Noded for posterity from the truly superb HedWeb - to be found at WWW.ANTIDEPRESSANTS.COM. All credit to the original author, David Pearce, who has gladly and freely granted permission for reproduction here.(..and possibly the longest node in existence?)


Could we live happily ever after? Perhaps. One's interest in the genetically pre-programmed states of sublimity sketched in The Hedonistic Imperative is tempered by the knowledge that one is unlikely to be around to enjoy them.
It's all very well being told our descendants will experience every moment of their lives as a magical epiphany. For emotional primitives and our loved ones at present, most of life's moments bring nothing of the sort. In centuries to come, our base-line of emotional well-being may indeed exceed anything today's legacy wetware can even contemplate. Right now, however, a future Post-Darwinian Era of paradise engineering can seem an awfully long way off. Mainstream society today has a desperately underdeveloped conception of mental health.

There's clearly a strong causal link between the raw neurobiological capacity to experience happiness and the extent to which one's life is felt to be worthwhile. High-minded philosophy treatises should complicate but not confuse the primacy of the pleasure-pain axis. So one very practical method of life-enrichment consists in chemically engineering happier brains for all in the here-and-now. Yet how can this best be done?

Any strategy which doesn't subvert our in-built hedonic treadmill of inhibitory feedback mechanisms in the CNS will fail. Political and socio-economic reforms offer at best a lame stopgap. To the scientific naturalist, all routes to happiness must ultimately be biological: "culture" must be neurochemically encoded to exert its effects. Some of these routes to happiness involve the traditional environmental detours. They are too technical, diverse and futile to tackle here. If the quality of our lives is to be significantly enhanced in the long term, then the genetically predisposed set-point of our emotional thermostats needs to be recalibrated. The malaise-ridden norm typically adaptive in humanity's ancestral environment must be scrapped.
So while we wait for germ-line gene-therapy to become standard, it's worth considering instead how ordinary early twenty-first century Homo sapiens can sustainably maximise emotional well-being with only present-day pharmacology to rely on. No less importantly, how is it possible to combine staying continuously high - one's embarrassment at using the frisson-charged term from the vernacular is revealing - with retaining one's sense of social and ethical responsibility to other people and life-forms?

Extracting reliable information on this topic is extraordinarily difficult for laity and professionals alike. The layman is more likely to be given heavily slanted propaganda. Unvarnished fact might confuse his uneducated and functionally diminutive brain. Career-scientists, on the other hand, are bedevilled by a different problem. Access to funds, laboratories, raw materials, journal publication, professional preferment, and licenses to conduct experimental trials is all dependent on researchers delivering results their paymasters want to hear. The disincentives to intellectual integrity could scarcely be greater; and they are cloaked in such reputable disguise.

By way of illustration, it's worth contemplating one far-fetched scenario. How might an everlasting-happiness drug - a drug which (implausibly!) left someone who tried it once living happily-ever-after - find itself described in the literature?

"Substance x induces severe, irreversible structural damage to neurotransmitter sub-system y. Its sequelae include mood-congruent cognitive delusions, treatment-resistant euphoria, and toxic affective psychosis."

Eeek! Needless to say, no responsible adult would mess around with a potent neurotoxin under this description.

Several excellent researchers play the game by the rules. They keep their heterodox opinions to themselves. Others find such cognitive dissonance too unpleasant. So they gradually internalise the puritanical role and tendency to warped scientific prose expected of them. (Whereas horribly-tortured experimental animals, for instance, blandly get "used" and "sacrificed", certain drugs always get "abused" by "drug-abusers") On the other hand, some of the most original and productive minds in the field of psychopharmacology - pre-eminently Alexander Shulgin - have already been silenced. Many more careers have been intellectually strangled at birth or consigned to professional oblivion. The danger of poisoning the wells of information, for whatever motives, is straightforward. When young people discover they have been lied to or deceived, over cannabis for instance, they will pardonably assume that they have been lied to or deceived over the dangers of other illegals too. And this, to put it mildly, would be exceedingly rash.

Most recently, the Internet daily delivers up an uncontrollable flood-tide of fresh ideas to counter official misinformation. Unfortunately, a lot of it isn't much more objective in content or style than the professional journals it complements. Devising one's own system of filtering and quality-control to drown out the noise is a challenging task for anybody.


One spectacularly incompetent route to a lifetime of happiness involves taking illegal psychostimulants such as cocaine or the amphetamines. In the short term, their activation of the sympathetic nervous system tends to elevate mood, motivation and energy. Users tend to talk a lot. Self-confidence is enhanced: these are "power drugs". Physical strength and mental acuity are variably increased. Whereas cocaine blocks the neuronal re-uptake of the catecholamine neurotransmitters noradrenaline and dopamine, amphetamine triggers to a much greater extent their synaptic release as well. It feels coarser, lasts longer and costs less.

In either case, libertarian indignation that the State presumes to subject its citizens to totalitarian-style mind-control should not obscure the fact that for most purposes these are not useful drugs. This is because the central nervous system supports a web of mutually inhibitory feedback-mechanisms. In response to a short-term increase of mood-mediating monoamines in the synapses, the genes and neuronal receptors re-regulate. So at best no real long-term benefit is derived from the use of such compounds. Neither cocaine nor amphetamine yield the sustained activation of intracellular signal-transduction cascades needed to cheat the hedonic treadmill.

Some people continue to take psychostimulants casually for years without serious harm. Yet the potential risks of adverse physical, psychological and social ill-effects are high. Hence their use is best discouraged.

The "depressant" opioids are somewhat more benign. They are effective painkillers. They can also be extremely pleasurable. In classical antiquity, Aristotle - admittedly not always the soundest authority on medical matters - classified pain as an emotion. Opium was a traditional remedy for melancholic depression; its efficacy is arguably superior to Prozac, though controlled clinical trials are lacking. In "animal models", opioids reverse the depressed behavior, learned helplessness and neuroendocrine responses associated with clinical depression. By contrast, opioid antagonists such as naloxone exacerbate them. To confuse matters further, modern so-called "antidepressants" can themselves act as "physical" painkillers. Conversely, mu-opioid receptor agonists offer both unsurpassed pain-relief and extraordinary emotional well-being. There is clearly an intimate link between "physical" and "emotional" pain. In defiance of dualist metaphysics, the opioids tend to be best at banishing both.

Contemporary medical orthodoxy classifies drug-induced bliss as an "adverse side-effect" of analgesics - even in the terminally ill. Yet we could all do with having our native endorphin systems enriched. Next century and beyond, the customised site-selective successors to today's opioid drugs will play a critical role in promoting emotional superhealth.

Unfortunately, present-day opioids are flawed. Taken at fixed dosage, they lose some their euphoriant and analgesic effect as tolerance sets in; opioid drugs are physiologically addictive. Overdoses can cause respiratory depression; pain, by contrast, is a potent respiratory stimulant. When taken recreationally, opioids inspire a dreamily contented disengagement from the problems of the world. Their use diminishes the drive to constructive activity. More insidiously, excess opioid consumption impairs the release of endogenous opiates normally induced by social interaction with friends and family. By diminishing the craving for human companionship, the addict substitutes one form of opioid addiction for another. Thus junkies are usually "selfish".

The physical risks of opioid use shouldn't be exaggerated. Most of the problems that users suffer ultimately derive less from their choice of drug itself than from the illegal status of narcotics in prohibitionist society. Yet even if they were legal and given away in cereal packets, opioids wouldn't make a good choice of mood-booster - or at least not in their present, crudely non-specific guise. Kappa-agonists, for instance, impair dopamine function. They have dysphoric and psychotomimetic effects: one might as well drink ethyl alcohol spiced with meths. The paradise-engineers of posterity will surely weed out such adulterants from their elixirs altogether.

By contrast to today's opioids, marijuana isn't usually addictive in the traditional sense of the term. It can still be habit-forming. It has euphoriant, psychedelic and sedative properties. Experiments with stoned rats suggest the drug reduces the amount of corticotrophin-releasing factor (CRF) in the amygdala. Excess secretion of CRF is associated with abnormalities in the HPLA axis and depression. The rebound surge of CRF on ceasing cannabis-use is associated with increased vulnerability to stress and a withdrawal-reaction, arguably one good reason not to stop in the first instance. A dysfunctional response to stress, linked to a chronically overractive HPLA axis, causes anxiety disorders and depression. The deeper roots of our malaise lie in the evolutionary past.

The primary psychoactive ingredient in marijuana is THC, tetrahydrocannabinol. Smoking or eating marijuana and its complex cocktail of compounds may rarely trigger episodes of depersonalisation, derealisation and psychosis. Sometimes it can induce paranoia, particularly in advocates of The War Against Drugs. More commonly, it just leaves the user pleasantly and harmlessly stoned. It's fun.
Sleepiness, pain relief and euphoria are typical responses. Indeed the first brain-derived substance found to bind to our cannabis receptors was christened "anandamide", a derivative of the Sanskrit word for internal contentment. Getting high may thus serve as an innocent recreational pastime in an uncaring world.

Yet marijuana is not a wonderdrug. Cognitive function in the user is often impaired, albeit moderately and reversibly. Marijuana interferes with memory-formation by disrupting long-term potentiation in the hippocampus. One of the functions of endogenous cannabinoids in the brain is to promote selective short-term amnesia. Forgetting is not, as one might have supposed, a purely passive process. Either way, choosing deliberately to ingest an amnestic agent for long periods is scarcely an ideal life-strategy. It's especially flawed given the centrality of memory to human self-identity. Some artists and professional bohemians, it is true, apparently do find smoking grass an adjunct to creative thought. For persons of a more philistine temperament, on the other hand, it's hard to see such a drug as a major tool for life-affirmation or the self-development of the species. This does not, one ought scarcely need to add, suggest users should be persecuted and criminalised.

The empathogen "hug-drug", ecstasy (methylenedioxymethamphetamine; MDMA) offers a wonderfully warm, sensuous, loving, and empathetic peak experience to the first-time user. Distrust, suspicion and jealousy evaporate. They are replaced by a serene sense of universal love. The sensorium remains clear. Emotion is intensified. Much recreational drug-use tends to be self-centred. It is often branded as selfish. Yet here is a "penicillin of the soul" which promises to subvert our selfish-DNA-driven tendency to self-aggrandisement.

Disappointingly, whether due to enzyme-induction or other causes not fully understood, most users never fully recapture the magic of their first few trips. Moreover ecstasy is neurotoxic to serotonergic axons. It may even be harmful at sub-therapeutic doses. As the uncertain process of neural recovery sets in, heavy users in particular may experience the subtle long-drawn-out reversal of all the good effects they initially enjoyed from the drug. Taking a post-trip selective serotonin re-uptake inhibitor (SSRI) such as fluoxetine (Prozac) 2-6 hours afterward is prophylactic against the measurable post-E serotonin dip otherwise experienced some 48 hours later. Yet taking SSRIs on a regular basis largely nullifies the already attenuated benefits of prolonged ecstasy use. In any case, the duration of the peak experience is a mere 90 minutes. So taking ecstasy scarcely amounts to a full-scale strategy for life either. It does, on the other hand, deliver an exquisite foretaste of the beautiful forms of consciousness that ultimately await us.

Another tantalising and deliciously sensuous hint of the sublime is offered - infrequently and unpredictably - by gamma-hydroxybutyrate (GHB). GHB usually takes the form of a clear, odourless, slightly salty-tasting liquid. It's also an endogenous precursor and metabolite of the inhibitory neurotransmitter GABA. GHB is non-toxic; but it mustn't be mixed with alcohol or other depressants. It's metabolised quickly to carbon dioxide and water. GHB's steep dose-response curve means naive users run the severe risk of falling asleep. When used lightly in recreational rather than stuporific or anaesthetic doses, GHB is a touchy-feely compound which typically induces deep muscular relaxation, a sense of serenity, and feelings of emotional warmth. Often it enhances emotional openness and the desire to socialise. Tactile sensitivity and the appreciation of music are enriched. Most remarkably, the moderate user may awake refreshed after a deep restful sleep: GHB appears temporarily to inhibit dopamine-release while increasing storage, leading to the brightened mood and sharpened mental focus of a subsequent "dopamine-rebound". GHB acts both as a disinhibitor and an aphrodisiac. The intensity of orgasm is heightened. Hence GHB is potentially useful in relieving the psychopathologies of prudery and sexual repression. Unfortunately, its therapeutic value has been eclipsed by its demonization in the mass-media. Stories of chaste virgins turning into sex-crazed nymphomaniacs make great copy and poor medicine. Moreover GHB is sometimes confused with the amnestic "date rape" benzodiazepine, flunitrazepam - better-known as the potent and fast-acting sedative-hypnotic "forget pill", Rohypnol. Bought on the street, GHB may be confused with all sorts of other substances too.

Yet even pure GHB is no magic elixir. Not everyone likes it. GHB's psychological effects are unpredictable and poorly understood. Nausea, dizziness, inco-ordination are common; reaction-time is slowed. GHB does not usually promote great depth of thought. Its very status as "an almost ideal sleep inducing-substance" makes it of limited use to those who aspire instead to be more intensely awake. The lack of any discernible body-count to fuel the periodic moral panics its use induces may allow a partial rehabilitation. Yet GHB evokes - at best - only a faint, fleeting parody of the life-long chemical nirvana on offer to our transhuman successors.

Alcohol - the traditional date-rape drug of choice - and, most insidiously of all, cigarettes are the really sinister mass-killers. With that poker-faced Alice-In-Wonderland logic popular amongst the world's sleazier governments, not merely do the authorities preserve the legal status of cigarette sales here in the UK on grounds of upholding personal liberty. The slickly expensive marketing and glamorisation of tobacco products to potential victims is sanctioned on similar grounds too. We ought to be as shocked at tobacco promotion as we'd certainly feel if instead the billboards urged kids to try heroin because it's cool. Yet familiarity breeds moral apathy. Youngsters are typically hooked before they are in any position to make an informed choice of poison - or even to abstain altogether. Meanwhile a state-supported export drive targets the poor in vulnerable Third World countries. With a cynicism that almost beggars belief, one celebrated British ex-Prime Minister accepted a million-dollar bribe from a leading member of the drug-cartels for her services. Her party's ineffable Home Secretary then delivered himself of blood-curdling calls for a crack-down on evil drug-pushers(!). He went on to increase the draconian penalties already available for personal users of cannabis.
So long as our governments collude with the organised drug cartels to share out the billions of dollars of tax revenues mulcted from nicotine-addicts - thereby keeping direct taxes visibly down and themselves visibly in office - there seems little hope of a more intelligent approach to psychoactive drugs as a whole.


The commonly recognised legal and illegal recreational drugs offer poor prospects for sustained biological mood-enhancement. So what about the heterogeneous group of compounds uninvitingly labelled as anxiolytics and antidepressants? Have they potentially anything significant to add to most people's quality of life? Official medical doctrine says no. Allegedly, only sufferers from clinically-sanctioned psychiatric disorders will benefit from such agents; though in recent years it has at last been formally recognised that depressive disorders are under-diagnosed and under-treated even by the twentieth century's abjectly poor standards of acceptable ill-being. Most of humanity, however, still doesn't fit any of the official diagnostic boxes. So can "diagnostic creep" triumph over therapeutic minimalism and enhance their quality of life? Yes. Must the goal of pharmacotherapy be as limited as Freud's aspiration for psychotherapy: "to transform hysterical misery into common unhappiness"? No.

First, the boring but crucial preliminaries. Optimal nutrition and exercise will increase the efficacy of all the potential life-enhancers touted here. A rich supply of precursor chemicals (e.g. tryptophan, the rate-limiting step in the production of serotonin) can also reduce their effective dosages. By choosing to eat an idealised "stone-age" diet rich in organic nuts, seeds, fruit and vegetables, and drastically reducing one's consumption of saturated fat (red meat, fried foods), sugar (sweets etc) and hydrogenated oils (found in margarine and refined vegetable oils), then one's baseline of well-being - or at least relative ill-being - can be sustainably lifted. Visitors to HedWeb (see WWW.HEDWEB.COM) probably don't expect to be assailed by sermons on the benefits of exercise any more than food-faddism. Yet regular and moderately vigorous physical exertion releases endogenous opiates, enhances serotonin function, stimulates nerve growth factors, and leads to a livelier, better-oxygenated brain.

Alas, clean living and wholesome thoughts typically aren't enough. We need stronger medicine to flourish. At first glance, however, the standard, State-rationed chemicals aren't a brilliant bunch.

The so-called minor tranquillisers, the benzodiazepines such as diazepam (Valium) and the shorter-acting temazepam, are sometimes useful but still dreadfully crude anti-anxiety agents. They act primarily on the GABA (gamma aminobutyric acid) receptor complex. GABA functions as the main inhibitory neurotransmitter in the central nervous system. The progress of molecular biology and neurogenetics in unravelling the fiendish complexity of GABA's receptor sub-types should eventually allow more targeted compounds to be developed. These more selective and site-specific drugs will lack the sedative and hypnotic properties of today's marketed brands. In the meantime, benzodiazepines in current use tend to induce dependence, dull consciousness and impair the intellect. So there's not much chance of radical life-enrichment here.

Buspirone (Buspar), is somewhat more promising. It acts to desensitise the inhibitory autoreceptor 5-HT1A subtype of serotonin receptor. It thereby promotes serotonin release. This means buspirone has mood-brightening properties too. Thus it is useful in anxious depressive states. Buspirone lacks the intellect-clouding effects of other clinical and alcoholic anti-anxiety agents. Yet its weak and equivocal effects on sub-types of dopamine function, while useful for the purposes of commercially touting its lack of "abuse-potential", mean it isn't very exciting or popular. Researchers hope that newer 5HT1A agonists in the pipeline will be more effective.

The so-called antidepressants fall into several categories. Their delayed-onset mood-brightening effect is correlated with alterations in the concentration of catecholamines and/or serotonin in the central nervous system and the long-term receptor re-regulation these changes provoke.

The tricyclics, prototypically imipramine (Tofranil), and their allies are relatives of the neuroleptic drug chlorpromazine. Chlorpromazine is also known as Largactil, the notorious "chemical cosh". Tricyclics block to varying degrees the reuptake of serotonin and noradrenaline into the nerve cell terminals from where they are released. The consequent changes in pre- and post-synaptic receptor sensitivity lighten the spirits of 60-70% of the depressives who take them. Perhaps unsurprisingly given their parentage, the tricyclics are all dirty drugs, though some are dirtier than others. Their anti-cholinergic effects harm memory, concentration and intellectual performance. Their anti-histamine action induces drowsiness and sedation. Their adverse effect on cardiac function makes them dangerous in overdose. Most "euthymic" volunteers on whom they have been tested don't like their dulling effects of consciousness. Unlike chlorpromazine, the tricyclic antidepressants don't noticeably block the dopamine receptors. But with one notable exception, they do precious little to stimulate dopamine function either. Hence they're not much fun even for the severely depressed people who can benefit from taking them. For three decades they were the mainstay of the treatment of clinically-acknowledged depression. They contributed to the widely-held medical opinion that anything classed as an antidepressant won't help "normal" people; unless of course they were "really" depressed. Basically, tricyclics are cheap, nasty and best avoided.

Much better, but still in some ways deeply flawed, are the selective serotonin reuptake inhibitors (SSRIs). Serotonin, "the civilising neurotransmitter", plays a vital role in mood, memory, appetite, sleep, pain perception and sexual desire.

Fluoxetine (Prozac), fluvoxamine (Luvox, Faverin), paroxetine (Paxil, Seroxat), sertraline (Zoloft, Lustral), and citalopram (Cipramil, Celexa) are currently licensed and marketed. More of their "me-too" tweaked and enhanced relatives are on the way from pharmaceutical companies eager for a lucrative piece of the action. The SSRIs all differ in their half-lives, chemical structure and precise specificities. Their functional effects are broadly similar, though Prozac is the most activating, longest-lasting and least selective. The mood-brightening, resilience-enhancing and anti-anxiety properties of the SSRIs really can make a (very) modest percentage of the population feel "better than well". As a class, SSRIs don't have the physically unpleasant and cognitively debilitating anti-cholinergic effects of the tricyclics. SSRIs don't demand the dietary restrictions of the MAOIs. Their dependence potential and withdrawal reaction is milder than the opioids. A much larger section of the community - folk who daily knock back huge quantities of ethyl alcohol in the socially accepted fashion - could surely gain from the durably enhanced serotonin function that SSRIs can yield. Such a switch would necessitate a big change in marketing strategy.

The beneficent properties of the SSRIs are celebrated in Peter Kramer's contemporary classic Listening to Prozac. Kramer has written a remarkably honest book. It's a discursive memoir by a therapist who is forced to admit that many of his clients seemed rapidly to fare far better on a pill than on his industrial-strength regimen of caring talk-therapy. Kramer's discussion of "cosmetic psychopharmacology" and "designer personalities", however, enraged traditionalists. For chemical Calvinist orthodoxy finds the notion that people should have a right to choose pharmacologically who and what they want to be profoundly offensive.

Two common problems limit the usefulness of SSRIs, at least when taken on their own. The problems stem from the indirect inhibitory effect of Prozac-style drugs on dopamine function, a consequence of deliberate selective targeting of the serotonin system.

First, SSRIs can compromise libido and sexual performance. This isn't always a disadvantage in over-excitable young males. It can still be a very distressing phenomenon for people too embarrassed to talk about it. Technical performance difficulties can sometimes be counteracted by taking the blood vessel dilators apomorphine or phentolamine; the alpha2-adrenergic antagonist yohimbine; the phosphodiesterase inhibitor sildenafil (better known as the sexual rocket-fuel Viagra); or a dopamine agonist, licit or otherwise, before bedtime action. Yet this is scarcely an ideal solution.

Second, though some subjects may feel mildly euphoric, in other users the SSRIs serve more as mood-stabilisers and -flatteners in their lives. By increasing the user's emotional self-sufficiency, too, SSRIs may subtly change the "balance of power" in personal relationships - for good or ill. In some cases, SSRIs may even act as thymoanaesthetisers which diminish the intensity of felt emotion; by contrast, a mood-brightening serotonin reuptake-enhancer like tianeptine may intensify emotion instead. Affective flattening may be welcome to someone in the pit of unmitigated clinical depression. It is scarcely a life-enriching property for "normal" people who lack any convenient diagnostic category which acknowledges their malaise.


What's missing, crucially, is vigorous and prolonged stimulation of meso(cortico-)limbic dopamine function.

This is really much more fun than it sounds. The currently available experimental evidence has persuaded many - but not all - researchers that the mesolimbic dopamine system serves as the final common pathway for pleasure in the brain. Enhanced responsiveness of post-synaptic dopamine D2/D3 receptors is crucial to long-term emotional well-being. All "serotonergic" and "noradrenergic" mood-brighteners eventually act on the mesolimbic dopamine pathway, albeit in differing degrees and with varying delay. And new anti-Parkinsonian and anti-Alzheimer's agents, notably roxindole and pramipexole, owe their exciting potential role as fast-acting antidepressants to their dopaminergic action.

The full story is inevitably complex. Dopamine agonists are often inadequate mood-brighteners by themselves. Dopamine isn't itself the magic pleasure-chemical, though its functional role is crucial. Researchers into affective disorders readily get over-attached to a particular neurotransmitter, its receptor sub-types and their signal-transduction cascades. Traditionally, serotonin and noradrenaline have attracted the fiercest rival partisans. "Dopaminergic" (and opioid) agents, by contrast, are suspect. They are politically incorrect since they are potentially "abusable". Moreover safe and sustainable empathogens are arguably as morally urgent as safe and sustainable mood-boosters. At any rate, mesolimbic activation, exclusively or otherwise, enhances the intensity of experience; increases pleasure and libido, and boosts cognitive performance. Even better, certain dopamine-enhancing drugs may have neuro-protective properties as well.

So what are the other contemporary options for chemical life-enhancement?


A SSRI can be combined ("augmented" sounds more soothing to the official medical ear) with a dopaminergic such as methylphenidate. As "Ritalin", methylphenidate is prolifically dispensed to American schoolchildren for different purposes altogether. In spite of its structural relationship to amphetamine, methylphenidate resembles in many ways a benign version of cocaine, yet with a much longer half-life. It blocks the reuptake, but doesn't significantly release, the catecholamines noradrenaline and dopamine. If it taken in sustained-release form or combined with an SSRI, all of which have anti-obsessive-compulsive properties too, the likelihood of dose-escalation is minimised.

Chewing coca leaves with a dash of powdered lime is a nutritious and energising way to sustain healthy mood. Unfortunately, it is not very good for one's teeth.

A more cautious but still interesting option might be minaprine. Minaprine blocks the reuptake of both dopamine and serotonin. It is also in some degree cholinomimetic. Thus it may exhibit both mood-brightening and nootropic properties. Much more research is needed.

Merital (nomifensine) showed great promise as a pleasantly stimulating dopaminergic which also potently inhibits the reuptake of noradrenaline and - to a much lesser extent - serotonin. It was withdrawn from licensed use after the discovery of its rare side-effect of precipitating a serious blood-disorder. For retarded melancholics, however, it was typically a very effective and well-tolerated mood-brightener with minimal side-effects. The risk/reward ratio of its carefully-monitored use may have been misjudged.


Bupropion (Wellbutrin) is possibly less effective than nomifensine. Yet it's useful because it lacks the adverse effects on sexual function characteristic of the SSRIs. In some subjects, in fact, libido, arousal, and the intensity and duration of orgasm may actually increase. Bupropion mildly blocks the reuptake, but diminishes the release, of dopamine. This may account for reports of its diminished propensity to induce mania in the genetically susceptible. Its active metabolites block the reuptake of noradrenaline. Chewed as a gum, bupropion is good for giving up smoking. Scandalously, it isn't licensed and marketed in Europe. (FryingLizard's note - I believe it was licensed in Britain in July 2000)

Amineptine (Survector) is a clean-ish, (relatively) selective dopamine reuptake blocker. Higher doses promote dopamine release too. Amineptine is liable occasionally to cause spontaneous orgasms. It is a mild but pleasant psychostimulant and a fast-acting mood-brightener. Unlike other tricyclics, it doesn't impair libido or cognitive function. Unlike typical stimulants and other activating agents, it may actually improve sleep architecture. Scandalously, amineptine isn't licensed and marketed in Britain and America. For it is feared it might have "abuse-potential".


Reboxetine (Edronax) is a well-tolerated, highly selective "noradrenergic" agent. Crudely, whereas serotonin plays a vital role in mood, noradrenaline is essential to maintaining drive and the capacity for reward. There's a fair bit of evidence that chronically depressive people have dysfunctional and atypical noradrenergic systems - particularly their alpha2- and beta-adrenoceptors. Reboxetine itself doesn't have the disruptive effects on cognitive function or psychomotor performance so annoyingly typical of older clinical mood-brighteners. Indeed the new NorAdrenaline Reuptake Inhibitors (NARIs) are probably under-used and under-hyped. NARIs - and dopaminergics like amineptine (Survector) - may be especially good for drive-deficient "anergic" states where the capacity for sustained motivation is lacking; and for melancholic depressives with a poor ability to cope with stress. Perhaps surprisingly, preliminary studies suggest reboxetine can actually reverse tranylcypromine-induced hypertensive crises. The "cheese effect" is usually triggered by ingesting tyramine-rich foods. Thus NARIs plus MAOIs may prove a potent form of combination-therapy.

Depressive hypersomniacs who fare poorly on SSRIs, or can't get hold of amineptine or EC-licensed reboxetine, might consider trying a so-called eugeroic ("good arousal") agent instead; more adventurous souls may wish to combine the two. Alpha1-adrenergic agonists like adrafinil and modafinil are centrally-acting stimulants that can brighten mood and sharpen mental focus. They stimulate the noradrenergic post-synaptic receptors and thereby boost alertness, activity and energy. At sensible dosages, they are remarkably free of side-effects. However, the approval process in the USA is so slow, costly and bureaucratic, and the marketing hurdles typically so formidable, that foreign companies are often deterred from seeking FDA acceptance. modafinil was licensed by the FDA as Provigil for the treatment of narcolepsy in Dec 1998 So elderly people continue to suffer the prescription of mildly dementing anticholinergics like the dumb-drug tricylcic imipramine. Adrafinil, by contrast, is at least as successful as hepatotoxic Anglo-Saxon products at treating the cognitive and memory impairments of incipient senility. Fortunately, a "French" drug like adrafinil can now be ordered over the Net; but it ought to be available at the local corner-store. It has the commercial disadvantage of being cheap.


NARIs are normally activating. Anxious and depressive insomniacs, on the other hand, may benefit more from "dual-action" mirtazapine or nefazodone.

Mirtazapine(Remeron) is a relative of the off-patent mianserin (Bolvidon). It is a comparatively new drug - a so-called NaSSA. By blocking central alpha2 adrenergic autoreceptors and stimulating only the 5-HT1A receptors, mirtazapine enhances noradrenaline and serotonin release while also blocking two specific (5-HT2 and 5-HT3) serotonin receptors implicated in dark moods and anxiety. By contrast, stimulation of the 5HT2A receptors accounts for the initial anxiety, insomnia and sexual dysfunction sometimes reported with the SSRIs; stimulation of the 5HT3 receptors causes nausea. Unfortunately, mirtazapine is a potent blocker of the histamine receptors too. So it tends to have a somewhat sedative effect. This profile may be good for agitated depressives and insomniacs. But it's scarcely a recipe for life-affirmation.

Nefazodone (Serzone) is another newish, "dual action", mainly serotonergic agent. It strongly inhibits the reuptake of serotonin while displaying post-synaptic 5-HT2A-receptor antagonism. This may be useful for anxious depressives; but again, it may cause feelings of weakness, drowsiness and lack of energy. Nefazodone is less likely to cause priapism than its older cousin trazodone (Desyrel). It is less likely to cause sexual dysfunction than the SSRIs.

Venlafaxine (Effexor) is a phenethylamine. Thus it's a benign chemical cousin of MDMA. Its manufacturers launched it as "Prozac with a punch". Venlafaxine inhibits the neuronal reuptake of serotonin, noradrenaline and dopamine in descending order of potency. If dopaminergically augmented, it offers another opening for creative psychopharmacology. Such augmenation-therapy remains (almost) clinically unexplored. Taken on its own at low dosage, venlafaxine acts primarily as a serotonin re-uptake inhibitor. At the high-level dosages most suitable for melancholic and hypersomnic temperaments, its noradrenergic (and weakly dopaminergic) action becomes more pronounced. Like the SSRIs, it is useful for a broad spectrum of disorders beyond clinical depression.

Phosphodiesterase-inhibitors, both selective (e.g. rolipram) and unselective, are another under-used option. Next century will take us much closer to the real intra-cellular action; for it is here that our minds will ultimately be healed, genetically or otherwise.


Hypericum is important for a different reason altogether. Many constitutionally unhappy people refuse to have anything to do with orthodox western medicine. They won't take "unnatural" pharmaceutical products at all. In consequence, they spend much of their lives trapped in a squalid psychochemical ghetto of chronic low spirits. The only sort of remedy which they'll conceivably contemplate taking must carry a "natural" label and soothingly "herbal" description. Unfortunately, most folk remedies are only marginally effective. Plants tend to manufacture psychotropics because they poison or debilitate creatures tempted to eat them - not to heal our psychic woes. Thus the Wisdom Of Nature is a quaint piece of make-believe. Hypericum, however, which is the active ingredient in St John's Wort, appears to be an effective mood-brightener and anxiolytic - by today's standards at least. Its efficacy and side-effect profile compare favourably with its synthetic counterparts. Hypericum's blend of serotonin-reuptake inhibiting and (mild) MAO-inhibiting properties (not a combination otherwise to be explored with potent synthetics: the risk of the potentially fatal serotonin syndrome is too great) contributes to - without wholly explaining - its generally benign effects. Once again, much more research is needed.


One further remedy, albeit at "unnatural" doses, is worth noting. Inositol levels tend to be low in depressives and high in euphoric people. Taking myo-inositol as a food supplement in doses of 12g and more per day represents perhaps the first successful use of the precursor strategy for a second messenger rather than a neurotransmitter in the search for long-term mood-brightening agents. Inositol and its derivatives serve as messenger molecules within the nervous system. The molecule itself is a naturally occurring isomer of glucose. It is a key intermediate of the phosphatidyl-inositol cycle. This is a second-messenger system used by several noradrenergic, serotonergic and cholinergic receptors. Adult westerners typically consume about one gram of inositol per day in their food. The richest dietary sources are fruits, nuts, beans and grains. The mood-darkening ("stabilising") effect of lithium in manically euphoric people may be explicable in terms of its inositol-depleting effect. Potentially, if taken in high doses, inositol seems to be a good way of lightening the spirits and diminishing anxiety in "euthymic" and depressed people alike. Dosages of even 50g and more reportedly produce no toxic side-effects. This regimen shouldn't be attempted unsupervised by people with a history of bipolar disorder. As usual, much more research is in order. One "problem" is that naturally-occurring compounds - such as inositol and SAMe - can't be patented. So the scope for high profit-margins is diminished. Progress is unlikely to be brisk.


A further option involves using both some of the oldest and the newest drugs on the block, the monoamine oxidase inhibitors (MAOIs). The older irreversible MAOIs certainly shouldn't be combined with SSRIs, and inadvisably with stimulants and many other drugs. Yet both old and new, they do have some very interesting properties.

Monoamine oxidase has two main forms, type A and type B. They are coded by separate genes. MAO may be inhibited with agents that act reversibly or irreversibly; and selectively or unselectively; these categories are not absolute. MAO type-A preferentially deaminates serotonin and noradrenaline, and also non-selectively dopamine; type B primarily metabolises dopamine, phenylethylamine (the "chocolate amphetamine") and various trace amines.

The substantial mood-elevating properties of the MAOIs were discovered quite by chance in a US veterans hospital early in the 1950's. Many patients given the anti-tuberculotic drug iproniazid were not merely cured of their tuberculosis. They became exceptionally happy as well. The animated enthusiasm for life of a previously crotchety bunch disconcerted their doctors. For it transpired that their new-found euphoria wasn't just an understandable reaction to being cured of physical disease. MAOIs typically have mood-brightening properties as well. At the time, there was no accepted and clinically-effective treatment for depression. Fortunately, via the usual circuitous routes, the appropriate lessons were eventually drawn. Many millions of people were successfully treated with MAOIs in consequence.

Sadly, the role of MAO in deaminating tyramine (from the Greek word "tyros", meaning cheese) wasn't at first understood. Certain MAOI-treated patients suffered hypertensive crises after eating varying amounts of tyramine-rich aged cheese; and several died. It is now recognised that the use of any MAOI which is both irreversible and unselective must be accompanied by dietary restrictions. But the adverse publicity of the initial inexplicable fatalities, combined with the introduction of a succession of dirty but sometimes tolerably effective tricyclic compounds, sent the use and reputation of MAOIs into a precipitous decline from which they still haven't fully recovered.

The older non-selective and (more-or-less) irreversible inhibitors tranylcypromine (Parnate), phenelzine (Nardil) and isocarboxazid (Marplan) are nonetheless valuable drugs. Outside the USA, they tend to have been eclipsed by the selective and reversible moclobemide. Similar therapeutic agents are in the pipeline. Of greater interest still are central-nervous-system-selective compounds, notably one known (not indeed especially widely) as MDL-72394. MAOIs which lack the peripheral effects of currently explored drugs herald an exciting new therapeutic window of opportunity.

SELEGILINE (l-deprenyl)

A recent New York study showed that smokers had on average 40% less of the enzyme, monoamine oxidase type-B, in their brains than non-smokers. Levels returned to normal on their giving up smoking. Not merely is the extra dopamine in the synapses rewarding. The level of MAO-b inhibition smokers enjoy apparently contributes to their reduced incidence of Parkinson's and Alzheimer's disease. Unfortunately they are liable to die horribly and prematurely of other diseases first.

One option which the dopamine-craving nicotine addict might wish to explore is switching to the (relatively) selective MAO-b inhibitor selegiline, better known as l-deprenyl. Normally the brain's irreplaceable complement of 30-40 thousand odd dopaminergic cells tends to die off at around 13% per decade in adult life. This diminishes the quality and intensity of experience. It also saps what in more ontologically innocent times might have been called one's life-force. Eighty percent loss of dopamine neurons results in Parkinson's disease, often prefigured by depression. Deprenyl has an anti-oxidant, immune-system-boosting and dopamine-cell-sparing effect. It boosts levels of tyrosine hydroxylase, growth hormone, superoxide dismutase and the production of key interleukins. It offers protection against DNA damage and oxidative stress by hydroxyl and peroxyl radical trapping; and against excitotoxic damage from glutamate.

Whatever the full explanation, deprenyl-driven MAOI-users, unlike cigarette smokers, are likely to be around to enjoy its distinctive benefits for a long time to come, possibly longer than their drug-naïve contemporaries. For in low doses, deprenyl enhances life-expectancy, of rats at least, by 20% and more. It enhances drive, libido and motivation; sharpens cognitive performance both subjectively and on a range of objective tests; serves as a useful adjunct in the palliative treatment of Alzheimer's and Parkinson's disease; and makes you feel good too. At dosages of below 10-15 mg daily, deprenyl retains its selectivity for the type-B MAO iso-enzyme. Nor does it tend to have the "cheese-effect"; tyramine is also broken down by MAO type-A. Deprenyl isn't addictive, which probably reflects its different delivery-mechanism and delayed reward compared to inhaled tobacco smoke. Whether the Government would welcome the billions of pounds of lost revenue and a swollen population of energetic non-taxpayers that a switch in people's MAOI habits might entail is unclear.


Humans now have the capacity to choose their own individual level of activity or inhibition of the two primary monoamine oxidases. This does not quite enable the fine-tuning of personality variables with the functional equivalent of a graphic equaliser. It still represents a promising start. In MAO-inhibition, as in life, more is not always better. Excessive dosages of l-deprenyl intake, for instance, may actually shorten, not increase, life expectancy - at least in Parkinsonians if it's combined with l-dopa. And levels of above 80% inhibition of MAO-A may lead to a sharp and possibly unwanted fall in dopamine synthesis. Repairing Nature's niggardliness will be a priority for the decades ahead.

Moclobemide (Manerix, Aurorix), the "gentle MAOI", is both a selective and reversible inhibitor of MAO-A. It marks the first RIMA to win clinical acceptance. It lacks anti-cholinergic side-effects. No dietary restrictions are needed. It is valuable as more than a mood-enhancer. For moclobemide is often useful in overcoming social phobia, panic disorder, obsessive-compulsive symptoms, irritability and aggression owing to the way it enhances serotonin function. (The casual use of gobbledygook such as "enhanced x function" will rightly alert the reader that many complications are being skirted or omitted. Those hungry for the greater technical detail of a non-popular account can rest assured the literature will leave them feeling abundantly well-nourished).


Gentleness doesn't suit everyone. Moclobemide isn't much good at lifting deep melancholy. Tranylcypromine (Parnate), on the other hand, is one of the older and non-selective MAOIs - and is often none the worse for it. Structurally related to amphetamine, it's generally the most stimulating, dopaminergic and relatively fast-acting of the MAOIs. Some doctors are uncomfortable with its properties. This isn't just because of the dietary restrictions it demands. In adequate doses, it tends to induce a mild euphoria even in "normal" subjects. In fact, its nicest effects, as for all of the compounds cited here, will vary in nature and extent from person to person. To some extent, optimal dosage and long-term drug-regimen of choice can be discovered only by cautious empirical investigation.

Tranylcypromine is of course vastly preferable to the amphetamines and cocaine. Yet frequently and perversely, the more hazardous the drug, then the easier it is to get hold of in our society. The carcinogenic cocktail that carries off more people than all other toxins combined can be purchased quite legally and effortlessly at any tobacconist or newsagent. Obtaining the less lethal - but scarcely desirable - opioids and psychostimulants requires a little more exertion. Yet they can still be readily purchased in pubs and clubs in all the big towns and cities. Most of the more beneficent drugs discussed here, on the other hand, are available on a prescription-only basis. They're not illegal to possess. But they are hard to obtain short of visiting countries where they're available over-the-counter or paying high mail-order prices for an uncertain service.

If the central principle at stake were the preservation of a drug-free society, then some sort of totalitarian (or, more euphemistically, paternalistic) argument could be cobbled together for violating personal freedom so oppressively. Yet that's rarely the issue. For in most cases, the issue effectively amounts, not to drugs or no drugs, but to allowing people the choice to opt for better ones. Perhaps 80% of the population in Western countries currently drink alcohol or smoke cigarettes. Often they do both. Whether viewed in terms of mortality, morbidity or overall quality of life, we'd be far better off if we switched to enhancing dopaminergic, serotonergic and cholinergic function by the relatively safe and often crudely effective agents touched on here; and to the much more exciting products currently in the pipeline. As a basic minimum, people shouldn't be legally robbed of the right to do so.

This freedom of choice isn't conventional wisdom. It will be suggested that the level of medical expertise required to make informed choices exceeds that of the average layperson; and a quasi-priestly caste wielding the power of the prescription-pad would doubtless wish to keep it that way. But the intrinsic difficulty and complexity of psychopharmacology or nutritional medicine, say, doesn't demand greater mental effort than, for instance, all those thousands of grimly unnatural hours spent by school students learning mathematics. Moreover it's far more interesting to study something palpably relevant to one's emotional well-being than something that demonstrably isn't. The notion of an education system geared to schooling people in, and for, happiness would nonetheless strike adherents of the reigning educational orthodoxy as abhorrent were it not so largely incomprehensible.


Suppose, for a moment, that the reproductive success of our DNA had been best served by coding for ecstatically happy vehicles rather than malaise-haunted emotional slum-dwellers. If this had been the case, then none of the pharmacological interventions discussed in The Good Drug Guide would be necessary. Life-long well-being would seem only "natural". We would all enjoy gloriously fulfilled lives. Each day would be spent enjoying gradients of total bliss. Unpleasant states of mind would be viewed as a tragic aberration. They'd be diagnosed as a freakish but clinically treatable type of psychopathology.

Of course, it didn't work out that way. Instead, the inclusive fitness of our genes has been promoted by the "natural" manufacture of some of the most vicious psychological adaptations imaginable.

The rot goes deeper. Selfish DNA can count on innumerable dupes to act as its distal representatives even today. The need for "character-building" emotional pain gets justified with all manner of sophistries, both religious and profane. Suffering is good for you, one may be told. It's all part of life's rich tapestry.

It exists because it was good for our genes. Apologists for mental pain are serving as the innocent mouthpieces of the nasty bits of code which spawned them. If pressed, DNA's unwitting spokesmen would presumably disavow the connection. Yet if one were purposely building an intelligent robotic survival-machine, then endowing it with the illusion of free-will would prove a highly fitness-enhancing adaptation. It's a trick which our genes merely stumbled upon; and then blindly exploited.

Fortunately, within the next few centuries humanity will be able to outwit its ancient genetic masters. Our present status as throwaway genetic vehicles will finally be subverted. When heavenly well-being becomes the genetically pre-programmed norm of mental health, then the very notion of tampering with our new-won "natural" condition and feeling "drugged" will come to seem immoral. It will also seem perverse. Why should anyone want to contaminate the divine ecstasy of their spirituo-biological soul-stuff with alien chemical pollutants? No thanks.

Today's twisted victims of the primordial genetic code, on the other hand, view the notion of sullying their natural state of being through drugs with a much more deep-seated ambivalence. They adopt it as a near-universal practice. Given the inadequacy of the third-rate stopgaps on offer, and the lack of serious drug-education, it's scarcely surprising we're so poor at using them. Thus concerned parents are surely right to worry about the trashy street drugs taken by their kids. Yet with the right new genes and designer-drugs, there's no reason why mature Post-Darwinian life shouldn't just get better and better.

Noded for posterity (because it's one of the most interesting articles about drugs I've ever read in my life) by FryingLizard, although again all credit belongs to the original author David Pearce. Again, see WWW.ANTIDEPRESSANTS.COM for further information, also recommended; WWW.COCAINE.ORG.

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