THE  RESPONSIBLE  PARENT'S  GUIDE
TO  HEALTHY  MOOD-BOOSTERS
FOR  ALL  THE  FAMILY

INTRODUCTION

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 baseline of emotional well-being may indeed surpass anything that human legacy wetware can even contemplate. Right now, however, any 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 biological 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 inbuilt 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 on the psyche. 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 until germ-line gene-therapy to promote mental superhealth can become standard, it's worth considering instead how ordinary early 21st 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 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 supposedly 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 subsystem 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 web-published material 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.

SOME DEAD ENDS

One spectacularly incompetent route to a lifetime of happiness involves taking unsustainable 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. Amphetamine 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 and keep us happy.

        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. Their use beyond narcolepsy and ADHD is best discouraged.

        The "depressant" opioids are somewhat more benign. They are effective painkillers. Opioids 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, sufferers of depression typically share an increased sensitivity to pain; and modern "antidepressants" can themselves act as "physical" painkillers. Conversely, mu-opioid receptor agonists offer both unsurpassed pain-relief and extraordinary emotional well-being; and delta-opioid agonists and enkephalinase inhibitors can function as antidepressants. There is clearly an intimate link between "physical" and "emotional" pain. In defiance of dualist metaphysics, opioids tend to be good 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 of their euphoriant and analgesic effect as tolerance sets in; opioid drugs are physiologically addictive. Overdoses can cause respiratory depression; by contrast, physical pain is a potent respiratory stimulant. When taken recreationally, opioids inspire a dreamily contented disengagement from the problems of the world. Their use diminishes our drive to constructive activity as consumers in today's competitive global marketplace. More insidiously, excess consumption of narcotics inhibits the release of endogenous opioids 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 opioid drugs were legal and given away in cereal packets, such drugs wouldn't make a good choice of mood-booster - or at least not in their present, crudely non-specific guise. Kappa receptor 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. Marijuana has euphoriant, psychedelic and sedative properties. Experiments with stoned rats suggest that cannabis use 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 correlates with increased vulnerability to stress and a withdrawal-reaction, arguably one good reason not to stop in the first instance. Stress-induced endocannabinoid deficit in the brain may induce melancholic depression in users and non-users alike. A dysfunctional response to stress, linked to a chronically overactive HPLA axis, causes anxiety disorders and depression; CRH-type 1 receptor antagonists like antalarmin are being investigated as potential anxiolytics and antidepressants. The deeper roots of our malaise lie buried 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, marijuana just leaves the user pleasantly and harmlessly stoned. It's fun. Sleepiness, pain relief and euphoria are typical responses. Cannabinoid CB(1) receptor agonists are potential antidepressants. 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 development of the human species. This shortcoming does not, one ought scarcely need to add, suggest marijuana users should be persecuted and criminalised.

        The disparate drugs we label “psychedelics” - lysergamides like LSD-25, tryptamines like DMT and psilocybin, and phenethylamines such as mescaline - are sometimes exhilarating. At best, they are life-transforming and soul-enriching. They can certainly be mind-wrenching. Taking major psychedelics can generate experiences too outlandish for our normal conceptual framework to accommodate. We haven't even names for the strange new modes of perception, selfhood and introspection their biochemical pathways disclose.

        Unfortunately, one can’t look after the kids, fill in one’s tax forms or carry out one’s social responsibilities while tripping on LSD. Psychedelics are typically too bizarre, exotic and ineffable in their effects to integrate into the rest of one’s life. By trapping most of us in "ordinary" waking consciousness, selfish DNA stumbled on a cunning trick to help its vehicles leave more copies of itself. Worse, the psychedelics aren't primarily euphoriants. They don’t directly stimulate the pleasure-centres and guarantee the user a good trip. Both the serotonin- and catecholamine-like families trigger psychedelia mainly via their role as partial agonists of the 5-HT2A receptors in the central nervous system; 5-HT2 heteroreceptors exert a tonic inhibitory effect on the striatal dopaminergic neurons. Such agents aren’t a dependable choice of clinical or recreational mood-brightener, whether in the short- or long-term. Depressives, neurotics and other troubled souls in search of enlightenment are most likely to undergo nightmarish freak-outs. Psychotic derealisation isn't illuminating - or fun. The drug-naïve mind can’t make an informed choice of whether to explore radically altered states. For aspiring psychonauts can’t know, in advance, the true nature of what they may be choosing - or missing.

        Ultimately, when our well-being is genetically hardwired and invincible, psychedelia can be safely explored. The study of consciousness can become an experimental discipline. The synthesis of tomorrow’s designer-psychedelics may unleash a revolution without precedent. Until then, psychedelic drugs are too unpredictable - and our dark, Darwinian minds are too poisoned - responsibly to promote their use.

        Apparently by contrast, the empathogen "hug-drug" Ecstasy (methylenedioxymethamphetamine; MDMA) offers a wonderfully warm, sensuous, loving, and empathetic peak experience to the first-time user - "a brief fleeting moment of sanity" [Dr Claudio Naranjo]. MDMA enhances the release of serotonin and dopamine at the synaptic terminals; it also inhibits their reuptake. In consequence, 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 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 E experience is a mere 90 minutes. So taking Ecstasy scarcely amounts to a full-scale strategy for life either. Ecstasy 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. In the brain, the GHB molecule is 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 naïve 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. 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 scientific 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.

        Ethyl alcohol - the traditional date-rape drug of choice - and, most insidiously of all, cigarettes are the really sinister mass-killers. Their total human death-toll to date is around 100 million and climbing. 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 their preferred 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 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.

DIRTY MOOD BRIGHTENERS

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 early twenty-first century's abjectly poor standards of acceptable ill-being. Most of humankind, however, still doesn't fit any of the official diagnostic boxes. So can "diagnostic creep" triumph over therapeutic minimalism and enhance our 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. l-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. There is mounting evidence too that an omega-3 fatty acid-rich diet or supplementation is protective against depression and other psychiatric disorders. Visitors to HedWeb 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 opioids, enhances serotonin function, stimulates nerve growth factors, promotes cell proliferation in the hippocampus, 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, benzodiazepines such as diazepam (Valium), chlordiazepoxide (Librium), alprazolam (Xanax), lorazepam (Ativan), clonazepam (Klonopin) and the shorter-acting sedative-hypnotic temazepam (Restoril), are 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. Ideally, these more selective and site-specific drugs will lack the sedative, amnestic and hypnotic properties of today's brands. Activation of GABA(A) receptors containing the alpha 1 subunit is responsible for benzodiazepine-induced sedation and memory deficits. It is hoped that newly-synthesised agonists selective for the alpha 2 GABA(A) receptor subtype may finally deliver a non-sedating antianxiety drug. Merck's investigational L838,417 is one such candidate. Human trials are eagerly awaited. The first non-benzodiazepine, non-sedating/amnesiac drug of its class to reach the market may prove to be DOV Pharmaceutical's ocinaplon. Ocinaplon is a GABA alpha-2 modulator. It exerts its anti-anxiety effect at doses (allegedly) substantially lower than doses that induce measurable sedation, amnesia, muscle relaxation and incoordination. Ocinaplon is in phase III clinical trials for anxiety (summer 2005; temporarily suspended August 2005). In the meantime, currently licensed benzodiazepines tend to induce dependence, impair memory and psychomotor peformance, dull consciousness and cloud the intellect. So there's not much chance of radical life-enrichment here, for now at least.

        Buspirone (Buspar) might seem more promising. It acts to desensitise the inhibitory autoreceptor 5-HT1A subtype of serotonin receptor, promoting serotonin release and (sometimes) a brightening of mood. 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. Unlike the benzodiazepines, it's not fast-acting. Researchers hope that newer 5-HT1A agonists in the pipeline will be more effective. Alas any therapeutic gain is likely to be modest. In June 2004, the FDA determined that Organon's gepirone (Ariza) was "not approvable".

         The ill-assorted drugs we today call 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, long-term receptor re-regulation, activation of specific transcription factors regulating gene expression, and new nerve-cell growth in the hippocampus. How do they really work? No one knows.

        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 usually best avoided.

        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 tweaked and enhanced relatives are on the way from pharmaceutical companies eager for a lucrative piece of the action. In a triumph of marketing hype and creative use of patent law if not clinical need, citalopram's S-enantiomer was FDA-licensed in 2002 as "Lexapro". 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, least selective and most likely to provoke dose-related akathisia; paroxetine has anticholinergic and sedating antihistaminergic effects; fluvoxamine most commonly induces nausea and has the shortest half-life; and citalopram is the most serotonin 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 (mostly) don't have the physically unpleasant and cognitively debilitating anticholinergic effects of the tricyclics. SSRIs don't demand the dietary restrictions of the MAOIs. Their dependence potential and withdrawal reaction is usually milder than the opioids.

        The (sometimes) 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. in Against Depression, published in May 2005, Kramer argues that depression should be eradicated altogether.

        Two common problems limit the usefulness of SSRIs, at least when taken on their own. The problems stem from the indirect inhibitory effect sometimes exerted by 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 older 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; a phosphodiesterase type-5 inhibitor like sildenafil (better known as the sexual rocket-fuel Viagra), long-acting tadalafil (Cialis) or newly licensed vardenafil (Levitra); or a dopamine agonist, licit or otherwise, before bedtime action. Investigational drugs that heighten female sexual arousal (e.g. melanocortin agonists like PT-141) are another option. Yet this is scarcely an ideal solution. One of the major signs of depression is loss of interest in sex and reduced libido. So it's questionable whether the FDA and the pharmaceutical industry should continue to promote serotonergic "antidepressants" that are anti-sexual; and collude to suppress antidepressants that are pro-sexual.

·         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 (Stablon) 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.

THE DOPAMINE CONNECTION

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 - investigators 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. Insofar as they work, all "serotonergic" and "noradrenergic" mood-brighteners eventually act on the mesolimbic dopamine pathway, albeit in differing degrees and with varying delay. Even SSRIs depend on sensitization of the mesolimbic dopamine D2 receptors for their (modest) mood-lifting effect. New anti-Parkinsonian agents, notably pramipexole (Mirapex), ropinirole (Requip), and cabergoline (Dostinex) owe their potential role as fast-acting pro-sexual antidepressants to their dopaminergic action. Likewise, the possible mood-brightening effect of low doses of the dopamine receptor antagonist amisulpride (Solian), more commonly considered an antipsychotic agent, is explicable because amisulpride preferentially blocks the presynaptic dopamine D2/D3 autoreceptors; dopaminergic transmission is thereby enhanced.

        The full story is inevitably complex. Dopamine agonists and reuptake inhibitors are often inadequate long-term mood-brighteners by themselves. The mesolimbic dopamine system mediates reward-signalling, incentive salience and a sense of urgency and significance, not the essence of pure bliss. Dopamine isn't itself the magic pleasure-chemical, though its functional role in conjunction with glutamate and mu opioid agonists in regulating medium spiny neurons of the rostral shell of the nucleus accumbens is critical. Researchers into affective disorders readily get over-attached to one particular neurotransmitter system, 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 it can be argued that the research and development of safe and sustainable E-like empathogens and socialbilizers is as morally urgent as the license of safe and sustainable euphoriants. At any rate, enhanced mesolimbic dopamine release, exclusively or otherwise, enriches the intensity of experience; increases pleasure and libido, and potentially boosts cognitive performance. Even better, whereas some dopaminergics are potentially toxic, some dopamine-enhancing agents may have neuroprotective properties as well.

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

METHYLPHENIDATE; MINAPRINE; NOMIFENSINE
        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. It is sometimes abused as an instrument of social control. 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. Methylphenidate blocks the reuptake, but doesn't significantly release, the catecholamines noradrenaline and dopamine. If it is taken in sustained-release form or combined with an SSRI, all of which have anti-obsessive-compulsive properties too, then the likelihood of dose-escalation is minimised. In North America, students sometimes take Ritalin to gain a competitive edge in exams. However, its long-term effect on the developing brain is poorly understood.

        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 (Cantor). 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. Unfortunately, minaprine is now obtainable only as a "research chemical".

        Merital (nomifensine) showed great promise as a pleasantly stimulating dopaminergic that also potently inhibits the reuptake of noradrenaline and - to a much lesser extent - serotonin. It was marketed by its manufacturers Hoechst with the slogan "vive la difference!" Merital 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. Nomifensine is now obtainable only as a research chemical too.

BUPROPION; AMINEPTINE
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 - particularly women - libido, arousal, and the intensity and duration of orgasm may actually increase. Bupropion weakly 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. Bupropion's active metabolites inhibit the reuptake of noradrenaline. Radafaxine, one of these metabolites, also blocks the dopamine transporters; radafaxine may in future be marketed as a slimming drug as well as an antidepressant. Bupropion itself, branded as Zyban, may help in giving up smoking. Scandalously, bupropion isn't licensed and marketed as an antidepressant in Europe - though doctors may prescribe Zyban to non-smoking depressives "off-label". Bupropion plus an SSRI is sometimes more effective than either agent alone.

        Amineptine (Survector) is a clean-ish, (relatively) selective dopamine reuptake blocker. Higher doses promote dopamine release too. Amineptine is pro-sexual and liable occasionally to cause spontaneous orgasms. It is a mild but pleasant psychostimulant and a fast-acting mood-brightener. Unlike most 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". FDA pressure led to its withdrawal in Europe too. This drove it onto the pharmaceutical grey market, discomfiting doctors and patients alike.

REBOXETINE; ADRAFINIL; MODAFINIL
        Reboxetine (Edronax) is a relatively well-tolerated, selective "noradrenergic" agent. Crudely, whereas serotonin plays a vital role in mood, noradrenaline is essential to maintaining drive, vigilance 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 typically doesn't have the disruptive effects on cognitive function or psychomotor performance common to older clinical mood-brighteners - though alas antimuscarinic effects are still not completely absent. The new NorAdrenaline Reuptake Inhibitors (NARIs) - and dopaminergics like amineptine (Survector) - may be especially useful in drive-deficient "anergic" states where the capacity for sustained motivation is lacking; and for melancholic depressives with a poor ability to cope with stress. Reboxetine can be safely combined with an SSRI, though there is evidence that NARIs themselves indirectly enhance central serotonin function by a mechanism that doesn't depend on reuptake inhibition. More surprisingly perhaps, preliminary studies suggest reboxetine can actually reverse tranylcypromine-induced hypertensive crises. The "cheese effect" is triggered by ingesting tyramine-rich foods. Thus NARIs plus MAOIs may prove a potent form of combination-therapy if first options fail.

        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. Alpha1-adrenergic agonists like adrafinil (Olmifon) and modafinil (Provigil, Alertec) are centrally-acting psychostimulants that can brighten mood and sharpen mental focus. They stimulate the noradrenergic post-synaptic receptors, increase glutamatergic transmission, and activate the wakefulness-promoting orexinergic neurons, thereby boosting alertness, memory, mood, motivation and energy. At sensible dosages, they are remarkably free of side-effects. However, the approval process i