin-producing 1647neurons regulate <a href="https://www.biopsychiatry.com/aggres5ht.htm">aggression</a>, impulse-control, mood, anxiety, <a href="https://www.biopsychiatry.com/5htrecep.htm">cognition</a>, temperature, appetite, 1648circadian rhythms, sexual activity, sleep, sensorimotor integration, sensitivity 1649to <a href="https://www.mdma.net/rats/antipain.html">pain</a>, emotional resilience and <a href="https://www.biopsychiatry.com/lovesero.htm">romantic 1650love</a>. Serotonin entering the axonal vesicles is released over time in response to action potentials by exocytosis into the 1651synaptic cleft, the narrow gap 10-20 nm across between pre- and post-synaptic 1652neurons. Seven distinct 1653families of serotonin neuronal receptors have been isolated; 14 sub-populations 1654of G-protein-coupled receptors and one family of ligand-gated ion channels (the 1655<a href="https://www.mdma.net/5-ht3/index.html">5-HT3</a> receptor) have been cloned. 1656Distribution, density and regulation of the serotonin receptors vary in different 1657areas of the brain. So does both the affinity of serotonin for its different receptor 1658subtypes and the effects of serotonin agonists on second-messenger systems. O
1658nly 1659a few hundred thousand of the 100 billion or so <a href="https://www.biopsychiatry.com/newbraincell/index.html">neurons</a> 1660in the brain manufacture serotonin. The serotonergic cell bodies are confined 1661to the raphé area in the brainstem, but their projections extend to almost all 1662areas of the brain and spinal cord. Most notably for E-users, serotonergic projections 1663innervate the dopaminergic nigrostriatal and mesocorticolimbic circuits. The serotonin 1664system has co-evolved with dopaminergic projections in the course of <a href="https://www.primates.com/classification/">primate 1665evolution</a>. Amongst many other roles, the serotonin system helps to regulate 1666a lifetime spent in complex social hierarchies where more ancient fight-or-flight 1667reactions have been offset by the need for an increasingly complex cognitive, 1668emotional and behavioural response. This unique signalling complexity of the serotonin 1669pathways and their multiple receptors ensures we can now be (un)happy in more 1670ways than ever before. 1671 1672 1673<P> The 1674serotonin/5-hydroxytryptamine molecule itself is an indole amine synthesized from 1675the essential amino acid <a href="https://www.biopsychiatry.com/5-htp.html">L-tryptophan</a> through the intermediate <a href="https://www.biopsychiatry.com/5-htp.htm">5-hydroxytryptophan</a>. 1676Although some serotonin is present in the cytoplasm of serotonergic cell bodies 1677and nerve terminals, most serotonin in the axonal terminals is sequestered in 1678small membrane-bound sacs, i.e. the synaptic vesicles. This prevents the neurotransmitter 1679from being metabolised by the enzyme <a href="https://www.rasagiline.com/mao.htm">MAO</a>. Serotonin is metabolised, mainly by MAO-type A, 1680into the inactive metabolite 5-hydroxyindoleacetic acid (<a href="https://www.mdma.net/serotonin/5-hiaa.html">5-HIAA</a>). Numerous studies 1681have shown self-destructive <a href="https://www.biopsychiatry.com/violence.htm">violence</a>, 1682aggression, poor impulse-control, reduced social status, <a href="https://www.biopsychiatry.com/serotonin-suicide.htm">suicide</a>, 1683and some types of depression are associated with low concentrations of cerebrospinal 1684fluid 5-HIAA. Consequently, these conditions are often conceived as disorders 1685of "low serotonin function". Firing of the serotonin neurons causes exocytosis, 1686a rapid calcium-dependent process of neurotransmitter release. Depolarisation 1687of the axon induces opening of voltage-sensitive calcium channels; the resultant 1688calcium influx causes synaptic vesicles to fuse with the plasma membrane, where 1689they empty their load of serotonin into the synaptic cleft. In the synapse, serotonin 1690exerts an action on both pre- and post-synaptic receptor sites. Extracellular 1691serotonin is then normally taken back up into the serotonergic neuron via the 1692highly efficient presynaptic transport pump. The structure of the transporter 1693protein determines how it couples ion gradients to substrate transport in ways 1694that still need to be clarified. <P> 1695 1696 1697 1698Whatever the precise details, taking MDMA causes a remarkable role-reversal of 1699normal transporter function. The MDMA molecule binds with high affinity to the 1700serotonin transporter and enters the presynaptic axon terminal. Current theory 1701suggests that MDMA causes serotonin release via a diffusion exchange mechanism 1702involving the serotonin transporter, not by calcium-dependent exocytosis of the 1703serotonin-containing secretory vesicles. MDMA taken up into the presynaptic terminal 1704unbinds from the uptake transporter, triggering a reconfiguration of the transporter 1705so it binds to serotonin <I>inside</I> the cytoplasm of the nerve terminal. The 1706reconfigured transporter then reverse-pumps the newly-bound <I>intra</I>cellular 1707serotonin <I>out</I> of the cell, changes configuration again, dumps the serotonin 1708into the extracellular space, and then takes up MDMA once more, repeating the 1709process of depletion rather than recycling the neurotransmitter. 1710 1711 1712 <P> The 1713ensuing flood of serotonin in the user's synapses sets the MDMA magic rolling. 1714The neurotransmitter binds to multiple serotonin receptor subtypes. The subtypes 1715play different excitatory and inhibitory roles. So which receptor subtypes are 1716of most long-term therapeutic and social-recreational interest to a notional <a href="https://www.bltc.com/faq.html">paradise-engineer</a>? 1717Like the proverbial drunkard who searches for his lost keys only under a lamp-post 1718"because that's where the light is", investigators focus first on wherever they 1719can probe most easily. The receptor-based account below will soon be superseded
1720by something deeper. But it probably at least offers clues to the full story. 1721 1722 1723<P> Serotonin 5-HT1 agonists, sometimes 1724termed <a href="https://www.biopsychiatry.com/eltoprazine.html">serenics</a>, show 1725pronounced anti-aggressive properties. Aggressive behaviour is modulated in by 1726the 5-HT1B receptors in particular. The presynaptic 5-HT1B terminal autoreceptors 1727form a vital part of a feedback mechanism regulating serotonin synthesis and release. 1728Receptor <a href="https://www.biopsychiatry.com/5ht1b-ko.htm">knock-out</a> mice 1729lacking the 5-HT1B receptor are superficially normal in appearance, feeding patterns 1730and breeding behaviour; but they are ferocious, and highly reactive. Such knockout 1731mice are also unusually partial to alcohol and supersensitive to the effects of 1732cocaine, though these traits may reflect a compensatory enhancement of the dopamine 1733system rather than offer a direct pharmacological model of 5-HT1B receptor function. 1734By contrast, 5-HT1B receptor agonists such as the drug <a href="https://www.biopsychiatry.com/anpirtoline.htm">anpirtoline</a> 1735exert "serenic" effects. In "animal models", 5-HT1B receptor agonists diminish 1736alcohol-heightened aggression. Surprisingly, perhaps, there is substantial evidence 1737to indicate that some endogenous serotonergic pathways normally activate rather 1738than suppress motor output. Acute activation of 5-HT1B receptors is known to play 1739a role in MDMA-induced <a href="https://www.mdma.net/5-ht1b/index.html">locomotor</a> 1740activity: 5-HT1B agonists and MDMA show cross-tolerance, suggestive of a common 1741mechanism of action. 5-HT1B antagonists restrain the hyperlocomotion that rodents and clubbers 1742typically undergo on serotonin-releasers like MDMA. Perhaps with this crude 1743behavioural measure in mind, some "unlicensed" psychonauts try combining a supposedly 17445-HT1B-selective agonist such as the piperazine derivative <a href="https://www.biopsychiatry.com/tfmpp/index.html">TFMPP</a> 1745[1(3-trifluoromethylphenyl)piperazine monohydrochloride] with psychostimulants like <a href=benzylpiperazine/bzp.html>1-benzylpiperazine</a> (<a href="https://www.mdma.net/tfmpp/tfmpp-bzp.html">BZP<a>, "A2", "Frenzy", "Nemesis", "Flying Angel", "Altitude", etc) 1746to try and replicate the acute effects of taking MDMA. The effect can indeed be <a href="https://www.mdma.net/legal-x/index.html">E-like</a>; but results are mixed. It is now 1747known that TFMPP binds at multiple serotonin receptors with only limited selectivity. 1748Taken in the absence of a dopaminergic psychostimulant, TFMPP does 1749not feel akin to MDMA. Even combined with a dopaminergic, TFMPP's activation of the 17505-HT2C receptors makes some users feel anxious. The MDMA effect is hard to emulate: 1751MDMA is "a multifaceted jewel", not a cheap-and-cheerful euphoriant. 1752<a name=bzp></a> 1753<P> Some <a href=benzylpiperazine/piperazines.html>1-benzylpiperazine</A> users report that low-dose BZP is itself mildly E-like. So-called Party Pills, Social Tonics, Legal Party Drugs, Legal Herbal Highs and the like are marketed under numerous brand names, commonly mixed with various amino acids, vitamins, herbs and other agents designed to modulate the core BZP experience and minimise side-effects. Over 20 million such tablets and capsules have reportedly been sold in New Zealand, currently the world leader in BZP consumption and export. BZP use is now spreading world-wide. Consumption is mostly by <a href="http://www.benzylpiperazine.com/party-pills.html">clubbers</a> seeking a safer legal alternative to MDMA or amphetamines. BZP is relatively safe if used in moderation. No fatality has yet been recorded from BZP use alone. Many BZP-based preparations contain black pepper, a tribute not to BZP's wholesome natural origins (it's synthetic), but to discourage thrill-seekers who might otherwise snort rather than swallow it. The Social Tonics Association of New Zealand 1754(<a href="https://info.scoop.co.nz/Social_Tonics_Association/" target="_blank">STANZ</a>) has developed a Code of Practice to encourage responsible use. 1755Inevitably, the FDA has now <a href="http://www.benzylpiperazine.com/scheduled-usa.html">banned</a> BZP on grounds of <a href="http://www.benzylpiperazine.com/bzp.htm">
1755abuse potential</a>. In 2002 the drug was made Schedule 1 and its US users criminalised. Sale in the <a href="https://www.mdma.net/uk/bzp.html">UK</a> was banned in 2007. BZP was originally (1944) <a href="https://www.designer-drug.com/pte/12.162.180.114/dcd/chemistry/bzp.html" target="_blank">synthesised</a>, developed and manufactured by Wellcome as a potential anti-parasitic. Many piperazine drugs tend to paralyse intestinal parasites, allowing unwanted fauna to be flushed from the body. In the 1970s, BZP was investigated as an <a href="http://www.benzylpiperazine.com/antidepressant.html">antidepressant</a>. Used experimentally, BZP proved effective in reversing melancholic/retarded/hypersomnolent depression. The BZP analogue N-ben-zyl-piperazine-picolinyl fumarate was even briefly marketed in Hungary under the brand name <a href="http://www.benzylpiperazine.com/antidepressant-trelibet.html">Trelibet</a> as an antidepressant, though no clinical trials have been conducted into its long-term efficacy. Development was halted after BZP was discovered to have <a href="http://www.benzylpiperazine.com/profile.html">amphetamine-like</a> properties. Amphetamine, methamphetamine and BZP alike do indeed release dopamine from non-vesicular pools; and the subjective effects of high-dose BZP cross-generalise to amphetamines in drug discrimination studies. However, the subjective effects of BZP are more subtle than crude speed; BZP promotes the release and (to a lesser degree) inhibits the reuptake of the monoamine neurotransmitters dopamine, noradrenaline and serotonin with different relative potencies. BZP also acts as a relatively non-selective serotonin agonist. The affinity of BZP for the serotonin 5-HT2A receptor is quite low, so psychedelic effects are comparatively minor at sensible doses. 1756Taking BZP doesn't give rise to the inner serenity, emotional release or extraordinarily empathetic compassion of MDMA; but nor is BZP a classic dopaminergic power-drug like <a href="https://www.amphetamines.org/refs/index.html">amphetamine</a>. Moderate behavioural activation, sensory enhancement and a low-key euphoria are typical. Dry mouth, appetite suppression and insomnia are common adverse side-effects. Unlike, say, <a href="https://www.erythroxylum-coca.com/">cocaine</A>, BZP use tends to be self-limiting, a critical advantage for a recreational drug. Yet subjects who hope to replicate the full richness of the MDMA experience will be disappointed. 1757 1758 <P> There 1759are further subtleties in the way of replicating MDMA's acute effects; and even 1760more obstacles to sustaining the magic indefinitely. The serotonergic system has 1761both 5-HT1B <a href="https://www.biopsychiatry.com/autoreceptor.htm">autoreceptors</a> 1762and <a href="https://www.biopsychiatry.com/5ht1b.html">post-synaptic</a> 5-HT1B 1763heteroreceptors; they play different <a href="https://www.biopsychiatry.com/5ht1bantidep.htm">functional</a> 1764roles. 5-HT1B receptors acting as autoreceptors regulate serotonin release via 1765inhibitory feedback at the presynaptic terminals of serotonergic neurons; turnover 1766and release of serotonin are typically increased under conditions of acute <a href="https://www.biopsychiatry.com/5ht1bauto.htm">stress</a>. 17675-HT1B <I>hetero</I>receptors are located on the terminals of <I>non</I>serotonergic 1768neurons. Thus 5-HT1B heteroreceptors regulate the release of other neurotransmitters. 1769A single serotonin neuron can modulate different brain functions and multiple 1770cellular targets in virtue of the thousands of non-synaptic varicosities on its 1771axonal branches that project to multiple areas and neurotransmitter systems. 5-HT1B 1772receptors within the ventral tegmental areas (VTA), for instance, function as 1773heteroreceptors to inhibit GABA release. Since the GABA terminals in the VTA and 1774substantia nigra exert a tonic inhibitory influence on dopamine function, inhibition 1775of GABA by inhibitory 5-HT1B heteroreceptors leads to the disinhibition of dopamine 1776activity. Thus agents acting directly or indirectly as 5-HT1B agonists can cause 1777the release of dopamine in the striatum and nucleus accumbens. Indirectly again, 1778dopamine release is also regulated by 5-HT1B heteroreceptors within the glutamatergic
1779hippocampo-accumbens pathways. Regulation of 5-HT1B receptor function itself is 1780under the control of <a href="https://www.biopsychiatry.com/5ht1banx.htm">5-HT-moduline</a>, 1781an endogenous tetrapeptide that controls 5-HT1B receptor efficacy. 5-HT-moduline 1782is a so-called allosteric modulator. Allosteric modulators bind to a different 1783binding site from the natural agonist and can, potentially, circumvent the development 1784of tolerance. 5-HT-moduline is released from adrenal medulla in response to acute 1785stress. 5-HT-moduline plays a pivotal role in synchronising the serotonergic signalling 1786activity of the different terminals of individual neurons, coordinating their 1787effects on a variety of different cerebral functions. Rationally designed synthetic 1788drugs that recognize the 5-HT-moduline binding-site on the 5-HT1B receptors, and 1789act on the 5-HT1B receptors as allosteric modulators themselves, may potentially 1790exert long-term serenic, <a href="https://www.biopsychiatry.com/5ht1banx.htm">anxiolytic</a> 1791and mood-brightening effects by increasing serotonin release. 1792 1793 <P> In 1794general, however, care must be taken in describing serotonin 5-HT1 agonists as 1795"serenics", even if such agents induce a syndrome outwardly suggestive of inner 1796tranquillity. The demeanour that an animal exhibits after "serenic" administration 1797may indeed be submissive, passive and timid - in contrast to the fierce, assertive 1798and aggressive behaviour of 5-HT1B knockouts. Yet "serenity" tends to connote 1799an inner E-like peace that may be lacking - and not just in the unfortunate laboratory 1800rodent. In fact some so-called "serenics" may enhance <a href="https://www.biopsychiatry.com/serenanx.htm">fear/anxiety</a> 1801reactions: it's only their use in combination with dopamine-releasing euphoriants 1802that makes such agents especially interesting to the psychonaut. Indeed supersensitive 18035-HT1B autoreceptors are implicated in depression and obsessive compulsive disorder. 1804By introducing <a href="https://www.biopsychiatry.com/serotonin/gene.html">extra 1805copies</a> of the gene for 5-HT1B receptors into serotonin neurons, researchers 1806can breed passive and depressive rats that show signs of abject misery [i.e. "<a href="https://www.biopsychiatry.com/lhmorph.htm">learned 1807helplessness</a>" and "<a href="https://www.biopsychiatry.com/behavioral-despair.htm">behavioural 1808despair</a>"]. The syndrome of learned helplessness is associated with excess 1809production of 5-HT1B receptors that are churned out in greater profusion by the depressive 1810brain. This isn't to deny that <a href="https://www.biopsychiatry.com/5-ht1b1d.htm">5-HT1B 1811agonists</a> may have therapeutic potential, whether in <a href="https://www.biopsychiatry.com/mandep.htm">bipolar 1812disorder</a>, autism, alcoholism or disorders of impulse-control and aggression. 1813Thus the <a href="https://www.biopsychiatry.com/triptans.htm">triptans</a>, serotonin 18145-HT1B/1D receptor agonists, are clinically effective for treating <a href="https://www.biopsychiatry.com/migproph.htm">migraines</a>; 1815they can also curb <a href="https://www.biopsychiatry.com/zolmitriptan.htm">aggression</a>. 1816But 5-HT1B <i>ant</I>agonists and <I>inverse</I> agonists such as <a href="https://www.biopsychiatry.com/sb-236057.htm">SB-236057-A</a> 1817are under investigation for possible clinical use as long-term and relatively 1818fast-acting antidepressants. Acute 5-HT1B autoreceptor blockade can increase serotonin 1819release. Cognitive function is affected by their use too. Whereas 5-HT1B agonists 1820may adversely affect memory via inhibition of acetylcholine release in the hippocampus, 1821antagonists and <a href="https://www.nootropic.com/5ht1bmem.html">inverse agonists</a> 1822of the 5-HT1B receptor can improve the consolidation of learning. This simplified 1823outline of the neurobehavioural role of a single family of serotonin receptor subtype illustrates 1824how inducing lifelong E-like states - as distinct from "mere" raw bliss - is going 1825to pose a formidable technical challenge. In this case, the possible existence of 1826multiple subpopulations of 5-HT1B autoreceptors and heteroreceptors makes inadequate 1827selectivity of ligands even more of a problem, especially for seekers of precision-tools 1828rather than chemical coshes. <P> 1829 1830 1831 Whereas 1832serotonin 5-HT1B receptor knockout animals are aggressive by nature, <a href="https://www.bi
1832opsychiatry.com/5ht1a.html"> 18335-HT1A knockouts</a> are timid, anxiety-ridden creatures. Whereas serotonin 5-HT1B 1834receptors are found mainly on terminal processes, <a href="https://www.mdma.net/mdmaeff.htm">5-HT1A</a> 1835receptors are located solely on serotonergic nerve cell bodies within the dorsal 1836raphé nucleus. Intriguingly, 5-HT1A receptor density is <a href="https://www.mdma.net/5-ht1a/spirituality.html">reported</a> to be inversely correlated with susceptibility to spiritual experience, 1837opening up the possibility of genetically amplifying our capacity for <a href="https://www.entheogens.com/godgene.html">spirituality</a> beyond anything humanly accessible today: it may be premature to assume that our descendants will be secular rationalists. Density of the 5-HT1A autoreceptors is also <a href="https://www.biopsychiatry.com/serotonin/5ht1a-rheostat.html">inversely</A> correlated with the reactivity of the <a href="https://www.biopsychiatry.com/amygdala.htm">amygdala</a> to threatening stimuli. However, the role of the 5-HT1A receptors in MDMA's acute subjective effects 1838still isn't clear. Pretreatment with a serotonin (5-HT1A) receptor antagonist apparently reduces MDMA's pro-social effect, in <a href="https://www.mdma.net/5-ht1a/role.html">rats</a> at least. Taken over a prolonged period, selective 5-HT1A receptor agonists 1839typically exert a delayed-onset anxiolytic as well as (sometimes) a mood-brightening activity. 1840Their (modest) therapeutic efficacy relies on an adaptive neuronal response. Acute 1841activation of the presynaptic 5-HT1A receptor on the raphé nuclei tends to reduce 1842both the rate of firing of serotonin neurons and the corresponding release of 1843serotonin from the nerve terminals; chronic activation causes the receptors to 1844desensitise, leading serotonergic neuronal activity to rebound. Clinically, <a href="https://www.biopsychiatry.com/buspirone/index.html">buspirone</a> 1845(Buspar), a 5-HT1A partial agonist, is licensed for generalised anxiety disorder. 1846Similar agents like <a href="https://www.biopsychiatry.com/gepirone.html">gepirone</a> 1847(Ariza), <a href="https://www.biopsychiatry.com/flesinoxan.html">flesinoxan</a>, 1848<a href="https://www.biopsychiatry.com/tandospiron.htm">tandospirone</a> and <a href="https://www.biopsychiatry.com/ipsapdop.htm">ipsapirone</a> 1849are under investigation. Alas taking them doesn't remotely engender the extraordinary 1850sense of inner peace induced by MDMA. In rats at least, 5-HT1A agonists facilitate 1851male sexual behaviour, hypotension, increased food intake and produce hypothermia, 1852none of which are prominent sequelae of MDMA use. In general, 5-HT1A agonists 1853are well tolerated. But they may also on occasion induce dizziness, nausea, and 1854headaches, probably linked to their postsynaptic receptor action rather than presynaptic 1855anxiolytic effect. Buspirone itself is also a dopamine D2 antagonist, albeit a 1856weak one. This may explain why it's never been wildly popular with patients. It's 1857also very slow to work. Gepirone, on the other hand, allegedly lacks significant 1858activity at the dopamine D2 receptors. Gepirone acts as an agonist at the presynaptic 18595-HT1A receptors and a partial agonist at the post-synaptic 5-HT1A receptors. 1860Hopefully, gepirone will prove a clinically useful anxiolytic and antidepressant. 1861However, though 5-HT1A <I><a href="https://www.mdma.net/5-ht1a/index.html">antagonists</a></I> 1862reduce discrimination of MDMA in animal models, the role of 5-HT1A receptor activation 1863in MDMA's effects needs elucidation via more first-person experimental studies. <P> 1864 1865<P> Recent research from Sydney University neuropharmacologist Iain McGregor suggests that post-synaptic serotonin 5-HT1A receptors contribute to MDMA's acute pro-social action via the enhanced release of <a href="https://www.mdma.net/oxytocin-release/index.html">oxytocin</a>. Oxytocin in turn reduces activity and weakens connections in the fear-processing circuitry of the amygdala. MDMA activates post-synaptic 5-HT1A receptors of the paraventricular nucleus and supraoptic nucleus of the hypothalamus. The paraventricular nucleus and supraoptic nucleus contain <a href="https://www.oxytocin.wiki/refs/">oxytocin</a> neurons. Oxytocin is a nine amino-acid peptide hormone and neurotransmitter that promotes <a href="https://www.oxytocin.wiki/oxytoc/love-science.html">pair-bonding</a>, trust and social recognition. Commercially, oxytocin is marketed by <a href="http://www.verolabs.com/" target="_blank">Verolabs</a> as a spray: so-called trust-in-a-bottle: "Liquid Trust Spray - the first Oxytocin product, formulated to enhance people's trust in you!"[sic]. In future, MDMA analogues may <a href="https://www.mdma.net/poster-advert.html">conceivably</a> be marketed with similar restraint. MDMA typically causes its users to <a href="https://www.mdma.net/ecstasy-honesty.html">trust</a> each other to an exceptional degree, confiding intimate personal feelings and secrets they would never otherwise share. Such drug-induced intimacy may partly be mediated by an increased release of oxytocin via MDMA-activated 5-HT1A receptors. Co-administration of MDMA and an oxytocin antagonist would test this hypothesis in humans. There are methodological problems with the use of rats as test subjects in this context; but the <a href="https://www.mdma.net/oxytocin-release/mdma-oxytocin.pdf" target="_blank">evidence</a> is suggestive. 1866 1867 1868<P> The MDMA molecule, especially 1869the dextrorotatory "+" isomer, has only a low affinity for the serotonin <a href="https://www.mdma.net/ketanserin/index.html">5-HT2</a> receptor. 1870This is why taking the drug within the normal dose-range typically induces only 1871minor perceptual changes. If prompted, many Ecstasy users report altered time 1872perception, but any visual distortions are usually mild: the N-methyl group of 1873the MDMA molecule prevents it from fitting as comfortably into the 5-HT2A receptor 1874as does the trippier (-)-MDA enantiomer of its structural parent. Experiments 1875with human as well as non-human animals show a correlation between a drug's psychedelic 1876potency and 5-HT2A receptor binding affinity. Activation of the 5-HT2A receptors
1877is a <a href="https://www.biopsychiatry.com/5ht2hal.htm">prerequisite</a> of the "classic" 1878hallucinogenic effects exerted by tryptamine psychedelics such as LSD and phenethylamine 1879psychedelics like DOM. Conversely, 5-HT2A receptor <I>inverse</I> agonists act 1880as <a href="https://www.biopsychiatry.com/5ht2aantipsych.htm">antipsychotics</a>. Despite the low affinity of MDMA for the 5-HT2 receptor, pharmacological blockade or genetic knock-out of the <a href="https://www.mdma.net/5-ht2/5ht2b.html">5-HT2B</a> receptor abolishes MDMA-induced hyperlocomotion and serotonin release in the nucleus accumbens and ventral tegmental area of the brain. 1881<P> 1882 1883 1884<P> None of this neurobabble should 1885disguise the fact that psychedelia is still scientifically uncharted. It's often 1886too weirdly exotic for words. <a href="https://www.physicalism.com/">Materialistic neuroscience</A> has failed to close the 1887ontological gulf between neural porridge and consciousness - whether "ordinary" 1888or "altered" states. Some psychonauts, understandably enough, feel the neurobabblers 1889have lost the plot. Most of today's storytelling about altered states and the 1890chemistry of mind will doubtless seem no less archaic to our descendants than 1891the Greek humoral psychology of classical antiquity strikes the contemporary molecular 1892biologist. Yet fortunately for the engineering purposes of inducing sustainable 1893E-like bliss, we need manufacture only the <I>sufficient neural conditions</I> 1894for beautiful states of consciousness. We don't need a deep understanding of how 1895and why consciousness is generated (or alternatively, some <a href="https://www.hedweb.com/philsoph/chalmers.htm">philosophers</a> 1896allege, its fundamental immanence in the world). We can guess even less about 1897the possible altered states of consciousness of our redesigned successors. We 1898don't know whether the "<a href="https://en.wikipedia.org/wiki/Explanatory_gap" target="_blank">explanatory 1899gap</a>" between the physical facts and phenomenal mind can ever be closed. But 1900either way, our emotionally invincible descendants should be able to explore <a href="https://www.peyote.com/">entheogens</a>, 1901and map out even the most outlandish reaches of psychedelia, in safety. Unlike 1902us, our genetically enriched descendants may revel in the assurance that bad trips 1903are inconceivable, and psychological damage is impossible. This is because their 1904obnoxious molecular substrates will have been edited out. 1905 1906 <P> Alas 1907our own less robust minds are psychologically vulnerable to even "physically" 1908harmless psychedelics that aren't also euphoriants. Dual-action dopamine- and 1909serotonin-releasers like MDMA are the latter, though they aren't always harmless. 1910With MDMA, as with so many psychoactive drugs, very often "less is more". This 1911piety is easy to intone but hard to practise, especially when taking fast-onset 1912euphoriants. The lucidity of the entactogenic effect of MDMA may be especially 1913pronounced at low-to-moderate dosages. "Optimal" dosage of psychotropic agents 1914taken for "non-approved" purposes is most often empirically determined by the user 1915investigating what level induces maximal enjoyment. Yet the effects of lower, 1916"sub-optimal" dosages that more subtly modulate consciousness may be of greater 1917value for facilitating personal growth. Low-to-moderate dosage E-experience may be easier to 1918integrate into the rest of one's E-less life. Nonetheless at higher, quite possibly 1919neurotoxic doses of 200mg or so, MDMA can itself sometimes deliver psychedelic 1920euphoria, entheogenic rapture, and some very interesting exotica indeed. Alas 1921the unique effects of such doses [and likewise higher doses of other stellar phenethylamines] 1922cannot safely be investigated in depth until the neurotoxicity of MDMA's <a href="https://www.mdma.net/metabolites/toxic.html">metabolites</a> 1923and/or toxic free radicals can be prevented. <P> 1924 1925 1926 In 1927the meantime, if the user desires a completely clear sensorium, then perceptual 1928alterations might seem eliminable altogether, in principle, by taking only the 1929(+)-MDMA enantiomer rather than the standard <a href="https://www.mdma.net/misc/cocaine.html">racemate</a>. Sadly, pure (+)-MDMA is 1930scarce; it's also hard to prepare at home. Thus one unintended consequence of 1931scheduling MDMA has been to widen youthful exposure to psychedelia, albeit psychedelia 1932in its warmest and most gentle introductory guise. (-)-MDMA at normal doses is 1933only minimally active at the "psychedelic" 5-HT2A receptor owing to its (comparatively) 1934bulky methyl group. By contrast, <a href="https://www.mdma.net/mda.html">MDA</a> (which lacks it) is an all-in-one cocktail 1935that can be hallucinogenic as well as empathetic and slightly speedy. 1936 1937 <P> Alternatively, 1938if uncomplicated perceptual clarity is sought then a 5-HT2 antagonist such as 1939<a href="https://www.mdma.net/ketanserin/index.html">ketanserin</a> or the 5-HT2A 1940selective <a href="https://www.mdma.net/protect/mdl-11939.html">MDL-11939</a> might 1941help preserve total lucidity. 5-HT2A antagonists have the additional advantage 1942of preventing MDMA-induced <a href="https://www.mdma.net/hyperthermia/mechanisms.html">hyperthermia</a> 1943that exacerbates toxicity. Neurotoxic hydroxyl radical formation is temperature-mediated; 1944conversely, <I>hypo</I>thermia-inducing agents enhance neuroprotection. <P> However, 1945there are complications. Stimulation of the serotonin 5-HT2A receptors contributes 1946to the rewarding effects of MDMA, or at least plays a permissive role in <a href="https://www.bi
1946opsychiatry.com/5ht2a-dopamine.htm">dopamine</a> 1947release. So trying to eliminate perceptual alterations completely while retaining 1948the full-blooded E-magic may be difficult. MDMA is often reckoned a "serotonergic" 1949drug. Compared to amphetamine this is true: MDMA's affinity for the serotonin 1950transporter is greater, and its ratio of serotonin to dopamine release is higher, 1951than amphetamine. Even MDMA's extra release of dopamine partly depends on its 1952activation of the 5-HT2A receptors. But <a href="https://www.mdma.net/misc/fenfluramine.html">serotonin-releasing</a> 1953agents [e.g. the halogenated amphetamine appetite-suppressant <a href="https://www.mdma.net/pmma/deriv.html">fenfluramine</a> 1954(Pondimin)], taken on their own, aren't notably rewarding or entactogenic/empathetic, 1955at least at ordinary dosages. The enhanced release and reuptake inhibition of 1956dopamine is essential to MDMA's tendency to promote blissful well-being and to 1957colour its entactogenic-empathetic effect. 1958 1959 1960<P> Convergent 1961strands of evidence indicate that dopamine release is critical to the MDMA magic. 1962Dopaminergic activity in the brain and motor behaviour may be crudely interpreted 1963as under the inhibitory control of the serotonin system. Yet the multiple serotonin 1964pathways play functionally different roles. According to one hypothesis, the extra 1965serotonin released by MDMA stimulates 5-HT2A receptors located on inhibitory gamma-aminobutyric 1966acid (GABA) <a href="https://www.mdma.net/misc/subnig.html">striatonigral</a> neurons. 1967VTA dopaminergic neurons in the brain's reward centres are under continuous inhibition 1968by GABA. Stimulation of the 5-HT2A receptors inhibits these GABA neurons, thereby 1969allowing the <a href="https://www.mdma.net/dopamine/potentiation.html">disinhibition</a> 1970of dopamine biosynthesis. Post-E levels of dopamine in the mesolimbic reward circuitry 1971are far higher than would be explained by MDMA's relatively weak additional release 1972of dopamine via the uptake carrier. <P> 1973 1974 1975 Animal 1976drug discrimination studies, and the human behavioural evidence, tend to support 1977this dopaminergic account. Although some MDMA users prefer reflective tranquillity 1978and intimate group hug-ins, many loved-up clubbers opt to <a href="https://www.mdma.net/raves/dance.html">dance</a> for hours at raves 1979- a form of hyperlocomotion one would expect from Peruvian marching-powder rather 1980than a serotonergic agent. 1981 1982 1983 <P> However, 1984this account is still simplistic. The release of serotonin following an MDMA-induced 1985reversal of the reuptake pump results in a stimulation of the 5-HT1B receptors 1986and, at higher doses, increasingly of the 5-HT2A receptors as well. Such receptor 1987stimulation can trigger marked hyperactivity, especially in young MDMA users who 1988rave. At lower doses, MDMA-induced locomotor activity is caused mainly by the 1989released serotonin's preferential activation of the 5-HT1B receptor. This is because 1990serotonin has a somewhat higher affinity for the 5-HT1 receptors than the 5-HT2 1991receptors. The greater flood of serotonin in the synapses triggered by higher 1992doses of MDMA promotes locomotor activity via 5-HT2A receptor-mediated dopamine 1993stimulation as well. To complicate matters, MDMA may itself bind, albeit weakly, 1994to the 5-HT2A receptor. A further complicating factor is that MDMA-induced release 1995of serotonin stimulates the <a href="https://www.mdma.net/review/index.html">5-HT2C</a> 1996receptors. <a href="https://www.mdma.net/gaba/serotonin.html">Activation</a> of the 5-HT2C receptors serves to <a href="https://www.mdma.net/5-ht2/5ht2c.html">mask</a> 1997expression of MDMA-induced hyperactivity, sometimes evidently more effectively 1998than others. The various subpopulations of 5-HT2C receptor located on GABAergic 1999neurons in the ventral tegmental area and the substantia nigra tend to exert a 2000tonic inhibitory influence over the mesolimbic dopamine system. Thus 5-HT2C receptors 2001tonically inhibit dopamine release in the nucleus accumbens, mostly it seems in 2002virtue of their constitutive activity i.e. entering the activated receptor state 2003in the absence of an agonist. Other things being equal, activation of 5-
2003HT2C receptors 2004is anxiogenic, demotivating and generally unpleasant. Certainly the stimulant 2005effects of MDMA are greatly enhanced following treatment with a 5-HT2C antagonist. 2006Sustained antagonism of the 5-HT2C receptors might well we harnessed to intensify 2007the hedonic properties of long-lasting E-like consciousness. Less speculatively, 20085-HT2C antagonists such as <a href="https://www.biopsychiatry.com/agomelatine.htm">agomelatine</a> (Valdoxan) 2009are under investigation as potential clinical antidepressants. 2010 2011 2012 <P> As 2013usual, there are complications: all 5-HT2C receptors are not the same. Numerous 20145-HT2C receptor isoforms are produced as a result of <a href="https://www.biopsychiatry.com/5-ht2c.htm">RNA 2015editing</a>, and their individual roles in modulating the MDMA effect aren't properly 2016understood. In general, the receptor story illustrates at the molecular level 2017that being blissful isn't the same as being blissed out. To sustain empathetic 2018love, simply banishing all capacity for social anxiety isn't going to work. Specific 2019and selective 5-HT2C receptor antagonism may well prove a worthwhile goal; but 2020it's too early to say what the MDMA experience may gain or lose in consequence, 2021whether socially or subjectively. Empathy entails caring about others, not lacking 2022a care in the world. Thus the MDMA-induced disinhibition from social anxiety, 2023and the lowering of psychological defensive barriers, is radically distinct from 2024the sort of <a href="https://www.biopsychiatry.com/anxiolytics.htm">anxiolysis</a> 2025induced by SSRIs or the <a href="https://www.biopsychiatry.com/librium.htm">benzodiazepines</a> 2026- or indeed by <a href="https://www.biopsychiatry.com/alcop.htm">alcohol</a> or 2027<a href="https://www.opiates.net/">opiates</a>. With none of these drugs or drug 2028categories is a reduction in the user's social anxiety matched by an E-like upwelling 2029of empathy or sensitivity to the feelings of others - in fact quite the reverse. 2030There are subtleties of the MDMA experience that haven't yet been explored. <P> 2031 2032 2033 If acute serotonin-mediated enhanced 2034dopamine-release is indeed essential to the magic of MDMA, then a wide range of 2035safe long-acting dopaminergics are already on offer to augment any hypothetical 2036subtype-selective "serotonergic" therapies. Compared to our descendants, we're 2037probably all anhedonic. So some form of dopaminergic augmentation is a therapeutic 2038step in the right direction. "<a href="https://www.amphetamines.org/depression/dualdeficit.html">Dual-deficit</a>" 2039models of everyday E-less malaise are plausible; and they naturally invite dual-action 2040remedies. Clearly, <a href="https://www.mdma.net/dopser.htm">inhibition</a> of 2041glutamate-evoked firing in the nucleus accumbens is an ingredient of the E-magic: 2042it is known that firing-inhibition depends on both dopamine and serotonin release; 2043and this process is mediated by both dopamine and serotonin receptors. But beyond 2044these superficial generalities, working out how to replicate sustainably at the 2045molecular level the precise neurochemical signature of peak experiences will be 2046hard. Until the dawning of the era of wholesale genomic rewrites and true designer 2047babies, using a cocktail of subtype selective serotonin agonists and gentle dopaminergic 2048psychostimulants still looks like the easiest way to mimic and enhance the entactogenic-empathogenic 2049effect induced by MDMA-like compounds. However, there are many pitfalls in choosing
2050the right dopaminergic for the job. 2051 2052 2053<P> In 2054contrast with intracranial electrical stimulation, a direct chemical assault on 2055the hedonic treadmill rarely works. This failure is witnessed by the unsatisfying 2056and usually <a href="https://www.amphetamines.org/depression/crash.html">counterproductive</a> 2057effects of using catecholamine-depleting psychostimulants. Darwinian-era mood 2058and motivation is regulated via a multitude of indirect mechanisms of feedback-inhibition. 2059So it's worth reviewing how and why the substrates of human well-being are held 2060in check; and what can be done about it. First, an unavoidably fast-and-furious 2061tour of the <a href="https://www.biopsychiatry.com/rds.htm">dopamine</a> system 2062is in order. The CNS has three main dopaminergic pathways. They regulate movement, 2063hormonal secretion, and emotion. Each projects from dopaminergic cell groups in 2064the midbrain. <I>1)</I> The nigrostriatal pathways extend from the substantia 2065nigra pars compacta to the striatum. This pathway is critical to the control of 2066involuntary motor movement; its dysfunction is implicated in the tremor, rigidity 2067and akinesia of the "dopamine deficiency disorder" <a href="https://www.mdma.net/misc/antiparkinsonian.html">Parkinson's 2068disease</a>, and several other neuropsychiatric disorders such as <a href="https://www.biopsychiatry.com/tourettes-syndrome.htm">Tourette's 2069Syndrome</a>. <I>2)</I> The tuberoinfundibular system extends from the hypothalamus 2070to the pituitary gland. It's involved in prolactin- and growth hormone-secretion, 2071and the regulation of lactation and fertility. <I>3)</I> The mesocorticolimbic 2072pathway extends from the ventral tegmental area to the nucleus accumbens and the 2073medial prefrontal cortex. The mesocorticolimbic system is central to emotion, 2074motivation, willed action and, more subtly, the <a href="https://www.biopsychiatry.com/dopaminecog.htm">modulation</a> 2075of thought-processes. In crude terms again, dopamine is critical to sensorimotor 2076integration; appetitive behaviour of all kinds; the capacity to switch from one 2077course of behaviour to another; and the orchestration and activation of the motor 2078output system. Dopamine has also traditionally been described as the brain's "pleasure 2079chemical", cueing potentially (Darwinian) fitness-enhancing stimuli so they can 2080acquire control over an organism's behaviour. Certainly, consistent with the 2081dopamine theory of reward, electrically or pharmacologically stimulating microcircuits 2082in the <a href="https://www.biopsychiatry.com/rostralshell.htm">rostromedial</a> shell 2083of the nucleus accumbens produces intense pleasure in the absence of any goal-seeking 2084behaviour. But this formulation can be misleading. The mesolimbic dopamine system 2085mediates "<a href="https://www.biopsychiatry.com/dopamine.html">wanting</a>" more 2086than "<a href="https://www.opioids.wiki/red.html">liking</a>"; and its <a href="https://www.amphetamines.org/refs/">drug-induced</a> 2087or <a href="https://www.wireheading.com/brainstim/">electrical</a> stimulation 2088may increase incentive-salience rather than the raw intensity of pleasure itself. 2089Dopaminergic neurotransmission is critical to incentive-motivation and all forms 2090of purposeful behaviour. Dopamine levels tend to rise if one is anticipating a 2091rewarding event; and levels then tend to fall if the anticipated reward fails 2092to materialise. Couched in the language of psychology rather than neuroscience, 2093enhanced dopamine release in the pleasure centres imparts a sense of urgency, 2094significance and a feeling of <I>things-to-be-done</I>. The molecular substrates 2095of <a href="https://www.opioids.wiki/speedballs/index.html">pure pleasure</a> are still 2096elusive. 2097 2098 2099<P> At the cellular 2100level, the dopamine system doesn't quite rival the molecular, pharmacological 2101and functional diversity of the serotonin system; but the two "classic" types 2102of dopamine receptor (D1-like and D2-like receptors) have several subtypes and 2103alternate splice-forms. Further, the number of different messenger RNA and dopamine 2104binding sites substantially exceeds the five dopamine receptor genes of the human 2105genome, a diversity that reflects the genetic polymorphism and alternative splicing 2106events in normal dopamine gene-expression. However, each type of dopamine receptor 2107belongs to the superfamily of G-protein-coupled receptors that activates or inhibits 2108different forms of adenylyl cyclase inside the cell. Intriguingly, the presence 2109or absence of variant alleles of dopamine receptor subtypes and their signal-transduction 2110mechanisms is correlated with variants of human behaviour and personality. For 2111example, individuals with genotypes containing the seven-repeat allele of the
2112dopamine <a href="https://www.biopsychiatry.com/d4.html">D4</a> 16-amino acid repeat 2113polymorphism tend to exhibit the personality trait of "<a href="https://www.biopsychiatry.com/personality-genetics.htm">novelty-seeking</a>". 2114This trait is characterised by a tendency to impulsiveness, risk-taking, exploration, 2115excitability, and an optimistic mood, though alas not a loving, E-like temperament. 2116For better or worse, within a few decades prospective parents will be able to 2117select such alleles and their rationally redesigned enhancements when choosing the parameters of their 2118future offspring. Such naturally loved-up kids may prove more easily adorable 2119than today's Darwinian default-models. 2120 2121 2122<P> Like 2123the other catecholamine neurotransmitters, dopamine itself is synthesised from 2124the non-essential amino acid <a href="https://www.biopsychiatry.com/tyrosine.html">L-tyrosine</a>. L-tyrosine is transported across the 2125blood-brain barrier into the dopaminergic nerve cell. L-tyrosine is converted 2126to <a href="https://www.mdma.net/dopamine/dopa.html">L-dopa</a> by the enzyme tyrosine hydroxylase. L-dopa is then rapidly converted 2127to dopamine by L-amino acid decarboxylase. Next dopamine is sequestered in synaptic 2128vesicles by a <a href="https://www.mdma.net/dopamine/transporter.html">dopamine transporter</a>. At the synapse, the dopamine nerve terminal 2129displays high-affinity uptake sites. They rapidly terminate the action of the 2130neurotransmitter on the receptors if it isn't metabolised by the MAO or COMT enzymes. 2131Depending on concentration gradient, the dopamine carrier can transport dopamine 2132back into the nerve cell, recycling it as normal, or <a href="https://www.amphetamines.org/dopamine/reverse.html">alternatively</a>, 2133after a user has taken a classic amphetamine, the <a href="https://www.amphetamines.org/dopamine/reverse-transport.html">carrier</a> 2134can transport dopamine from the cell terminals into the synaptic cleft. In common 2135with amphetamine, MDMA inhibits the neuronal reuptake of dopamine, albeit more 2136weakly than <a href="https://www.mdma.net/mda/opticalisomers.html">MDA</a>. Further, 2137increased post-E administration activity of the serotonin 5-HT1B and 5-HT2A receptors causes 2138the dopaminergic neurons themselves to fire more rapidly. This higher impulse-frequency 2139causes increased dopamine-release via exocytosis of the dopamine-containing vesicles 2140in the normal manner. 2141 2142 2143<P> So what 2144leaves so many "normal" Darwinian people - who are neither <a href="https://www.biopsychiatry.com/dopdef.htm">clinically</a> 2145depressed nor loved-up on MDMA - comparatively anhedonic and <i>hypo</I>dopaminergic? 2146The dopamine neurotransmitter is under powerful homeostatic control. So is the 2147density and signal-transduction efficiency of the receptors to which it binds. 2148Feedback-inhibition of dopamine synthesis, dopamine release and spontaneous action-potential 2149generation in dopamine-producing cells is modulated by a variety of functionally 2150distinct dopamine autoreceptors that regulate membrane excitability. The dopamine 2151neurotransmitter itself functions as an end-product inhibitor of tyrosine hydroxylase, 2152the rate-limiting step in dopamine production. Dopamine plays this role by competing 2153with a tetrahydrobiopterin co-factor for a binding site on the enzyme. Dopamine 2154synthesis is also modulated by the rate of impulse-flow from the nigrostriatal 2155pathway. In addition, presynaptic dopamine receptors modulate the rate of tyrosine 2156hydroxylation; and most mesolimbic dopamine neurons possess cholecystokinin-autoreceptors 2157and neurotensin-autoreceptors that regulate dopamine function as well. Indeed 2158activity of the mesocorticolimbic dopamine system is regulated by multiple neuronal 2159pathways containing different neurotransmitters, notably serotonin, <a href="https://www.opioids.wiki/refs/">opioids</a>, 2160<a href="https://www.biopsychiatry.com/glutamategaba.htm">GABA</a> and <a href="https://www.biopsychiatry.com/glutamate.html">glutamate</a>. 2161Precisely what dopamine actually does in the all-important dopamine-sensitive 2162shell of the nucleus accumbens is unclear. The main effect of its release seems 2163to be the inhibition of the GABAergic medium spiny projection neurons (<a href="https://www.bi
2163opsychiatry.com/nucleus-accumbens.html">MSNs</a>). 2164These neurons come in two types. One subtype expresses dopamine D2 receptors and 2165enkephalin. This sort of GABAergic medium spiny cell projects from the nucleus 2166accumbens to the ventral pallidum. It is activated by "reward stimulation" of 2167the ventral tegmental area. The other subtype of GABAergic medium spiny projection 2168neuron co-expresses <a href="https://www.biopsychiatry.com/substance-p.htm">substance 2169P</a>, <a href="https://www.opioids.wiki/dynorphin/depression.html">dynorphin</a> 2170and dopamine D1 receptors. This subtype projects directly back to the ventral 2171tegmental area. It regulates motivation and pleasure, or our deficit thereof. 2172 2173 2174<P> So how can this cruel and 2175complex web of inhibitory <a href="https://www.biopsychiatry.com/nacc.htm">feedback</a> 2176mechanisms best be modified? If our aim were pure-and-simple cloud nine euphoria, 2177then better drugs to decrease glutamate and GABA currents in the critical medium 2178spiny neurons of the nucleus accumbens might be adequate - at least until new 2179genes and gene networks can be more readily inserted in the genome, and the regulation of old 2180ones improved. But well-controlled, high-functioning euphoria is more elusive 2181than mind-blowing rapture. Crude "natural" interventions to enrich dopamine function 2182aren't effective. For instance, some psychonauts, clubbers and alternative therapists 2183alike have explored taking free-form amino acid supplements of <a href="https://www.biopsychiatry.com/tyrosine.htm">L-tyrosine</a> 2184and L-phenylalanine in a bid to boost native dopamine levels or reanimate a drug-frazzled 2185brain. But tyrosine hydroxylase is normally saturated. So unlike tryptophan-loading 2186and/or 5-HTP-loading to increase neural levels of serotonin production, this "dopaminergic" 2187precursor strategy typically doesn't work. On the other hand, taking L-dopa <I>does</I> 2188increase synaptic dopamine levels. This is especially so when L-dopa is combined 2189(as in <a href="https://www.biopsychiatry.com/sinemet.htm">Sinemet</A> for Parkinsonians) with a peripheral decarboxylase inhibitor such 2190as carbidopa to prevent its metabolism outside the brain, At least for a minority 2191of "normal" subjects, taking L-dopa can be an effective motivator, libido-enhancer 2192and <a href="https://www.biopsychiatry.com/levdophi.htm">mood-brightener</a>. In 2193a more controlled setting, rodents engineered so they can't synthesize dopamine 2194initially develop quite normally, only to die miserably a few weeks after birth 2195following a failure to eat, drink or do very much in this world at all. Yet when 2196such dopamine knock-out mice are abundantly maintained on L-dopa, they can flourish. 2197Indeed L-dopa-maintained dopamine knock-out mice become hyperactive and sexually 2198vigorous. This manipulation has not yet been attempted in dopamine knock-out humans. 2199Augmentation should in any case be tried only <a href="https://www.mdma.net/dopamine/l-dopa.html">cautiously</a> and in controlled-release 2200preparations (e.g. Sinemet SR) since high levels of L-dopa may increase oxidative 2201stress. Whatever the mechanism, simply increasing raw dopamine levels <I>per se</I> is not enough. 2202For instance, an agent such as <a href="https://www.biopsychiatry.com/catecholdep.htm">alpha-methylparatyrosine</a> 2203that inhibits tyrosine hydroxylase, the rate-limiting enzyme in catecholamine 2204synthesis, might be expected to produce a state of <a href="https://www.biopsychiatry.com/melanbi.html">melancholic</a> 2205depression; but in non-depressives it doesn't reliably do so. This complicates 2206any simplistic <a href="https://www.biopsychiatry.com/nordopmono.htm">catecholamine-depletion</a> 2207theory of <a href="https://www.biopsychiatry.com/retard.html">retarded</a> depression. 2208Nevertheless, dopamine-releasing agents demonstrably tend to induce euphoria. By contrast, 2209dopamine receptor antagonists like <a href="https://www.mdma.net/dopamine/haloperidol.html">haloperidol</a> 2210are dulling and dysphoric. All the classical dopamine D2-blocking neuroleptics blunt will-power
2211and flatten emotion. Administering dopamine D2-blockers tends to induce apathy and anhedonia, 2212and ruins the MDMA magic. Nasty but instructive, such magic-prevention experiments 2213are an important pointer to what's needed to sustain the MDMA spectrum of consciousness. 2214It's known that <I>stimulation</I> of the dopamine D2-like receptor causes an increase 2215in phosphatidylinositol hydrolysis by activating enzyme phospholipase C. Enhanced 2216phosphatidylinositol hydrolysis is implicated in euphoric <a href="https://www.biopsychiatry.com/high.htm">mania</a>. 2217Conversely, the <a href="https://www.biopsychiatry.com/lithprot.htm">lithium</a> used 2218to treat "uncontrolled" euphoria inhibits the phosphatidylinositol second messenger 2219system and darkens mood in nondepressed "euthymic" people. Understanding the principles 2220behind the pharmacological induction of <I>controllable</I> non-stop euphoria 2221will be a first step on the route to designing lifelong variations of the subtler 2222forms of magic. <P> 2223 2224 2225 In the meantime, 2226dopamine <I>ant</I>agonists like <a href="https://www.amineptine.com/aminepvamisulp.htm">amisulpride</a> 2227(Solian) can be used at <I>low</I> doses preferentially to antagonise the synthesis-, 2228release- and impulse-modulating presynaptic dopamine <a href="https://www.biopsychiatry.com/amid2d3.htm">D2/D3</a> autoreceptors. Thus a regimen 2229of low-dose amisulpride may potentially enhance dopamine release and boost mood 2230and motivation, whereas many dopamine reuptake inhibitors [e.g. <a href="https://www.mdma.net/dopamine/vanoxerine.html">vanoxerine</a>, 2231<a href="https://www.bupropion.com/">bupropion</a>, <a href="https://www.nomifensine.com/">nomifensine</a>] 2232"adaptively" diminish the neuronal release of dopamine over time, even though 2233their action on reuptake inhibition increases the neurotransmitter's synaptic 2234availability. Unfortunately, pre-treatment with high doses of dopamine reuptake 2235inhibitors blunts MDMA-induced release of dopamine, though not to the same degree
2236as SSRIs blunt MDMA-induced release of serotonin. Other crude strategies to augment 2237dopamine function involve taking dopaminergic agents such as the dopamine agonists 2238<a href="https://www.biopsychiatry.com/pergolide.html">pergolide</a> (Permax) and 2239<a href="https://www.biopsychiatry.com/bromocriptine.html">bromocriptine</a> (Parlodel); 2240the potent, pro-sexual, long-acting D2 agonist <a href="https://www.biopsychiatry.com/cabergoline.htm">cabergoline</a> 2241(Dostinex); selective D2/D3 agonists such as <a href="https://www.biopsychiatry.com/pramipexole.htm">pramipexole</a> 2242(Mirapex) or <a href="https://www.biopsychiatry.com/pramropbi.htm">ropinirole</a> 2243(Requip); catechol-o-methyltransferase (<a href="https://www.biopsychiatry.com/comt.htm">COMT</a>) 2244inhibitors such as <a href="https://www.biopsychiatry.com/tolcapone.htm">tolcapone</a> 2245(Tasmar); selective MAO-B inhibitors such as <a href="https://www.selegiline.com/refs/index.html">selegiline</a> 2246(Eldepryl) or <a href="https://www.biopsychiatry.com/rasagiline.html">rasagiline</a> (Azilect); 2247<a href="https://www.biopsychiatry.com/adenant.htm">adenosine</a> 2A receptor antagonists; 2248and centrally active nicotinic receptor agonists. Oral, centrally-active dopaminergic 2249"pro-drugs" with higher bioavailability and fewer adverse side-effects are also 2250under investigation. But there are obvious problems. For instance, dopamine-release 2251promoting agents, if fast-acting and taken in the absence of anything subtype 2252selectively "serotonergic", may not induce serenely motivated well-being as distinct 2253from compulsive pleasure-seeking, thought disturbances or manic excitement. Any 2254tendency to cause uncontrolled dose-escalation is likely to cause toxicity, florid 2255psychoses and abuse. Regrettably, these worries about the "abuse-potential" of 2256<a href="https://www.amphetamines.org/refs/">psychostimulants</a> frequently generalise 2257in mainstream wisdom to an unwarranted fear of all "<a href="https://www.amineptine.com/">dopaminergic</a>" 2258antidepressants/mood-brighteners. 2259 2260 2261 <P> This 2262taboo against "excessive" well-being can have serious medical consequences. Even victims of <a href="https://www.biopsychiatry.com/melser.htm">melancholic</a> 2263or retarded depression are widely denied access to clinically <a href="https://www.nomifensine.com/refs/index.html">effective</a> 2264catecholaminergic antidepressants. This is one reason why so many remain depressed 2265or "partial responders"; another is <a href="https://www.opioids.wiki/index.html">opiophobia</a>. 2266MDMA itself rapidly banishes all kinds of depression, albeit not for long. In 2267spite of its relatively powerful indirect dopaminergic activity, MDMA is sometimes 2268likened in the media to the much more commonly prescribed selective serotonin 2269reuptake inhibitors; <a href="https://www.mdma.net/mdmafluox.html">fluoxetine</a> 2270(Prozac) was the first and most famous SSRI. In reality there are profound differences 2271between MDMA, the SSRIs and other "serotonergic" antidepressants. Like an SSRI, 2272MDMA occupies the serotonin transporter and prevents serotonin from binding, increasing 2273its availability in the synapse. However, MDMA is small enough to be taken up 2274by the serotonin reuptake transporter into the serotonergic cell. The serotonin 2275transporter pulls the MDMA molecule up into the axon, where its release from the 2276transporter allows the transporter to bind to intracellular cytoplasmic serotonin, 2277which it releases into the synapse before taking back more MDMA into the terminal. 2278Quite aside from their different molecular mechanisms of action, however, there 2279are striking differences in subjective effect between MDMA and "serotonergic" 2280centrally active psychiatric medicines. Clinically-licensed SSRIs [<a href="https://www.biopsychiatry.com/fluoxetine/index.html">fluoxetine</a>/Prozac; 2281<a href="https://www.biopsychiatry.com/sertraline/index.html">sertraline</a>/Zoloft; 2282<a href="https://www.biopsychiatry.com/fluvoxamine/index.html">fluvoxamine</a>/Luvox; 2283<a href="https://www.biopsychiatry.com/paroxetine/index.html">paroxetine</a>/Paxil;
2284and <a href="https://www.biopsychiatry.com/citalopram/index.html">citalopram</a>/Celexa] 2285may make a small minority of people feel durably "better than well". More typically, 2286SSRIs are mood-blunters and even, for some people, psychic anaesthetisers. SSRIs 2287commonly make those who take them more resilient and less anxious. But they don't 2288promote depth of feeling, intellectual dynamism or clarity of thought. SSRIs can 2289also diminish the intensity of <a href="https://www.sensualism.com/love/brain.html">love</a>. MDMA, by contrast, is a veritable love-potion, 2290what Claudio Naranjo aptly christened a "feeling intensifier". On MDMA, emotions 2291are heightened as well as enriched. Compared to loved-up ecstatics on MDMA, the 2292rest of us have the emotional intensity of zombies; and zombies have no real insight 2293into what they're lacking, even if some of us can talk as though we do. Ironically, 2294at a time when the loss of personal liberty entailed by prohibitionist drug laws 2295is justified by the societal costs of illicit drug-taking, "psychiatric" drugs 2296are clinically prescribed by physicians regardless of the likely effect of a medication 2297on the personal relationships of the patient. SSRIs, by enhancing the user's emotional 2298self-sufficiency, can either save marital relationships or wreck them. By reducing 2299"neediness", SSRIs also diminish what today passes for love. SSRIs are prone to 2300impair romantic ardour as well as <a href="https://www.biopsychiatry.com/ssrisex.html">libido</a>. 2301One technical (and ideological) challenge of the pharmacogenomic revolution in 2302prospect at the interface between genetics and <a href="https://www.biopsychiatry.com/sexpharm.htm">drug-design</a> 2303will be to investigate how the emotional honesty and extraordinary depth of feeling 2304induced by MDMA can be sustained over a period of months, years and decades rather 2305than for two-hour bursts. <P> 2306 2307 2308 There 2309are further complications to overcome if any bid to replicate and sustain full-spectrum 2310E-like consciousness is to succeed. MDMA triggers the release of the neurotransmitter 2311<a href="https://www.mdma.net/mdma/mdmaacety.html">acetylcholine</a> via a histaminergic 2312H1 mechanism. MDMA is also a weak agonist of the acetylcholine muscarinic M1 receptors. 2313MDMA's modest cholinergic activity may contribute to the exquisite lucidity of consciousness 2314characteristic of pure MDMA taken in a therapeutic setting. For the 2315cholinergic system is vital to memory, higher thought-processes and verbal fluency. 2316Cholinergics such as <a href="https://www.nootropic.com/piracetam/index.html">piracetam</a> 2317(Nootropil) are used as <a href="https://www.nootropic.com/refs/">nootropics</a> or 2318"<a href="https://www.nootropic.com/smartdrugs/brainviagra.html">smart drugs</a>"; 2319and acetylcholinesterase inhibitors like <a href="https://www.biopsychiatry.com/galantamine.htm">galantamine</a> 2320(Reminyl), <a href="https://www.biopsychiatry.com/rivastigmine.htm">rivastigmine</a>
2321(Exelon), <a href="https://www.biopsychiatry.com/tacrine.htm">tacrine</a> (Cognex) 2322and <a href="https://www.nootropic.com/donepezil/aricept.html">donepezil</a> (Aricept) 2323are used as palliative treatments of Alzheimer's disease. Acetylcholine-release 2324and muscarinic receptor activation probably play no direct role in the rewarding 2325hedonic effects of MDMA. Yet their subtle contribution to the texture of the magic 2326can't be discounted. "<a href="https://www.biopsychiatry.com/dumbdrug.htm">Dumb-drug</a>" 2327<I>anti</I>muscarinic agents commonly induce mild <a href="https://www.nootropic.com/anticholinergic.html">euphoria</a> 2328via their indirect enhancement of dopamine function. Their mood-brightening effect 2329stands in contrast to many cholinergic (e.g. muscarinic <a href="https://www.biopsychiatry.com/muscarinic.htm">M4</a> 2330receptor) agonists and cholinesterase inhibitors which have a tendency to <a href="https://www.biopsychiatry.com/acetph.htm">subdue</a> 2331mood. A wide range of cholinergics is now under development for the palliative 2332treatment of <a href="https://www.biopsychiatry.com/alzheim.htm">Alzheimer's disease</a>, 2333a progressive neurodegenerative disorder characterised by profound cholinergic 2334deficits. Some depressives, however, may actually benefit from the antimuscarinic 2335anticholinergic effects that more intellectually fastidious clinicians would call 2336an adverse side-effect of the older <a href="https://www.biopsychiatry.com/tricy.htm">tricyclics</a>. 2337While a great many depressed people report intellectual sluggishness and poverty 2338of thought, other melancholic and introspective depressives endure "hypercholinergic 2339frenzy", possibly owing to dysregulation of the <a href="https://www.biopsychiatry.com/cholman.htm">cholinergic-adrenergic</a> 2340axis. Sadly, innumerable depressives among life's walking wounded today find the 2341examined life scarcely worth living: they cope with life only by "just getting 2342on with it". By contrast, MDMA allows introspection to become insightful and enjoyable 2343even to the naturally angst-ridden. On MDMA, both philosophising and emotional 2344self-honesty can be illuminating and fun. It's a shame that such self-insight can't 2345more readily be prolonged. 2346 2347 2348<P> Another 2349enigma is the role of <a href="https://www.mdma.net/dhea/index.html">DHEA</a>. 2350MDMA causes a rise in the adrenal corticosteroid dehydroepiandrosterone (DHEA). 2351DHEA is the precursor to <a href="https://www.biopsychiatry.com/testosterone/index.html">testosterone</a>, 2352<a href="https://www.biopsychiatry.com/progesterone.htm">progesterone</a>, estradiol 2353and other steroids. The rise and peak physiological values of DHEA between around 23541 to 2½ hours post-MDMA administration is correlated with user-reported 2355euphoria, though DHEA's precise contribution to the mood-elevation is unclear. 2356In general, levels of DHEA decline with age after early adulthood. Long-term supplementation 2357with DHEA seems to have beneficial effect on libido, immune function and some 2358forms of cognition. However, in spite of a wealth of research, no firm conclusions 2359have yet been reached on the advisability of taking DHEA supplements, or an optimal 2360dosage if taken. Nor is it known what role enhanced DHEA might play in sustaining 2361enriched quality of life over the longer term. Taken on its own, DHEA may brighten 2362mood; but it's scarcely an E-like effect. 2363 2364 2365<P> One 2366<i>un</I>wanted effect of MDMA, especially when taken at higher doses, is its 2367tendency inhibit to <a href="https://www.mdma.net/tryptophan-hydroxylase/index.html">tryptophan 2368hydroxylase</a> by triggering a rapid oxidation of the enzyme's sulphydryl sites. 2369Tryptophan hydroxylase is the rate-limiting enzyme in serotonin synthesis. Even 2370though the acute functional loss of tryptophan hydroxylase in the cell terminal 2371is reversible, the axon's vulnerability to oxidative stress is increased. In order 2372sustainably to enhance our capacity for empathetic bliss, and certainly to prevent 2373any functional serotonergic deficit, tryptophan hydroxylase function must be enhanced, 2374not inhibited. However, to date no stimulator (or inhibitor) of the biosynthesis 2375of serotonin has been commercially marketed. Interestingly, the use of interventions 2376to increase the biosynthesis of serotonin prior to MDMA use tends to trigger an 2377increased synaptic release of dopamine, thereby enhancing the user's euphoria. 2378Unfortunately, increased serotonin synthesis also aggravates post-E neurotoxicity. 2379The two mechanisms are separable in principle. In the meantime, restraint is prudent. 2380 2381 2382<P> Ultimately, we may be able 2383to generate sublime MDMA-like states - at will, to order, and indefinitely - only 2384when the intracellular signal-transduction mechanisms, and regulation of genetic 2385switching beyond the post-synaptic cascade, are better understood. The orchestrated 2386"overexpression" of some genes and the receptor proteins they code, the redesigned 2387"under-expression" of others, and perhaps the selective <a href="https://www.bi
2387opsychiatry.com/rna.htm">silencing</a> 2388of gene expression via RNA-mediated interference of anything really nasty, can 2389amplify desirable facets of our consciousness and suppress its darker and more 2390poisonous variants. Thus at one terrible extreme, <a href="https://www.biopsychiatry.com/suicide.htm">suicide</a> 2391victims, for instance, tend to show heightened levels of serotonin <a href="https://www.biopsychiatry.com/5ht2arev.htm">5-HT2A</a> 2392receptors. Before death, they show a greater activity in the genetic machinery 2393churning out the 5-HT2A receptor itself. So as well as developing gene-therapy 2394to prevent <a href="https://www.biopsychiatry.com/suifit.html">suicidality</a> 2395- and forestall the whole spectrum of deeply unpleasant para-suicidal and <a href="https://www.biopsychiatry.com/bulimia.html">self-destructive</a> 2396states - it should be possible, conversely, to engineer an unimaginably richer 2397love of life, of ourselves and each other by genetically enhancing our own minds. 2398Freedom to optimise (or at least improve) one's genome should prove at least as 2399personally liberating as the freedom to optimise one's drug-regimen. Doubtless 2400a regulatory minefield lies ahead. <P> 2401 2402 2403One momentous development is perhaps only a decade or so away. In the imminent 2404era of genomic healthcare, we may each enjoy access to a read-out of our own individual 2405genotype i.e. the set of particular forms of genes - alleles - peculiar to each 2406individual who isn't a monozygotic twin [triplet etc]. Harnessed to <a href="https://www.biopsychiatry.com/pharmacogenetics.htm">pharmacogenetics</a>, 2407the study of how an individual's distinctive genetic inheritance affects the body's 2408response to drugs, such intimate genetic self-knowledge should allow the design 2409and prescription of a drug-regimen tailored to each unique person, whether for 2410medical, social, research or "recreational" purposes. At first, only the crudest 2411stratification of patient populations by genotype may be the medical norm. This 2412is because commercial drug companies prefer large markets. Yet eventually we should 2413all have optional access to the gene-expression profile of each neurotransmitter-specific 2414neuronal subtype in the mind-brain. Such access offers scope for fine-grained 2415manipulations of the chemistry of our souls inconceivable in the Dark Ages of 2416pre-genomic medicine. <P> 2417 2418 2419 Genetically 2420personalised medicine offers another bonus. It should eliminate the possibility 2421of idiosyncratic drug reactions caused by genetic abnormalities - for example 2422rare <a href="https://www.mdma.net/metab.html">polymorphisms</a> of the cytochrome 2423<a href="https://www.mdma.net/p450-2d6/index.html">P450-2D6</a> system critical 2424to drug metabolism. Owing to genetic polymorphisms in drug-metabolising enzymes, 2425receptors and transporters, a range of drugs beneficial to c.99% of the population 2426can't get regulatory approval. In some cases, valuable licensed medicines are 2427pulled after post-marketing surveillance. This therapeutic opportunity is wasted 2428because, say, 1%, 0.1%, or even 0.01% of people who take such agents suffer severe 2429adverse reactions. The advent of genetically personalised medicine should mean 2430that these atypical cases can be excluded; and given other medication instead. 2431Useful older drugs can be dusted off the shelves and re-licensed. New 2432agents can be developed and given faster regulatory approval. 2433 2434 2435 <P> Psychoactive 2436drug users in particular should benefit from the prospect of genetic 2437self-knowledge. Cytochrome P450 forms a superfamily of hepatic enzymes with hundreds 2438of different isoforms that catalyse the oxidative metabolism of a huge diversity 2439of substrates, including MDMA. The duration of action and/or intensity of the 2440effect of numerous drugs are determined by their rate of metabolism by cytochrome 2441P450. Whereas some "housekeeping" enzymes are expressed constitutively i.e. they 2442are perennially active, other enzymes are expressed essentially only when triggered 2443by the presence of the exogenous chemical. Inducible enzyme isoforms increase 2444both in amount and activity in response to drugs. 2445 2446 2447 <P> The 2448precise role of <a href="https://www.mdma.net/metabolism/p4502d6.html">CYP2D6</A> in MDMA <a href="https://www.mdma.net/pharmacology/index.html">pharmacology</a> 2449is still unclear. MDMA is not merely a substrate for CYP2D6; it also binds to 2450the enzyme, forming an inhibitory complex. The CYP2D6 enzyme is soon saturated
2451even in efficient metabolisers. Other human cytochromes P450 such as CYP-1A2, 2452CYP-3A4 and CYP-2bB are critically involved in the oxidative metabolism of MDMA. 2453It is possible these other metabolic pathways play an important role in everything 2454from idiosyncratic responses to MDMA to the notorious "loss of magic". If enzyme 2455induction accounts wholly or in part for the loss, then the roots of disenchantment 2456can be investigated and prevented, whether for MDMA or perhaps its still imperfect 2457successors. If, however, central processes of neuroadaptation are at work, either 2458instead or as well, then longitudinal neuroimaging studies comparing the brain-scans 2459of, say, drug-virgins ninety minutes or so after dropping their first magical 2460E (or perhaps its safer successor(s)) with brain-scans taken during their hundredth-odd 2461trip should allow the neurochemical basis of any loss of magic to be pinpointed 2462and reversed. Indeed the magic itself can presumably be amplified, probably more delightfully 2463than an unenchanted Darwinian mind can grasp. 2464 2465 2466 <P> 2467More broadly, genomic medicine will deliver the freedom to choose who or what 2468we want be, both as individuals and collectively as a species. In the long run, 2469a spectrum of mental superhealth that is orders of magnitude richer than anything accessible 2470today can be genetically pre-programmed. "Phenotypic plasticity" (the nearest 2471analogue to free will a molecular geneticist will recognise) can be both vastly extended 2472to enhance personal autonomy and, no less importantly, constrained where it's 2473cruel and unwanted. Thus better designed gene-and-drug combinations can perpetuate 2474truly sublime modes of consciousness whereas, conversely, a predisposition to 2475such ancient Darwinian horrors as sociopathy or suicidality can be genetically 2476cured. A rewritten genome can potentially liberate us from all trace of psychopathy 2477and depression - the enemy from without and, all too often, the enemy within. 2478When taken today, MDMA rapidly banishes the horrors of both. Alas they soon return; 2479the acute effects of MDMA are mostly all too reversible. Prediction is always a hazardous 2480business, but to our <a href="https://www.hedweb.com/object35.htm">descendants</a>, breeding kids with anything like our own corrupt 2481code may seem like wanton child abuse. <P> 2482 2483<a name=mdmadarwin></a><br><h3>Post-Darwinian Medicine</h3>Decoding 2484the human genome offers the promise of lifelong emotional health via somatic or 2485germline therapy. Such well-being may be modulated at will via entactogens-empathogens 2486akin to MDMA; by <a href="https://www.entheogens.com/">entheogens</a>, <a href="https://www.psychedelics.org/salvia-divinorum.html">psychedelics</a>, 2487<a href="https://www.nootropic.com/review.htm">nootropics</a>; or agents from categories 2488currently too exotic to imagine. Or alternatively, our descendants may opt to 2489abandon psychotropic drugs as pollutants of their genetically-enriched minds. 2490 2491 2492 2493<P> The biotechnology revolution 2494throws up <a href="https://www.mdma.net/mk-ultra/index.html">darker</a> scenarios too. The spectre of biowarfare, bioterrorism, and perhaps 2495totalitarian state control over our reproductive decisions tends to loom larger 2496in the contemporary imagination than utopian visions of boundless love and joy. 2497Clearly genetic engineering and designer-drugs, like the printing press, can be 2498put to <a href="https://www.utilitarianism.com/">unethical</a> use. Nightmarish 2499dystopias make spine-chilling science-fiction and, maybe more plausibly, better 2500futurology than wide-eyed technophilia. The <I>near</I> future may indeed be bleak. 2501Those of us who aren't morbidly interested in pain and suffering probably underestimate 2502how dreadful primordial Darwinian life can be at its worst. Some mental and physical 2503torment is so bad its victims would snuff out the whole world to end it. Disturbingly, 2504the sense in which its victims could be deluded in evaluating its dreadfulness 2505is unclear. 2506 2507 2508<P> Yet human nature 2509as encoded in our DNA isn't immutable. Mankind's barbaric track-record to date 2510is an unreliable guide to our post-human future. If <I>Homo sapiens</I>' nastier alleles 2511and their more sinister combinations can be silenced or edited out of the genome, 2512and new improved code-sequences inserted instead, then the pessimists will be 2513confounded. A major discontinuity in the development of intelligent life lies ahead. Providentially, 2514we've learned that the DNA-driven world isn't written in <a href="https://www.wireheading.com/wired.html">God-given</a> 2515proprietary code it would be hubris to tamper with, but in bug-ridden open source 2516amenable to improvement. 2517 2518 2519<P> 2520Given our current design-limitations, any planning for a post-human population 2521endowed with invincible mental health sounds ambitious in scope if not messianic 2522in spirit. Even granted that <a href="https://www.paradise-engineering.com/">paradise-engineering</a> 2523is <I>technically</I> feasible, the <a href="https://www.abolitionist.com/">abolitionist 2524project</a> still amounts, by today's lights, to a breathtakingly bold strategic move 2525for our species. It may never happen. Most philosophers assume that <a href="https://www.bltc.com/buddhism-suffering.html">suffering</a> 2526will endure as long as life itself. Only the horrific, purposeless cruelty of
2527a living world evolved by natural selection makes an abolitionist agenda of "unnatural" 2528selection so morally urgent. That said, any mental health plan aimed at underwriting 2529lifelong emotional well-being for the world's population no more entails developing 2530a millenarian blueprint for a post-human Utopia, or prophesying the imminent End 2531Of History <I> à la </I> <a href="https://en.wikipedia.org/wiki/The_End_of_History_and_the_Last_Man" target=_blank">Francis Fukuyama</a>, than the still radically incomplete 2532conquest of "physical" <a href="https://www.general-anaesthesia.com/misc/painfree-surgery.html">pain</a> dictates specifying the particular kinds of pain-free 2533lives we should all lead. The lifestyle options following success in either case 2534are effectively limitless. Thus any fleshed-out examples of possible post-Darwinian forms of 2535life are purely illustrative. If mental superhealth does become the societal norm, then 2536<a href="https://www.gradients.com/">gradients</a> of genetically predestined bodily and emotional well-being can constitute 2537the presupposed <i>backdrop</I> to the diversity of everyday life, not its focus. 2538Gradients of lifelong happiness can <a href="https://www.hedweb.com/hedethic/pigdefend.htm">enrich</a> 2539our autobiographical narratives, not supplant them. Ecstasy needn't be orgasmic; 2540though it can be. <P> 2541 2542 2543 As contemplated 2544today, scenarios of a post-Darwinian era of lifelong bliss demand a greater effort 2545of imagination than the possibility of lives spent "merely" without "physical" 2546suffering. The futuristic scenarios feel "unreal". The prospect of <a href="https://www.superhappiness.com/">lifelong happiness</a> strikes 2547us as far more utopian in conception than the prospect of lifelong <a href="https://www.supercentenarian.com/archive/eternal-life.html">bodily</a> health. 2548Yet in both cases, gradients of well-being can play a role informationally analogous 2549to their nastier Darwinian counterparts while shorn of their unpleasant (and sometimes 2550harrowing) subjective textures. Assuming here without argument a functionalist 2551model of computational mind, what's indispensable to intelligence in the broadest 2552sense of the term are the triple processes of information, computation and feedback. The "raw 2553feels" of unpleasantness are neither necessary nor sufficient for intellectual 2554progress. Thus our silicon robots don't suffer anguish, even when we recode their 2555"affect programs"; and it seems they're getting <a href="http://www.nickbostrom.com/2050/outsmart.html" target="_blank">smarter</a> 2556a lot faster than we are. <P> 2557 2558 2559 2560The existence of lives animated by <I>gradients</I> of well-being should be distinguished 2561from lives spent in a state of <I>uniform</I> well-being. Chronic heavenly bliss, 2562like chronic pain and despair, is a condition that's <I>technically</I> possible 2563to implement in the vertebrate CNS. For good or ill, such uniformity would be 2564a recipe for stasis. The intra-cranially self-stimulating <a href="https://www.wireheading.com/wired.html">rat</a> or monkey - or human 2565<a href="https://www.wireheading.com/wirehead.html">wirehead</a> - isn't going 2566anywhere. By contrast, if a predisposition to gradients of ecstatic well-being 2567is ever genetically encoded as our default mood-spectrum, then critical discernment 2568can be functionally retained, and self-motivation enhanced, without sacrificing 2569the humane <a href="https://www.hedweb.com/object25.htm">ethic</a> of a cruelty-free 2570world. This conjecture isn't idle. Some <a href="https://www.hedonistic-imperative.com/">bioethicists</a> 2571would argue a world without suffering is the precondition for any civilised society. 2572Plausible or not, the lack of any <I>inevitable</I> tradeoff between happiness 2573and critical insight undercuts one ideological obstacle to global mood-enrichment. 2574 2575 2576 2577<P> Predicting the dial-settings 2578on the emotional thermostats of our <a href="https://www.repugnant-conclusion.com/index.html">descendants</a> is unavoidably speculative. But 2579if (<I>very</I> controversially) post-Darwinian humans will innately feel superwell, 2580albeit in varying degree, precisely what modes might their genetically enhanced 2581and perhaps pharmacologically modulated well-being most plausibly take? Will such well-being 2582be the egoistic happiness of amoral, emotionally self-reliant <i>ubermenschen</I>? 2583Or could being loved-up on Ecstasy, or perhaps long-acting brands of entactogen-empathogen 2584cleaner and safer than MDMA, offer a better model of social life in centuries 2585to come? <P> 2586 2587 2588 This sort of crystal-ball 2589gazing clearly demands scepticism as well as a lively imagination. As Dr Shulgin 2590reminds us <a href="http://www.cognitiveliberty.org/shulgin/" target="_blank">elsewhere</a>, any 2591prediction is hopelessly entangled with the wishes of the predictor. Such bias 2592might seem to defeat the enterprise from the start. Fortunately (or <a href="http://www.fascism.com/holocaust-faq.htm">otherwise</a>), 2593however, some scientific prophecies can become self-fulfilling if ever their makers acquire
2594the power to implement them. In this instance, <i>technically</I> at least, <I>Homo 2595sapiens</I> will soon have the collective scientific expertise to redesign our 2596own <a href="https://www.primates.com/chimps/genome-dupl.html">nature</a>. So <I>if</I> we ever aspire to enjoy, say, lifelong ecstasy for our minds 2597and bodies, then we can have it. If we're so minded, then <a href="https://www.primates.com/classification/index.html">apes</a> can become <a href="https://www.bltc.com/apes-angels.html">angels</a>. 2598The ultimate stumbling-block, if there is one, will be traditional Darwinian-era 2599ideologies, not scientific ignorance of how to redesign the molecular machinery 2600of emotion. For sure, the vision of a whole civilisation, and not just an all-weekend 2601<a href="https://www.mdma.net/raves/chemi-kids.html">rave</a>, founded on the neural substrates of an E-like "Peace, Love, Understanding 2602and Respect" sounds sociologically naïve and (socio-)biologically impossible. 2603Stated so bluntly, the loved-up edition of scientific utopianism is perhaps the 2604most implausible (and unreadable) premise for a sci-fi novel one can imagine. 2605The <I>non-specific</I> prediction of genetically preprogrammed well-being for 2606our descendants is contentious enough as it stands. Any more detailed explorations 2607of the possibility that such enriched well-being might be, say, E-like rather 2608than egoistic are therefore <I>hugely</I> more speculative; and quite probably 2609mistaken. But for the following reasons, a civilization based on relationships 2610of, say, mutual loving empathy and intensified E-like consciousness is not impossible, 2611just far-fetched. At a minimum, it's worth sketching out an extended family of 2612E-like scenarios as a corrective to a routine but unargued assumption that underlies 2613rival predictions. This assumption is that societies based on the behavioural 2614genetics of primate-style dominance-and-submission <a href="https://www.hedweb.com/huxley/rankmood/alphaomega.htm">hierarchies</a> will endure indefinitely. 2615Thankfully, both the reproductive biology and mode of selection pressure at work 2616in the new era of genomic medicine will be different from the evolutionary past. Our genetic programming 2617will no longer be "blind", even if its early (re-)programmers will be only partially 2618sighted. Varieties of (post-)human genotype won't just be quasi-randomly generated 2619via sex, genetic crossing-over and mutation. Instead, genotypes will be purposely (re)designed 2620- even if the early designers barely know the <a href="https://www.paradise-engineering.com/biotechnology/index.html">ramifications</a> of what they'll be 2621doing. <P> 2622 2623 2624 For we're presently 2625on the brink of the era of "unnatural" selection. Throughout the living world, 2626a regime of blind natural selection acting on effectively random mutations has governed the 2627evolution of information-bearing self-replicators since the origin of life itself.
2628The Darwinian Era has lasted for over four billion years. Most recently, in the 2629aftermath of the post-Cambrian explosion of multicellular animal life and the 2630evolution of central nervous systems, selection pressure has created suffering 2631beyond belief. Mercifully, a regime change is imminent. Within a few centuries 2632at most, intelligent life will be able to rewrite the vertebrate genome and redesign 2633the planetary <a href="https://www.hedweb.com/animutop.htm">ecosystem</a>. Sooner 2634still, <I>if</I> we want our genetically enriched (grand-)children to be happy, 2635then in the impending reproductive era of preplanned designer babies we will also 2636have to choose - either actively or by default - whether the kinds of heritable 2637well-being our offspring enjoy will tend to be solipsistic or social, orgasmic 2638or intellectual, hypomanic or serene, loving or self-centred, or perhaps ultimately 2639take forms that can't be grasped by the contemporary Darwinian mind. Whatever 2640criteria are used, an increasing range of genotypes will soon be chosen in deliberate 2641<I>anticipation</I> of their phenotypical effects. Needless to say, no such calculated 2642sets of genetic decisions can be taken by prospective breeding couples at present. 2643"Genetic choice" in the early 21st century usually means nothing more ambitious than choosing the gender 2644of one's child, often in less than ideal circumstances. Yet as the human genome 2645is deciphered, and eventually the "<a href="https://www.biopsychiatry.com/transcriptome.htm">transcriptome</a>" 2646and <a href="https://www.biopsychiatry.com/proteomics.htm">proteome</a> beyond, 2647a staggering extension of freedom of choice will be thrust upon us. As <a href="https://www.wireheading.com/index.html">wiring</a> 2648up the neural reward centres with microelectrodes shows, the practicalities of 2649inducing - and then sustaining - the neural substrates of bliss are technically 2650quite easy. Viewed as an engineering problem, no one needs to suffer; suffering is an unnecessary evil. This is true even 2651with today's embarrassingly clumsy interventions. <a href="https://www.wireheading.com/roborats/index.html">Modulating</a> 2652 bliss in controllable ways is trickier - whether by drugs, microelectrodes 2653or gene-therapy. Short-term technical snags aside, our state-space of life-enriching 2654options is poised rapidly to expand. Of course even with utopian biotechnology 2655and mature <a href="https://www.nanotechnologist.com/">nanotechnology</a>, constraints 2656won't be absent. The menu of practical choices on offer to our enriched descendants 2657isn't entirely limitless. For instance, decades spent in unceasing, paroxysmal 2658<a href="https://www.wireheading.com/orgasmatron/">super-orgasms</a>, or perhaps 2659immersion in fantasy wish-fulfilment in <a href="http://www.thematrix.com/" target="blank">virtual 2660reality</a> software, may well be viable lifestyle options one day for individuals. 2661They are technically feasible to implement. Yet it's hard to imagine parents wanting 2662such modes of existence for their kids, or to devise evolutionary <a href="http://www.gametheory.net/" target="_blank">game-theoretic</a> 2663models where the prevalence of genotypes that permit such lifestyles could be 2664globally <a href="https://www.hedweb.com/object27.htm">stable</a>. In any post-Darwinian 2665reproductive era ahead, "unnatural" selection pressure will still be at work, 2666at least until the abolition of <a href="http://research.mednet.ucla.edu/pmts/sens/sen2article.htm" target="_blank">senescence</a> 2667brings the throwaway era of traditional DNA <a href="https://www.supercentenarian.com/records.html">mortals</A> to a close. Thus any currently 2668foreseeable civilisation will be social in character, not quasi-solipsistic. If 2669so, then one urgent challenge will be to make our social interactions less emotionally 2670costly. Today, for a few hours, MDMA offers perhaps the richest chemical tool 2671for social intimacy in existence. If nothing else, the MDMA experience demolishes 2672the conventional wisdom that "artificially"-induced happiness must be amoral and 2673<I>selfish</I> - hedonistic, one-dimensional and shallow. More generally, the 2674sense of heightened authenticity, love and self-insight induced by entactogen-empathogens 2675will no longer seem an escapist holiday from Real Life when entactogenic-empathogenic 2676states can be sustained indefinitely - whether by gene-therapies or soul-medicines 2677or varieties of both. In theory, at least, mental superhealth can become the new 2678benchmark of consensus-reality against which any departures are defined, not 2679drug-induced psychotic episodes. 2680 2681 2682<P> It's 2683safe to say MDMA itself isn't going to change the world. Yet as a taster of what's 2684feasible in <a href="https://www.opioids.wiki/legal/index.html">post-prohibitionist</a> 2685culture and a possible genetically-enriched future beyond, the MDMA experience 2686shows social life at its best. MDMA promotes a more altruistic mode of consciousness 2687than has maybe ever existed on the planet, certainly among testosterone-driven 2688young males. On MDMA, one can love thy neighbour as thyself; and the lion can 2689lie down with the <a href="http://www.games-theory.com/">lamb</a>. Feelings of 2690hostility, bigotry and intolerance evaporate. Competitiveness is replaced by love, 2691tolerance and respect. Such social harmony seems "unnatural" if not miraculous 2692when viewed from the poisonous miasma of mainstream society. For outside the embraces 2693of loved-up ecstatics, we tend to pay a terrible price for the benefits of group 2694living. The costs of social existence are attested by the grisly chronicles of 2695human history, Gibbon's "register of the crimes, follies, and misfortunes of mankind". 2696It's not as though we have much choice about living together. Even in the absence 2697of MDMA, human beings are still compulsively sociable. This compulsion to socialise 2698is generally seen as healthy rather than dangerously <a href="https://www.oxytocin.wiki/oxytoc/love-science.html">addictive</A>, despite the traumas 2699it brings. In abnormal conditions of social isolation, the personality starts
2700to deteriorate: solitary isolation, whether real or figurative, is rightly viewed 2701as a cruel and unusual punishment. Our genes, via the reward pathways and the 2702neural projections they code, make us chronically hooked on the company of others. 2703Our very identities are bound up with our social roles. We are physiologically 2704dependent on the <a href="https://www.opioids.wiki/index.html">opioidergic</a>, 2705<a href="https://www.oxytocin.wiki/refs/index.html">oxytocinergic</a>, dopaminergic 2706and serotonergic mechanisms that friends, family and colleagues may trigger within 2707us. 2708 2709 2710<P> At its best, this chronic 2711dependence on human company gives short-term highs and even warm afterglows. But 2712dependency, craving, and withdrawal-reactions are common when significant others 2713are taken away from us or adulterated. Purity varies; supply is erratic; and adverse 2714reactions are common. Cue-elicited craving readily triggers relapse. Our sociability 2715can spin out of control into a financially ruinous habit. We spend lots of time 2716and effort thinking about how to get more of whoever stimulates our mesolimbic 2717reward circuitry most vigorously, possibly romanticised under more poetic descriptions. 2718Without friends, lovers or family, most people tend to become lonely, sometimes 2719agonisingly so. In extreme cases, <a href="https://www.mdma.net/misc/loneliness.html">loneliness</a> and lovesickness can induce suicidal 2720despair. Bereavement and abandonment can be as traumatic as <a href="https://www.opioids.wiki/heroin.html">heroin</a>-withdrawal; 2721and they share similar neural substrates. 2722 2723 2724<P> Alas 2725given a Darwinian genome the compulsion to socialise is all too often a dangerous, 2726self-destructive addiction. Living without Ecstasy, we are predisposed by our 2727genes to conflict with each other: mothers and children, men and women, brothers 2728and sisters, friends and relatives - all have different and often conflicting 2729genetic interests. Only monozygotic ("identical") twins may hope to be spared 2730this insidious rivalry. Camouflaged genetic conflict underlies our disposition to squabble 2731and fight amongst ourselves, even though we compulsively need each other's company 2732too. Thus testosterone-driven males find themselves enacting decades-long competitive 2733rituals to attract and retain genetically superior mates. Competitive status-seeking 2734in its subtle - and not-so-subtle - guises is a cross-cultural universal, deeply 2735rooted in our biology. Conflict to the point of warfare is genetically predisposed 2736in our make-up. It's endemic to human society. Right from conception and the implantation 2737of the conceptus in the womb, genetically-driven <a href="https://www.biopsychiatry.com/pregnancy.html">conflict</a> 2738plays itself out, often leading to trauma (e.g. preeclampsia etc.) for mother 2739and unborn child alike. Later on, even the noblest of human sentiments are fragile. 2740<a href="https://www.sensualism.com/love/index.html">Love</a> all too easily turns into hatred, admiration into contempt. By way of illustration, 2741consider, say, proverbial "lover's quarrels". There are innumerable "proximate" 2742explanations of why star-crossed lovers often argue so painfully and vehemently. 2743But the "ultimate" evolutionary explanation seems to be, at least in part, that 2744tempestuous rowing and its consequences serve as a brutal but effective way for 2745prospective breeding couples to test each other out. Evolutionary psychology suggests 2746that, from a gene's eye view, it's better to discover if a prospective partner 2747will let you down sooner, when (s)he's goaded under conditions of stress, rather 2748than later after you've sunk a substantial investment of time and resources in 2749the partnership. Arguing can be traumatic; but the capacity to do so is [genetically] 2750adaptive. 2751 2752 2753<P> Human relationships 2754can bring psychological rewards too. Anyone having fun right now would find this drumbeat 2755of misery, heartache and emotional squalor all a bit overblown. Yet if anything 2756the nastiness alluded to here is understated; the worst pains in life are inexpressible. Under 2757the genetic <I>status quo</I>, most of us are condemned at different stages of 2758a lifetime to re-enact the messy - and sometimes desperately sad - personal dramas 2759of our ancestral past. TV soap-operas and teledramas serve to sanitise just how 2760emotionally unpleasant Darwinian life can be. For as human generation succeeds human generation, 2761we replay the age-old sagas of sexual betrayal, jealousy, loneliness, and rejection. 2762We are forced to endure the savage competition of <a href="https://www.sensualism.com/beauty/attraction.html">lookism</a> - an inadequate, frivolous 2763term for a cruel and omnipresent phenomenon in human society. Less colourfully, 2764a multitude of pettier but still wounding frustrations, humiliations and misunderstandings 2765can mar daily social life and sour personal relationships. 2766 2767 2768<P> The 2769genetic rot goes deeper. Evolutionary psychiatry suggests that the cross-culturally
2770ubiquitous phenomenon of <a href="https://www.biopsychiatry.com/resource/index.html">depression</a>, 2771and the wider spectrum of depressive and <a href="https://www.biopsychiatry.com/dysth.htm">dysthymic</a> 2772disorders, is not a genetically dysfunctional anomaly. Counter-intuitively, a 2773conditionally activated tendency to depression may represent a fitness-enhancing 2774<I><a href="https://www.huxley.net/rankmood/">adaptation</a></I> to group living. 2775The (involuntary) capacity for depression is one of a number of ancient, genetically 2776adaptive mechanisms and strategies for dealing with "<a href="https://www.biopsychiatry.com/depression/index.html">social 2777defeat</a>" in a tribal environment. Group living conferred advantages on otherwise 2778vulnerable individual primates on the African savannah. Embracing tribal life 2779forms a valuable defence for a puny "naked ape" against big predators. But thanks 2780to the pressure of sexual selection, human tribal society imposes a cruel <a href="https://www.primates.com/monkeys/sexy-pics.html">pecking-order</a> 2781of subordination relationships among members of the tribe. For sure, depression has many 2782proximate causes; there are many subtypes of depression; and not all depressive 2783moods and behaviours are genetically adaptive. Yet viewed in <a href="https://www.biopsychiatry.com/depression/adaptive.html">evolutionary</a> perspective, 2784a syndrome of sustained melancholy, behavioural suppression, and a preoccupation 2785with personal failure and inadequacy is the internalised correlate of the yielding 2786or "losing" behavioural sub-routine. On this "rank theory" hypothesis, the involuntary activation 2787of submissive and depressive states is an unpleasant but effective defence-mechanism 2788for weaker individuals where any tendency to initiate or escalate conflict with 2789a powerful dominant rival might easily be disastrous. Thus states of depression 2790or low mood ensure the weak "keep their heads down" and don't overreach themselves. 2791By contrast, the (hypo-)<a href="https://www.biopsychiatry.com/maniauni.htm">manic</a> 2792spectrum of mood and behaviour is a manifestation of the "winning subroutine". 2793Clearly, not all submissive people are unhappy, and not all dominant and/or aggressive 2794people are (hypo-)manic. So there are complications to the hypothesis and a legion 2795of exceptions. A capacity to switch mode can sometimes be adaptive too; hence 2796the probable evolutionary origins of <a href="https://www.biopsychiatry.com/bipolarity.htm">bipolarity</a>. Yet down at the bottom of the 2797social heap, there are proportionately far more crushed and wounded spirits than 2798there are at the top. Socially dominant Alpha males tend to be temperamentally 2799expansive and optimistic. Conversely, even life's "winners", if deposed 2800and defeated, may become depressed themselves, and slink away to die, metaphorically 2801or otherwise. Depression in human societies is far more prevalent than (hypo-)mania, 2802albeit far less visible. This greater prevalence probably reflects conditions 2803in the evolutionary environment of adaptation where the spectrum of depression, 2804mania and bipolarity first arose. But whatever the ultimate evolutionary roots 2805of mood variation and affective disorders as interpreted by rank theorists, contemporary 2806humans in all known societies are obsessively status-conscious. Status-competition 2807corrupts personal relationships in societies stratified by caste, class and money 2808alike. Even apparent counter-examples don't challenge the generalisation. Thus 2809societies based around the potlatch, the Pacific Coast Native American custom 2810of conspicuous gift-giving rather than wealth-accumulation, reflect 2811a disguised expression of competitive power relationships. Indeed the tradition 2812of rival displays of gift-giving finds echoes today in the competition between 2813billionaire American plutocrats to endow the biggest charitable trust foundations. 2814 2815 2816 2817<P> The poison of competitive 2818status-seeking might seem incurable. [<I>"If everybody is somebody, then nobody 2819is anybody"; "It's not enough to succeed. Others must fail"</I>] Yet short-term 2820symptomatic relief for this syndrome already exists; and its long-acting analogues 2821may one day offer complete remission. Taken communally, MDMA induces an almost 2822miraculous transformation in the structure and relationships of any social group. 2823At MDMA-animated raves, no one who's loved-up is trying to "diss" anyone else. MDMA 2824abolishes the desire to put anyone down. On MDMA, primate dominance hierarchies 2825dissolve in an egalitarian love-in. A lifetime's <a href="https://www.bi
2825opsychiatry.com/inferiority.htm">inferiority-feelings</a>, 2826snobberies, and status-anxieties dissipate in a flood of augmented serotonin and 2827dopamine release. Intriguingly, the euphoria experienced by MDMA users doesn't 2828take the form of uncontrolled manic excitement, even where the drug induces "behavioural 2829activation". MDMA's indirect, <a href="https://www.mdma.net/misc/vamph.html">serotonin-mediated</a> 2830enhanced dopamine-release produces psychostimulant, emotional and perceptual effects 2831that feel very different from crude dopamine-releasing <a href="https://www.amphetamines.org/amphetamine/neurotransmitter-release.html">amphetamine</a>. Even the most 2832animated ravers taking pure MDMA tend to experience a profound sense of inner 2833calm, a "peace that passeth all understanding". Identifying the neurochemical signature of states combining inward serenity 2834and outer dynamism presents a wonderful therapeutic opportunity. The contrast 2835between raves packed with loved-up clubbers on hugdrugs and parties fuelled by 2836alcohol or cocaine is striking. 2837 2838 2839 <P> 2840Back in the harsh, E-less world, inferior social status is associated with low serotonin 2841function and low mood. Thus dominant males tend to have far higher serotonin function, 2842as measured by CSF 5-HIAA levels, than subordinate males. The neurological basis 2843of social rank order can be investigated by various manipulations. Experimentally 2844boosting or depleting the serotonin levels of social animals enhances or sabotages 2845an individual's place in the pecking-order. Revealingly, there are also gender 2846differences in serotonin activity. The mean rate of <a href="https://www.biopsychiatry.com/serotonin-gender.htm">serotonin 2847synthesis</a> in men is over 50% higher than the mean rate of serotonin synthesis 2848in women. Women are more sensitive than men to both the MDMA magic and MDMA's 2849adverse side-effects. Women are also more likely to suffer from the post-E serotonin 2850dip; more prone to depression; and more likely to benefit from <a href="http://www.fluoxetine.info/index.html">Prozac</a>. Yet such 2851comparisons are invidious. Men and women alike of any social status at all can 2852flourish far better in E-like states - while they last. Unfortunately, communal 2853E-like consciousness simply isn't sustainable via chronic MDMA use. In wider E-less 2854society, "winners" probably don't do [serotonin-depleting] drugs, though idealistic 2855E-users might suggest that zero-sum status-games are best not played at all. For 2856better or worse, a heavy, serotonin-depleting E-regimen can disrupt the user's 2857social status in the competitive urban jungle - and probably elsewhere. Admittedly, 2858there are too many confounding variables to test this hypothesis in methodologically 2859rigorous studies on humans. Even so, a proposed "E-users are losers" research 2860proposal is more likely to gain official funding than a well-controlled trial 2861of, say, the health benefits of MDMA-assisted psychotherapy. 2862 2863 2864 <P> Of 2865course the aspiration for a civilisation founded on relationships of shared <a href="https://www.sensualism.com/love/elixir.html">love</a> 2866and respect sounds impossibly idealistic. A society based on "winners" and "losers" 2867intuitively strikes us as natural. With today's genes and the kinds of culture 2868they promote, adversarial social relationships are probably inevitable. Like depression, 2869the evolutionary roots of everyday sociopathy run deep. For speculatively, applying 2870here <a href="https://en.wikipedia.org/wiki/The_Extended_Phenotype" target="_blank">Richard Dawkins</a>' "extended 2871phenotype" theory, not merely has it been genetically adaptive for weaker social 2872primates to have an inbuilt conditionally-activated capacity for depression, it 2873can also be genetically adaptive for Alpha males (and aspiring Alpha males) to 2874subdue potential rivals by making <I>them</I> depressed too. Perennially chastened, 2875socially anxious and chronically depressive potential competitors are less likely 2876to be sexually active and promiscuous. Crushed, anhedonic and submissive, they 2877are less of a challenge to the inclusive fitness of one's genes. Happy, dominant, 2878extroverted males, by contrast, are potential sexual rivals who directly or indirectly threaten one's 2879reproductive success. Thus we witness their downfall with equanimity. Even within
2880the bounds of holy wedlock, too much happiness for one's nearest and dearest doesn't 2881always suit one's genetic interests. A cowed and depressive wife, whose only solace 2882in life is looking after the kids, can be less threatening to one's genetic prospects 2883than an exuberant, sociable and possibly sexually adventurous bundle of joy. If 2884we are looking for an evolutionary perspective on why we often behave so vilely 2885to each other - sometimes seemingly gratuitously so - then this kind of sexual 2886selection pressure offers one possible explanatory framework. If it is adaptive 2887to have others exhibit a spectrum of behaviour characteristic of low mood or high 2888social anxiety, then other things being equal, alleles and allelic combinations 2889may flourish if they conditionally promote the capacity to induce such anxiety 2890and depression whether in strangers or tribe members who aren't allies or close 2891kin - and if occasion demands, even in those who are both. Depending on a lot 2892of other factors too, the (behavioural effects of the) happiness of others, male 2893or female alike, can indirectly detract from our own Darwinian fitness. Consequently 2894their perceived happiness doesn't tend to give us as much joy as moralists might 2895wish. Sad to say, reports of good fortune befalling our fellows do not always 2896inspire a warm glow of vicarious satisfaction. On the contrary, news of another 2897person's lottery-win, for instance, or its traditional counterpart on the African savannah, 2898is liable to trigger involuntary feelings of jealousy and resentment, or at best 2899an envious ambivalence. Of course, it's worth stressing that natural/sexual selection 2900doesn't care about the subjective textures of misery or happiness <I>per se</I>. 2901Selection pressure works on the spectrum of behaviour such mood traits engender. 2902What was selected <i>for</I> [as distinct from adventitiously selected] in the 2903ancestral environment of adaptation wasn't the capacity to make others feel miserable 2904as distinct from behave miserably. To selfish DNA, our suffering itself is incidental. 2905The distinction, however, is of limited comfort to its victims. 2906 2907 2908<P> 2909Fortunately we're not systematically spiteful, even though we're not naturally 2910loved-up. If human malice were really genetically hardwired, then any nostrums for 2911social reform, life-enriching lovedrugs or improving the vertebrate genome would 2912be futile. Thankfully, a malignant streak of human nastiness is matched by a 2913common if ineffectual desire to improve ourselves and help others. This good-will 2914just needs genetic and pharmacological amplification. 2915 2916 2917 <P> So 2918granting human beings no more than a minimal and diffuse benevolence, what can 2919be done to make us temperamentally nicer to each other as well as happier and 2920<a href="https://www.nootropic.com/sceptic/index.html">smarter</a>? Would we individually 2921and collectively be better off if perpetually loved-up on more advanced and sustainable 2922analogues of E? Or are loved-up ecstatics just too vulnerable to genetic invasion 2923by "defectors" and wolves in sheep's clothing for such genes or allelic combinations 2924to flourish? Vulnerability to predatory and Machiavellian genetic rivals is presumably 2925the reason why sweetheart suckers living in blissfully E-like states are thin 2926on the ground in the drug-free Darwinian world. What reasons are there, if any, 2927for predicting that the nature of adaptive traits in the era of genetic engineering 2928will change in ways that make beautiful minds more widespread? 2929 2930 2931 <P> 2932If genetic engineering or rational drug design are to deliver us from the Darwinian 2933rat-race into everyday states of ecstatic grace, or anything at all like it, then 2934there are short-term and wider evolutionary constraints to be overcome. Truly 2935far-sighted genetic re-programming is a formidable challenge. Some genetic manipulations 2936may involve computing the interactions between dozens or ultimately hundreds of 2937alleles. Often their contributions to mental and behavioural traits won't be additive 2938but dependent on a plethora of environmental contingencies. This Problem of Conditional 2939Activation threatens a combinatorial explosion of possibilities to calculate. 2940It presents a daunting task of prediction and control. Other interventions, however, 2941might seem (comparatively) more straightforward. For instance, the action of testosterone, 2942and its hormonally active dihydrotestosterone metabolite, is in large part responsible 2943for war, social violence and competitive dominance behaviour, territoriality, sexual aggression, reduced male life-expectancy, 2944and going bald. The genetic and/or pharmacological manipulation of testosterone 2945may play a vital role in undercutting the darker horror scenarios for the future 2946so popular in the science-fictional literature. <P> 2947 2948 2949 2950Yet first there are many problems to be resolved here too. Testosterone can't, 2951realistically, just be edited out of the genome, as distinct from edited and re-regulated. 2952The eradication of testosterone would indeed spell a world without war. But <a href="https://www.bi
2952opsychiatry.com/steroids/anabolic.html">androgenic</a> 2953hormones can't be deleted altogether, even if the option of rearing functionally 2954emasculated or chemically castrated offspring were an idea palatable to prospective 2955parents, an unlikely prospect right now. Testosterone is the stereotypical "male 2956hormone". Yet testosterone is present in women too, albeit in smaller amounts: 2957it's important to female <a href="https://www.biopsychiatry.com/aphrodisiacs/passionpill.html">sexual</a> 2958response, just as it's responsible for spontaneous nocturnal erections in males. 2959Testosterone plays a role in female bone-strength, muscle-mass and a general sense 2960of <a href="https://www.biopsychiatry.com/testos.htm">well-being</a>. Moreover, 2961expository convenience aside, androgenic hormones are no more intrinsically evil 2962than the MDMA molecule is intrinsically good. Thus testosterone promotes what 2963might be described as "strong-mindedness". Today the trait of strong-mindedness 2964fosters what's often little more than callousness in pursuit of unworthy ends. 2965But not always. Even in a mature post-Darwinian civilisation, most of us may well 2966prefer to cultivate "strong personalities". The popularity of performance-enhancing 2967<a href="https://www.biopsychiatry.com/anabolic.htm">anabolic steroids</a> with 2968athletes and bodybuilders stems only in part from the way such drugs enhance strength, 2969power, speed, endurance and muscle-mass. For anabolic steroids are popular because 2970they can also act as mood-elevating, mind-toughening personality-pills. Taking 2971anabolic steroids induces a sense of well-being sometimes amounting to euphoria, 2972an increased tolerance of stress, and a sense of competitive "edge". The price 2973of using such drugs can be hypermasculine aggressiveness ["roid rage"], increased 2974dominance behaviour and even a propensity to sexual violence. Normal endogenous 2975male production of their native anabolic counterparts is risky enough already. 2976If our species is to survive its newfound capacity to build weapons of mass-destruction, 2977and tackle the genetic origins of male violence and all-round nastiness, then 2978we must somehow curb the biological roots of masculine aggression. This particular 2979intervention strikes us as a disconcerting prospect. Darwinian sexual and gender 2980identities are central to social existence today, and usually integral to who 2981we think we are. However, the long-term role of the Y chromosome in the evolution 2982of intelligent life is uncertain; and the ethical value of testosterone-driven 2983masculinity is unproven at best. The phenomenon of sexual reproduction itself 2984has only persisted and evolved as a defence against parasitism; an additional 2985mechanism that promotes genetic variability is a powerful weapon in the evolutionary 2986arms race against pathogens. In the new reproductive era ahead, however, genetic 2987diversity can be intelligently pre-planned. So at the very least, enlightened 2988biomedicine should be able to edit out a predisposition to the more sociopathic 2989forms of masculinity from the genome. More far-reaching strategies can be contemplated 2990too. On the other hand, recalling H.G. Wells' <i>The Time Machine</I> (1898), 2991we don't want to turn into enfeebled and weak-minded Eloi, even if we live in 2992a world without Moorlocks. It's good to wake up each morning feeling ready to 2993take on the world and win, even if we eventually discover that the rest of the 2994world is on our side; and some day it may be conspiring to help us. 2995 2996 2997 <P> Today 2998the world generally isn't on our side. Low testosterone function is associated 2999with social defeat, passivity and subordination. Low testosterone levels are also 3000implicated in depressed mood. The syndrome of depression has both proximate and 3001evolutionary roots. Depression is popularly viewed as a sign of weakness; and 3002folk-wisdom is right. Such a perception leads to its systematic underreporting, 3003especially among males, thereby painting a falsely rosy picture of (male) mental 3004health. Depressive illness is reported to be twice as common among women as men. 3005Conversely, it's sexy for men to be cool, confident and 'sussed' - the sort of 3006personality often faked if you aren't, though for evolutionary reasons depressives 3007find it harder to bluff. Therapists and sensitive physicians may take determined
3008steps to reassure their clients that <a href="https://www.biopsychiatry.com/alt-depression/faq1-5.html">depression</a> 3009<I>isn't</I> a sign of weakness. Alas this assurance typically isn't true. Depressives 3010characteristically tire quickly, act ineffectually and give up too easily. Potential 3011new antidepressants are correspondingly tested for their capacity to reverse the 3012learned helplessness and behavioural despair induced by chronically "stressing" 3013[torturing] non-humans in "animal models". Whereas exuberant hypomania is a signal 3014of strength and resolve, albeit a risky signal, depressives can't pursue their 3015projects with fanaticism, nor can they work indomitably to pursue what they believe 3016to be morally right. For their capacity to anticipate reward is blunted. Life 3017for depressed people too easily seems <a href="https://www.utilitarianism.com/gurney/index.html">meaningless</a>, 3018absurd and pointless - the nihilistic polar opposite to a hyperdopaminergic sense 3019of urgency and significance. For the mesocorticolimbic dopamine system mediates 3020not just the salience and intensity of <a href="https://www.wireheading.com/article/">anticipated</a> 3021reward; it also determines <a href="https://www.wireheading.com/hypermotivation.html">strength 3022of will</a>. By contrast, the spirit of depressives is easily broken; and there's 3023no natural remedy for weakness of will. 3024 3025 3026<P> This 3027grim diagnosis isn't a counsel of despair. On the contrary: well-designed genetic 3028and pharmacological interventions should in principle allow weaker spirits to 3029be invigorated and frailer personalities empowered. With better drugs and better 3030genes, one's idealised persona can be made flesh. We'll soon have the option of 3031making ourselves <a href="https://www.nietzsche.com/">stronger</a>, better-motivated 3032and more steely-minded in character than even the bravest palaeo-Darwinian primitive 3033or Nietzschean <i>ubermensch</I>. It's an open question whether such strength 3034of character will be egoistic or empathetic, cocaine-like or E-like, or something 3035different altogether. Yet with the right gene-and-drug combos, we can be superheroes, 3036even if the need for heroism may shortly pass. In the meantime, innovative pharmacotherapy 3037and/or genetic medicine will be vital if the weak-mindedness and weak willpower 3038blighting so many lives today is to be overcome. 3039 3040 3041<P> Weak-mindedness 3042takes many forms. One effect of administering MDMA is the way it eliminates jealousy. 3043Even anti-<a href="https://www.abolitionist.com/">abolitionists</a>, normally so 3044eager to hymn the character-building virtues of suffering stoically borne, rarely 3045find many positive words to say about the ennobling attributes of the green-eyed 3046monster. Jealousy is a persistently nasty, vicious, and pervasive feature of Darwinian 3047human social relationships. It's also about as voluntary as sneezing; and far 3048harder to cure. Like MDMA, <a href="https://www.biopsychiatry.com/ssrijeal.htm">SSRIs</a> 3049tend to diminish jealousy. SSRIs also act more sustainably than short-acting clubdrugs. 3050But SSRIs also tend to diminish the intensity of being in love. On MDMA, by contrast, 3051people of either sex can and frequently do spontaneously embrace and caress each 3052other - complete strangers as well as intimate friends. On MDMA, everyone naturally 3053tends to love each other, almost as if we were <a href="https://www.human-clone.com/">clones</a> 3054rather than genetic rivals. <P> 3055 3056 3057 Such 3058behavioural effects present a bizarre and perhaps disturbing spectacle to the 3059E-less Darwinian outsider. Yet the lessons to be drawn from the use of today's 3060crude hugdrugs and lovedrugs extend far wider than the recipe for a good weekend 3061out clubbing. One way to put the world to rights invokes the tired nostrums of 3062socio-economic and political reform. Such social engineering hasn't proven effective 3063at curbing the frightfulness of life to date. Pursued in a biological vacuum, 3064so to speak, any kind of environmental approach to building a world without <a href="http://www.amnesty.org/" target="_blank">cruelty</a>, 3065<a href="http://www.chromosome5.com/fear.html">
3065fear</a> and pain is bound to fail. 3066The other, biologically based strategy for saving the world will involve treating 3067our, say, congenital androgenic, serotonergic, <a href="https://www.opioids.wiki/opiates.html">opioidergic</a>, 3068dopaminergic, <a href="https://www.cacao-chocolate.com/pea.html">PEA</a> and <a href="https://www.mdma.net/endocannabinoid/index.html">endocannabinoid</a> 3069dysfunction via gene-therapy and rationally designed pharmaceuticals. Critically, 3070it entails choosing <a href="https://www.opioids.wiki/dynorphin/depression.html">kinder</a> 3071genotypes for our offspring. This option doesn't amount to a very soul-stirring 3072prospect. Like our notions of psychoactive drugs, the concept of "eugenics" is 3073horribly tainted. The word itself, originally a coinage of <a href="https://www.huxley.net/contexts/index.html">Sir Francis Galton</a> 3074(1822-1911), is indelibly tarred with the pseudoscientific quackery of the Third 3075Reich - though it's worth recalling that Nazi "<a href="http://fascism.com/">race-hygienists</a>" 3076didn't use happiness as their touchstone of genetic excellence. Yet the lethal 3077dangers posed by the genetic <I>status quo</I> coupled with advanced military 3078technology are <I>far</I> greater than the risks of a genetic reform program predicated 3079on the goal of world-wide personal happiness. Warnings from history aside, unless 3080the Darwinian masculine identities of our evolutionary past are superseded, then 3081jealousy, conflict and warfare will go on for ever (or kill us off); and the prophets 3082of doom will be right. <P> 3083 3084 3085 Alas 3086Ecstasy itself is something of a false prophet. MDMA-induced love is no more everlasting 3087than its older and fitness-enhancing counterpart. Two days after taking the magic 3088lovepill(s), the drug-catalysed outpouring of affection has subsided. "<a href="https://www.sensualism.com/love/romantic-brains.html">Natural</a>" 3089love sometimes lasts longer; but Darwinian love is still ephemeral, eventually 3090killed off by receptor desensitisation and down-regulation no less effectively 3091than E-induced love is ended by serotonin depletion. For the fickleness of Darwinian 3092affection has hitherto been genetically adaptive. It's an adaptation that remains 3093a shabby substitute for genetically-underwritten true love. Only by subverting 3094some exceedingly cruel feedback-inhibition mechanisms can the depth and range 3095of our affection for each other be enriched and sustained. As it is, most Darwinian 3096social life is soulless and loveless. But our genes do allow their vehicles to 3097fall in and out of love with a small percentage of prospective mates in ways that 3098tend to serve our reproductive success. In a largely anonymous mass-society, love 3099and affection are in even shorter supply than among tribal hominids in African 3100prehistory. Where love does sporadically flicker or flare up among us, its expression 3101is tightly regulated. E-less love is rarely all-embracing: such Darwinian love 3102tends to be <a href="https://www.sensualism.com/jealousy/index.html">jealous</a>, possessive and exclusive. The law and social sanction impose 3103penalties for loving too much or too little, loving the wrong person at the wrong 3104age or the wrong gender. "He who is rational about love is incapable of it"; but 3105this isn't true in the eyes of the law or of our peers. 3106 3107 3108 <P> At 3109MDMA-driven raves, by contrast, women can feel safe in public, gay people feel 3110truly at ease, and sexually straight or bisexual clubbers can express love and 3111affection for each other free from overt or internalised homophobia. Taboos on 3112touching and the whole gamut of tactile experience are relaxed. The body no longer 3113feels like a prison for the soul but an extension of it. The classic dopaminergic 3114psychostimulants like cocaine promote a hard-edged, don't-touch-me egoism. MDMA 3115promotes intimacy, warmth, and an empathetic sense of other humans beings as fellow 3116subjects rather than objects. <P> 3117 3118 3119 3120 Of 3121course, after a weekend of being "loved-up", mood-congruent post-E "reality" soon 3122sets in. Did one really let slip those gushing effusions to strangers one barely 3123knew? Did one really hug that hateful brute of a rival for the affections of one's 3124heart's desire? Viewed from [state-dependent] "reality" again a few days later, 3125being nice to everyone, truly loving oneself, and feeling (and being) wonderful 3126all seem faintly embarrassing, perhaps even a chemically-fuelled madness. "It 3127was the just the E talking". One may recall from English literature the effect 3128of taking <a href="https://www.huxley.net/soma/somaquote.html">soma</a>, the "ideal 3129pleasure drug" featured in <a href="https://www.huxley.net/ah/index.html">Aldous Huxley</a>'s uncannily prescient <I><a href="https://www.huxley.net/bnw/index.html">Brave 3130New World</a></I> (1932). After <a href="https://www.huxley.net/whoswho.htm#savage">John 3131the Savage</a> threatens to disrupt their soma supply, the angry low-caste Deltas 3132riot. They are promptly pacified by the riot police with soma-gas, and the rioters 3133end up hugging each other: <blockquote> <I> "Two minutes later the Voice and the 3134soma vapour had produced their effect. In tears, the Deltas were kissing and hugging 3135one another - half a dozen twins at a time in a comprehensive embrace. Even Helmholtz 3136and the Savage were almost crying. A fresh supply of pill-boxes was brought in 3137from the Bursary; a new distribution was hastily made and, to the sound of the 3138Voice's richly affectionate, baritone valedictions, the twins dispersed, blubbering 3139as though their hearts would break. "Good-bye, my dearest, dearest friends, Ford 3140keep you! Good-bye, my dearest, dearest friends, Ford keep you. Good-bye my dearest, 3141dearest..." </I> </blockquote>Too far-fetched? In 1998, a former South African 3142government scientist told a hearing of the Truth Commission that the minority 3143Apartheid government had planned to use MDMA on rioters. Desperate to retain their 3144faltering grip on power, the embattled regime apparently ordered its chemists 3145to make one tonne of Ecstasy for riot-control. Thus the <I>Calgary Herald</I> 3146(10 June 1998) reports:<blockquote><I>"Dr. John Koekemoer, former head of chemical 3147and biological weapons research, at the secret Delta G facility, said he disapproved, 3148"I did not believe Ecstasy was a good incapacitant and I told my superiors that", 3149he told the commission, which is investigating human rights abuses during the 3150apartheid era. "Ecstasy enhances interpersonal relationships. I told them I did 3151not want to kiss my enemy."</I> </blockquote>The scary notion of kissing one's 3152enemies, perhaps half-recalled cameos from Huxley's satirical fiction - and the 3153reality of strangers of either sex at raves hugging each other on E and telling 3154each other how wonderful they are - contribute to the perception that E-like states 3155of blissful empathy are inauthentic, shallow or false. How can the MDMA experience 3156have true emotional depth if the cosmic hug-bunny of the dance-floor reverts back 3157at the office next week to his old Darwinian mindset - and the (anti-)social vices 3158it spawns? A corrosive cynicism easily sets in. For <I>that's</I> the nature of 3159social reality, an emotionally frazzled post-Ecstatic may reflect, not the magical 3160interlude of Peace, Love and Understanding and Respect. 3161 3162 3163<P> 3164 3165 3166 Sadly,
3167in today's world, this may be so. The <a href="https://www.biopsychiatry.com/depressive-realism.htm">depressive 3168realism</a> of the serotonin-depleted and jaded cynicism of the chronically world-weary 3169are often justified. Yet our descendants may recognize that <I>we</I> are the 3170sociopathic emotional primitives in the grip of an affective psychosis. Jealousy, 3171envy, resentment, ridicule, hate, anger, disgust, spite, contempt, <I>schadenfreude</I> 3172and a whole gamut of nameless but mean-spirited states we undergo each day are 3173a toxic legacy of our Darwinian past. More commonly, perhaps, our genetic make-up 3174ensures we simply feel indifference to the plight of all but a handful of significant 3175others in our lives. Right now, for instance, one knows dimly at some level that 3176there is frightful and preventable suffering in the world. Yet most of us feel 3177no overpowering moral urgency to do anything about it. Idealists might vaguely 3178entertain the second-order desire to care more deeply and give, say, a larger 3179proportion of one's money to Third World charities dedicated to those who need 3180the resources more urgently than we do. Yet the biological roots to sustain "saintly" 3181self-sacrifice just aren't there in most of us. In contrast, taking MDMA can give 3182rise to a prodigious sense of compassion in even the otherwise morally inert. 3183Regrettably, such compassion is usually ineffectual; it's too short-lived to do 3184much good. If and when we understand the neurochemical basis of empathy, however, 3185then <a href="https://www.empathogens.com/altruizine/index.html">sustaining</a> the molecular substrates of empathetic love can turn boundless 3186compassion into an automatic reaction to distress, not a sign of drug-induced 3187psychiatric disorder. Intervention can go further. If we decode and opt to amplify 3188the molecular machinery of volition too, then such heightened compassion can be 3189translated into effective action. <P> 3190 3191 3192 3193 Fortunately, 3194compassion if not empathy for others may ultimately be redundant. In the long 3195run, <i>if</I> biotechnology can be used to <a href="https://www.paradise-engineering.com/heav5.htm">eradicate</a> 3196suffering from the living world, then a shared celebration of life, not sympathy 3197for the misfortunes of others, may come to seem as natural as breathing. Yet right 3198now too many people walk the Earth who have no cause to celebrate anything. Therapeutic 3199agents designed to deepen empathy and sustainably awaken our compassion are a 3200priority. The functional prototype of what's needed exists today in the form of 3201a fast-acting hugdrug; but MDMA itself is not the recipe for perpetual sainthood. 3202 3203 3204 3205<P> The design of richer functional 3206analogues of MDMA entails more than finding <a href="https://www.biopsychiatry.com/medication.html">medicines</a> to make us sweeter-natured. 3207Improving human nature is perhaps ethically all-important, but MDMA is also an 3208entactogen - a more elusive concept than that of an empathogen. MDMA offers "insight 3209without fear" (Dr Shulgin). The nature of entactogenesis is far harder to fathom, 3210let alone communicate, than the nature of empathy. The word for such states comes 3211close to being a primitive term, its sense semantically inaccessible to the MDMA-naïve. 3212The clarity of MDMA-mediated self-insight is perhaps a form of what <a href="http://www.paradigm-sys.com/" target="_blank">Dr 3213Charles Tart</a> calls "state-specific knowledge". E-less cynics may be sceptical. 3214Just what's the propositional content of this so-called "insight"? Couldn't it 3215be delusive? ["It's not hard to hear voices. It's knowing whether they tell you 3216the truth."] But on pure MDMA, the subject can inwardly access the kind of person 3217s/he wants to be; "the ideal me". Whether this idealised self-identity is created 3218or discovered may be philosophically debatable. But the deeply-felt sense of authenticity 3219and emotional self-honesty of the MDMA experience is an unexpected delight. One 3220just won't ever get to read about its nature in the peer-reviewed <I>Journal of 3221Introspective Studies</I>. <P> 3222 3223 3224 In 3225Western culture, a capacity for reflective self-insight is not highly prized. 3226Introspective genius and a talent for meditation aren't respected in either academia 3227or business. Nothing in our education system is geared toward making young people
3228feel that introspective self-analysis, enhanced self-awareness or personal growth 3229matters in the slightest. How can they be tested, graded and quantified? What's 3230their market value? Anyone in Western society with a tendency to quiet contemplation 3231is likely to be stigmatised as lazy, feckless and unenterprising - unlike the 3232sound and fury of the lionised Man Of Action, and his larger-than-life ego on 3233whose life-energies lesser mortals may feed. In similar manner, our (limited) 3234vision of future civilisations tends to focus on their technological marvels - 3235and the supposed Darwinian dominance-battles of their science-fictional inhabitants 3236- rather than on odysseys into the inner depths of their souls. Yet the design 3237of long-acting entactogens - and their neurological analogues - should allow introspective 3238depth and a capacity for higher-order self-reflection to be fabulously enriched 3239as well. Tomorrow's counterparts of today's bunch of furtive adolescent introspectionists 3240won't have to shuffle around faint little tickles of thought. Drugs to 3241enrich self-insight and heighten self-reflection may eventually become commonplace. 3242They may be distributed as freely as aspirin if not smarties; and prove safer 3243in excess than either. <P> 3244 3245 3246 3247 This 3248prospect is some way off. Full-blooded pharmacological and genetic emancipation 3249is still decades away. Even so, we are poised to acquire a literally life-transforming 3250technology - a toolkit for enlightenment powerful enough to implement Heaven-On-Earth 3251and beyond - yet we balk at the sorts of public health policy decision needed 3252to accelerate the transition. An enriched conception of mental health is blocked 3253by entrenched elites who've never sampled what they outlaw - whether designer 3254genes or utopian pharmacology. In the jaundiced eyes of (most of) the older generation, 3255Ecstasy and rave-culture are an aberration, not a portent. "Peace, Love, Understanding 3256and Respect" sounds like a hollow slogan. Today, in the wider world, the words 3257can't be anything else. Ecstasy itself is too short-acting, unsustainable and 3258neurotoxic at high doses to form part of anyone's global health plan. But a permanent 3259distillation of the MDMA magic, if feasible, offers an extraordinary if unorthodox 3260vision of one post-Darwinian paradise to come. <P> 3261 3262<a name=ecstasymdma></a><br><h3>Beyond MDMA : mental 3263superhealth?</h3>Moore's Law in computing is named after semiconductor engineer 3264and Intel co-founder Gordon Moore. It states that processing power in computers 3265doubles every eighteen months or so. Moore's Law has roughly held good since 1965 3266when it was first propounded. It's a rule-of-thumb about how many transistors 3267we can cram onto successive generations of chip rather than a fundamental truth 3268about Nature. Yet the <a href="https://www.abolitionist.com/exponential.html">trend</a> it captures seems set to continue, at least until 3269chip designers run up against the physical constraints of the nanoscale later 3270next decade, or perhaps until quantum computers allow calculations orders of magnitude 3271more powerful than today's toys. <P> 3272 3273 3274 Unfortunately, 3275the dizzying rate of technical progress that Moore's law quantifies hasn't been 3276matched by an analogous law of progress for generations of <i>human</I> mental health. 3277On average, we are probably no happier than our malaise-ridden hominid ancestors. 3278We aren't noticeably fonder of each other. By way of consolation, we can 3279take refuge in the pre-scientific notion that <a href="https://www.biopsychiatry.com/happiness/happyfut.html">happiness</a> is <a href="https://www.paradise-engineering.com/happiness/">unquantifiable</a>. Yet 3280if such quasi-objective indices of mental health as suicide rates are anything 3281to go by, then we would probably be psychologically better off as hunter-gatherers. Over 800,000 people 3282in the world took their own lives last year. The World Health Organisation (<a href="http://www.who.int/en/" target="_blank">WHO</a>) 3283estimated that this figure will rise to around 1.5 million by the year 2020. Here 3284in the UK, suicide is the most common cause of death for men under 35 years old. 3285Globally, several hundred million people are clinically or "sub-clinically" depressed;
3286and a spectrum of chronic <a href="https://www.biopsychiatry.com/anxiety/index.html">anxiety disorders</a> 3287afflicts further hundreds of millions more. Even as we progressively conquer physical 3288disease as conventionally defined, the toll of psychological distress is still 3289rising. Admittedly, "mental illness" and "mental health" are value-laden, ideologically 3290contested terms. Even the new scientific discipline of biological psychiatry is 3291inescapably culture-bound. Yet "Progress" that doesn't leave us emotionally better off 3292would seem something of a misnomer. <P> 3293 3294 3295 Not 3296merely has there been no discernible growth in average mental health to 3297match the tempo of scientific advance, technophobes claim there never will be such a mental health revolution. 3298As long as we rely on the same legacy wetware to animate our lives, the neo-Luddites 3299and religious fundamentalists may even be right. Our levels of well-being - and 3300ill-being - compute fitness functions that served the inclusive fitness of our 3301DNA in our ancestral environment in Africa. Our genes didn't design us with the emotional 3302welfare of their throwaway vehicles in mind. So the genetically adaptive hedonic 3303treadmill - for many of us better named the dolorous treadmill - ensures that 3304average levels of well-being/ill-being of Darwinian life remain stagnant. Six 3305months after winning the national lottery or becoming quadriplegic in a catastrophic 3306accident, the winner/victim statistically reverts to his or her average level 3307of ill-being/well-being before the win/trauma. Hence such affirmations as Rajinder Johar's "<a href="https://www.mdma.net/misc/joy-of-quadriplegia.pdf" target="_blank">The Joy of Quadriplegia</A>". Illustrating the hedonic treadmill at its 3308most extreme, "locked-in syndrome" leaves its victims <a href="https://www.wireheading.com/brainstim/thought.html">paralysed</a>. 3309The subject is fully conscious but unable to move any extremities, talk, or make 3310horizontal eye movements. Yet in the words of James Hall, longest surviving (2002) 3311American victim of a midbrain pontine stroke: "In some ways, my stroke was a blessing....Since 3312my stroke, I've published books, articles, poems. I'm busier and happier than 3313I've ever been." Completely paralysed, Mr Hall communicates by focusing on particular 3314letters that his computer picks up from his limited eye-motions. 3315 3316 3317 <P> Such triumph-of-the-human-spirit 3318stories are comforting, up to a point. The downside of the emotional <a href="https://www.hedweb.com/wirehead/homeostasis.html">
3318homeostasis</a> they reflect is 3319that millions of temperamentally depressive and dysthymic people would feel gloomy 3320in the Garden of Eden. Again, this hypothesis isn't easy to test rigorously. The 3321more dramatic manifestations of emotional homeostasis at work are hard to investigate ethically 3322in well-controlled prospective studies. Anecdotes and impressions aren't science. 3323Yet the cumulative evidence for a genetically constrained "<a href="https://www.biopsychiatry.com/hedonicsp.htm">set-point</a>" 3324in our pleasure-pain axis is compelling. The dismally low dial-setting doesn't bode 3325well for any utopian project based around mere <I>social</I> reform. <P> Fortunately 3326there is no reason, in principle, why an analogue of Moore's law can't be implemented 3327in successive generations of the reward circuitry of organic life-forms. The affective, 3328aesthetic, intellectual, interpersonal (and spiritual?) well-being of neurochemical 3329robots like us can be genetically pre-coded. If rationally redesigned, our enlightened 3330successors may view today's "natural" rewards as poor surrogates for genetically underwritten 3331happiness. When the <a href="https://www.wireheading.com/pleasure.html">mechanisms</a> underlying bliss and its gradients are understood, 3332the molecular machinery of the sublime can be modulated - and amplified indefinitely. Within a 3333few decades at most, we will be scientifically enlightened enough to redesign the neurochemical 3334pathways of emotion. Meanwhile our pleasure centres are too small for us to flourish; and their functional 3335architecture is inefficient. They needn't be either: our normal homeostatic "set-point" 3336of well-being can be genetically ratcheted up to a far higher plane; and archaic Darwinian 3337notions of mental "illness" and "wellness" consigned to oblivion. Gradients of 3338indescribable happiness can potentially animate our lives no less powerfully than gradients 3339of ill-being. Until this fabulous era dawns, then - to borrow the words of Oscar Wilde - "we are all in the gutter, but some of us are looking 3340at the stars".<P> 3341 3342 3343 Critically, such 3344<a href="https://www.gradients.com/">gradients</a> of celestial bliss can also be <a href="https://www.mdma.net/mdma/mdmaacety.html">lucid</a>, 3345serene, entactogenic and empathetic - i.e. MDMA-like and better, not <a href="https://www.biopsychiatry.com/manvar.htm">manic</a> or 3346vulgarly hedonistic. The godlike powers of tomorrow's biotechnologists 3347will allow the neurological substrates of <a href="https://www.empathogens.com/empathy/wired.html">empathy</a> and self-insight to be permanently 3348up-regulated. Aesthetically, the mundane ugliness of life in the present epoch can be replaced 3349by gradations of hitherto unimaginable <a href="https://www.sensualism.com/beauty/pretty-women.html">beauty</a>. Potentially again, an E-like magic 3350can imbue the texture of normal waking consciousness. If we so wish, our emotional 3351palette can be genetically enriched, mixed and then pharmacologically refined 3352in ways that transcend the crude primary colours of our Darwinian past. <P> 3353 3354 3355 Counter-intuitively, 3356yet indispensably for the long-term evolutionary stability of a ecstatic society 3357of redesigned 3358<a href="https://www.hedweb.com/transhumanism/index.html">post-humans</a>, allelic combinations that promote blissful <a href="https://www.empathogens.com/empathy/index.html">empathy</a> 3359can also potentially be fitness-enhancing - in the technical Darwinian as well 3360as in the popular sense of "fitness". The dawning reproductive era of "designer-babies" 3361promises to be empowering because the capacity for parental love and nurture 3362can be genetically and pharmacologically enhanced, not just levels of personal 3363happiness, health and <a href="https://www.nootropic.com/smartmice/index.html">superintelligence</a>. 3364The age-old scourge of child-neglect (and worse) can be relegated to evolutionary history. <i>Very</I> 3365speculatively, our future offspring may not merely be more loved by their caregivers, 3366but much more "loveable" too. For if given the [genetic] freedom to choose, then 3367parents-to-be may understandably want their offspring to be loving as well as 3368smart and happy. <P> 3369 3370 3371 The prospect 3372of unleashing such parental freedom is disturbing to most of us. Why not leave babymaking, 3373as before, either to the mysterious workings of Providence or the blind shufflings of 3374selfish DNA? Yet now we're imminently free to choose, there is nothing self
3374-evidently 3375morally admirable about playing genetic Russian-roulette with the lifeforms we 3376create. Many of the nastier behaviours and modes of consciousness that so often 3377proved fitness-enhancing in the ancestral environment will cease to be adaptive 3378if the alleles that promote them tend to be shunned by prospective parents intent 3379on creating the children of their dreams. The "nastier" alleles may well get out-competed. 3380<a href="https://www.reproductive-revolution.com/index.html">Selection pressure</a> will tend to favour a very different range of heritable adaptive 3381traits once evolution is no longer "blind" i.e. when genotypes are parentally 3382chosen or designed <I> in anticipation</I> of their likely effects on a child's 3383behavioural phenotype. If we want to, we can systematically redesign ourselves 3384and choose the traits of our offspring. The details, for sure, are sketchy. Reproductive 3385science and genetic engineering are in their infancy. But <I>Homo sapiens</I> is poised to bootstrap its 3386way out of the cruel Darwinian <a href="https://www.abolitionist.com/anti-natalism.html">abyss</a>. <P> 3387 3388 3389 Inevitably, 3390talk of treating humans like organic robots, and then mooting a baseline of mental 3391health <a href="https://www.superhappiness.com/">orders of magnitude</a> richer than the Darwinian mind can contemplate, 3392sounds fantastical today. In the context of our traditional conceptual framework, 3393the idea of an analogue of Moore's law for successive generations of human mental 3394health evokes thoughts of cloud-cuckoo-land, not a global health-plan. Set against the daily messiness 3395of our ecstasy-impoverished lives, the prospect of using biotechnology to <a href="https://www.hedweb.com/hedethic/end-suffering.html">abolish</a> suffering, 3396and a post-Darwinian transition to paradise-engineering, strikes most of us as 3397fanciful, its liberatory potential just a mirage. At best, such heady words fall 3398lifelessly off the page or screen. Yet a major discontinuity - a momentous evolutionary 3399transition in the development of life on earth - is imminent as the biotechnology 3400revolution unfolds. The advent of genomic medicine is set to challenge the old 3401Darwinian regime of natural selection and the emotionally crippled minds it 3402spawned. <P> 3403 3404 3405 In the long run, 3406genomic medicine can underwrite mental and physical superhealth for everyone. 3407For in principle, lifelong well-being can be genetically hardwired from conception. 3408In the short run, better-designed research tools and therapeutic agents can probe, 3409and then repair, our damaged minds. As chemical stopgaps go, MDMA is a magical 3410revelation. It's perhaps the best aid to insight-oriented psychotherapy ever synthesized. 3411Tragically, when MDMA is used to excess the outcome can be harmful, not healing. So as a weekend 3412<a href="https://www.mdma.net/toxicity/washpost.html">club drug</a>, MDMA is seriously 3413flawed. Today, of course, empathogens and entactogens are outlawed for any purpose. The altered states 3414of consciousness they induce are criminalised. People who take such agents are 3415stigmatised as "drug abusers". Yet some MDMA users feel, rightly or wrongly, they've 3416been granted a tantalising glimpse of what true <a href="https://www.abolitionist.com/">mental health</a> may be like in centuries 3417to come; and an insight into what the rest of us are missing.<P><br> 3418 3419 3420<small> 3421<a href=sashashulgin-davidpearce.html>David Pearce</A><br> 3422(last updated 2024)</small><P> 3423 3424<center> * * * </center><P> 3425 3426<a name=update></a><b>2023 Update.</b><br> 3427Safe, sustainable analogues of MDMA do not yet exist. The prospect of <a href="https://www.hedweb.com/social-media/beyond-humanism.pdf">gene therapy</A> to enable existing human and nonhuman animals to enjoy perpetual MDMA-like consciousness is still decades away. Likewise, routine access of all prospective parents to preimplantation genetic screening, counselling and gene-editing to enable innate MDMA-like mental health as a default condition of everyday life can seem like science-fiction in the wake of the <a href="https://en.wikipedia.org/wiki/He_Jiankui_affair" target="_blank">He Jiankui</A> affair and the public backlash against "designer babies". Reflex invocation of the "<a href="https://www.eugenics.org/">e</A>" word still retards progress towards genome reform and a <a href="https://www.reproductive-revolution.com">reproductive revolution</A>. 3428<P> 3429However, three encouraging developments are worth noting. <p> 3430<b>First</B>, <a href="https://maps.org/" target="_blank">MAPS</A>' Phase 3 clinical trial of MDMA-assisted therapy for PTSD, <a href="https://www.nature.com/articles/s41591-021-01336-3" target="_blank">published</A> on May 10, 2021, in <I>Nature Medicine</I>, showed statistically significant improvement. In 2017, the FDA granted Breakthrough Therapy designation for MDMA-Assisted therapy for PTSD (<I>cf</I>. <a href="https://en.wikipedia.org/wiki/MDMA-assisted_psychotherapy">MDMA-assisted Psychotherapy</A> (Wikipedia)). The positive MAPS trial augurs well for FDA approval of MDMA-assisted therapy in 2024. The media routinely describe MDMA as a "psychedelic"; but the distinction between psychedelics and entactogen-empathogens is worth preserving. Putative "psychedelic therapy" for dark, Darwinian minds may be too dangerous and unpredictable. MDMA is different. 3431 3432<P> 3433<b>Second</b>, <a href="https://pharmala.ca/" target="_blank">PharmAla Biotech</a>'s MDXX drug discovery program of MDMA analogues delivered its lead drug candidate, <a href="https://won in AI heralds a passable imitation of artificial general intelligence. <a href="https://en.wikipedia.org/wiki/GPT-4">GPT-4</A> is a gamechanger. Digital zombies can now write more intelligently about consciousness and MDMA than the vast majority of humans. For example, see <a href=chatgpt/index.html>ChatGPT-4 on MDMA</A>. In collaboration with human investigators, GPT-4 and its cousins can play a role in psychoactive drug discovery and n
3433ovel MDMA-analogues in a recursive cycle of improvement. To be clear, classical Turing machines and connectionist systems are <I>idiots savants</I> whose insentience is architecturally hardwired. "Digital mind" is an oxymoron. Phenomenal <a href="https://www.hedweb.com/hedethic/binding-interview.html">binding</A> into <I><a href="https://www.hedweb.com/quora/2015.html#categorize">mind</A></I> is classically impossible. So classical computers are not going to "wake up" and become psychonauts - i.e. phenomenally-bound subjects of experience like humans who explore myriad state-spaces of consciousness. In consequence, full-spectrum superintelligence - <a href="https://www.biointelligence-explosion.com/parable.html">supersentience</A>, so to speak - will most likely retain a neuronal core. But AI plus psychonautic research promww.biospace.com/article/releases/pharmala-submits-pre-ind-dossier-for-novel-mdma-analog-to-fdaala-002-is-pharmala-s-lead-drug-candidate-showing-exceptional-safety-and-efficacy-in-preclinical-rodent-models/" target="_blank">ALA-002</A>. Information on the subjective effects of ALA-002 is scanty even within the scientific counter-culture. In November 2022, PharmAla announced it had submitted its <a href="https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/otat-pre-ind-meetings">pre-IND</A> data meeting package on ALA-002 to the FDA. PharmAla hopes that ALA-002 can be used in the treatment of adults diagnosed with Autism Spectrum Disorders, broadly defined. The Canadian biotech company researches and develops Novel Chemical Entities (NCEs) based on the MDXX class of molecules with a view to improving their safety and efficacy. The base MDMA molecule can be <a href="https://ca.finance.yahoo.com/news/patent-application-published-pharmala-biotech-130000383.html" target="_blank">improved upon</A>. If PharmAla Biotech succeeds in its mission, Utopian Pharmacology can become more than an empty label. 3434<P> 3435<b>Third</b>, a revolution in AI heralds a passable imitation of artificial general intelligence. <a href="https://web.archive.org/web/20240112090934/https://en.wikipedia.org/wiki/GPT-4">GPT-4</a> is a gamechanger. Digital zombies can now write more intelligently about consciousness and MDMA than the vast majority of humans. For example, see <a href="https://web.archive.org/web/20240112090934/https://www.mdma.net/chatgpt/index.html">ChatGPT-4 on MDMA</a>. In collaboration with human investigators, GPT-4 and its cousins can play a role in psychoactive drug discovery and novel MDMA-analogues in a recursive cycle of improvement. To be clear, classical Turing machines and connectionist systems are <i>idiots savants</i> whose insentience is architecturally hardwired. "Digital mind" is an oxymoron. Phenomenal <a href="https://web.archive.org/web/20240112090934/https://www.hedweb.com/hedethic/binding-interview.html">binding</a> into <i><a href="https://web.archive.org/web/20240112090934/https://www.hedweb.com/quora/2015.html#categorize">mind</a></i> is classically impossible. So classical computers are not going to "wake up" and become psychonauts - i.e. phenomenally-bound subjects of experience like humans who explore myriad state-spaces of consciousness. In consequence, full-spectrum superintelligence - <a href="https://web.archive.org/web/20240112090934/https://www.biointelligence-explosion.com/parable.html">supersentience</a>, so to speak - will most likely retain a neuronal core. But AI plus psychonautic research promise an awesome future for sentience in the cosmos. </p><p> 3436 3437 3438<a name=update></a><b>2024 Update.</b><br> 3439In June 2024, a <a href="https://onlinelibrary.wiley.com/doi/full/10.1111/jnc.16149">study</A> published in the <I>Journal of Neurochemistry</I> identifies three new variants of MDMA as promising candidates for safer use: ODMA, TDMA and SeDMA. The three drugs have been developed with a view to retaining the extraordinary positive effects of taking MDMA while reducing adverse after-effects. The authors write: âOur findings suggest that these new MDMA bioisosteres might constitute appealing therapeutic alternatives to MDMA, sparing the primary pharmacological activity at hSERT, hDAT, and hNET, but displaying a reduced activity at 5-HT2A/2B/2C receptors and alternative hepatic metabolism. Whether these MDMA bioisosteres may pose lower risk alternatives to the clinically re-emerging MDMA warrants further studies." 3440<P> 3441 3442 3443 3444Also in June 2024, a U.S. Food and Drug Administration advisory committee <a href="https://edition.cnn.com/2024/06/04/health/mdma-ptsd-fda-advisers/index.html" target="_blank">voted</A> that evidence is lacking that MDMA-assisted therapy is effective for treating post-traumatic stress disorder (<a href="https://www.nature.com/articles/s41591-023-02565-4" target="_blank">PTSD</A>). The advisory committee reported that the benefits of MDMA-assisted therapy donât outweigh the risks to patients. Panellists voiced various concerns with the data. Issues ranged from study design; uncertainty whether MDMA-assisted therapy offers long-lasting benefits; and the potential risk of heart problems and abuse. The sponsor of the MDMA treatment, <a href=https://lykospbc.com/" target="_blank">Lykos Therapeutics</A>, formerly MAPS, conducted two clinical trials showing that patients treated with MDMA experienced a significant improvement in their PTSD symptoms relative to subjects who received only a placebo. Unfortunately, the consciousness-altering properties of MDMA also vastly complicate the <a href="https://www.statnews.com/2024/05/31/mdma-therapy-ptsd-lykos-fda-advisory-meeting-psychedelics/" target="_blank"> double-blind</A>, placebo-controlled gold-standard for clinical trials. An FDA official, Tiffany R. Farchione, told the panel that although the agency had asked Lykos to report impacts associated with abuse, Lykos did not note effects such as âeuphoriaâ or âelated mood.â <p> 3445On August 9th, the FDA accepted the advisory committee's recommendation and <a href="https://www.bbc.com/news/articles/c624jd9g3z3o" target="_blank">declined</A> to approve MDMA-assisted therapy for PTSD. In its letter of rejection, the FDA asked the drugmaker Lykos Therapeutics further to study the safety and efficacy of the proposed treatment. The decision was widely reckoned a setback for the nascent field of psychedelic medicine. But classifying MDMA as a <a href="https://www.hedweb.com/quora/2015.html#psychedelics">psychedelic</A> in the first instance is problematic. Not least, psychedelics don't tend to promote a heightened sense of authenticity: <I>this-is-the-real-me</I>. MDMA is in a class of its own.<p> 3446 3447Research on safe and sustainable MDMA analogues continues. See <a href="https://en.wikipedia.org/wiki/ODMA_(drug)" target="_blank">ODMA</A>
3447, <a href="https://en.wikipedia.org/wiki/TDMA_(drug)" target="_blank">TDMA</a>, <a href="https://en.wikipedia.org/wiki/SeDMA" target="_blank">SeDMA</a> (Wikipedia). But the vision of loved-up life and civilization sketched in <I>Utopian Pharmacology</I> (2002, 2024) is currently a distant dream. <P> 3448 3449 3450 3451 3452 3453 3454 3455 3456 3457 3458 3459 3460 3461 3462 3463 3464 3465 3466 3467 3468 3469 3470 3471 3472 3473 3474 3475 3476 3477 3478 3479 3480 3481<br> 3482<center> * * * </center><P> 3483 3484 3485 3486 3487 3488 3489 3490 3491 3492 3493 3494 3495 3496<center> 3497<P>E-mail<br> <b> <a href="mailto:[email protected]">[email protected]</a></b><p><b> <a href=refs/index.html><img src=swan.jpg width=100 height=92 border=0 alt="mdma.net"></a><br> 3498<br><a href=refs/index.html>Refs</a><br></b> and further reading<p><b> 3499<a href="https://www.hedweb.com/">Hedweb</a><BR> 3500 3501<a href=ecstasy/index.html>MDMA 3502hotlinks</a><BR><a href=claudio-naranjo/index.html>Claudio Naranjo</a><BR> <a href=mdma.html>MDMA synthesis</a><br> 3503<a href="https://www.superhappiness.com/">Superhappiness?</A><BR> 3504 3505 3506<a href=chatgpt/index.html>ChatGPT on MDMA</A><br> 3507<a href="https://www.hedweb.com/social-media/">Social Media 2026</A><BR> 3508 3509 <a href="https://www.biopsychiatry.com/interview/index.html">Alexander 3510Shulgin</a><br> 3511 3512<a href="https://en.wikipedia.org/wiki/MDMA">MDMA (Wikipedia)</A><BR> 3513<a href="https://en.wikipedia.org/wiki/MDMA">MDMA (Grokipedia)</A><BR> 3514 3515 <a href=accidental-ecstasy.html>Accidental Ecstasy?</a><BR> 3516<a href="https://www.biopsychiatry.com/">The 3517Good Drug Guide</a><br> 3518 3519 3520 3521<a href=ecstasy-honesty.html>Ecstasy and Honesty</a><BR> 3522 3523<a href="https://www.abolitionist.com/">The Abolitionist Project</a><br> 3524 3525 3526<a href="https://www.hedweb.com/quora/index.html">Quora Answers 2015-26</A><BR> 3527<a href="https://www.huxley.net/"><b>Critique of <I>Brave 3528New World</I><br> 3529 3530<a href="https://www.reproductive-revolution.com/index.html">The Reproductive Revolution</A><BR> 3531<a href="https://www.biointelligence-explosion.com/index.html">The Biointelligence Explosion</A><p> 3532 3533</B><P> <P> <p> <br> </B></center></font></blockquote></blockquote></blockquote></blockquote> 3534 3535</body></html> 3536
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