THE RESPONSIBLE PARENT'S GUIDE
TO HEALTHY MOOD-BOOSTERS
FOR ALL THE FAMILY
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.
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?
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.
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?
x induces severe, irreversible structural
damage to neurotransmitter subsystem y. Its sequelae include mood-congruent cognitive delusions, treatment-resistant
euphoria, and toxic affective psychosis."
to say, no responsible adult would mess around with a potent neurotoxin under this description.
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.
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
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.
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.
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.
"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.
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.
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".
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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
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.
(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.
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
crucially, is vigorous and prolonged stimulation of meso(cortico-)limbic dopamine function.
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.
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.
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. 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.
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.
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
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 (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 (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.
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
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; and in September 2003, an advisory panel to the FDA endorsed its use for treating shift work sleep disorder and sleep apnea] 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.
course, many millions of insomniacs suffer from the opposite problem. They simply want regular sleep. Supracor's new sleep-aid eszopiclone (Lunesta) can be taken on a nightly basis indefinitely. It will be the first sleeping pill not to carry
an FDA warning against long-term use.
VENLAFAXINE; DULOXETINE; ROLIPRAM
NARIs are normally activating. Anxious
and depressive insomniacs, on the other hand, may benefit more from "dual-action" mirtazapine or nefazodone; or from newly-licensed duloxetine.
Mirtazapine (Remeron) is a structural analogue of the off-patent mianserin (Bolvidon). It is a comparatively new drug - a so-called NaSSA. By blocking the inhibitory presynaptic 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 5-HT2A receptors
accounts for the initial anxiety, insomnia and sexual dysfunction sometimes reported with the SSRIs; stimulation of the 5-HT3
receptors causes nausea. Unfortunately, mirtazapine is a potent blocker of the histamine H1 receptors too. So it tends to have a somewhat sedative effect. This profile may be good for agitated depressives and insomniacs. Again, it is scarcely a recipe for life-affirmation.
Nefazodone (Serzone) is another newish, "dual action", mainly serotonergic agent. It 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. But nefazodone can also be toxic
to the liver, albeit rarely. It may soon be withdrawn.
Venlafaxine (Effexor) is a phenethylamine. Thus it's a benign if distant 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. Venlafaxine lacks anticholinergic activity; but some users are troubled by its
antihistamine side-effects. Like the SSRIs, it is useful for a broad spectrum of disorders beyond clinical depression.
It is possible that duloxetine (Cymbalta, Xeristar, Yentreve), licensed by the FDA in autumn 2004, and milnacipran (Ixel, Dalcipran, Toledomin), available in Europe, may be more effective than venlafaxine (Effexor) for a segment of the population that can benefit from dual serotonin-noradrenaline reuptake
inhibition. Pain-ridden depressives in particular may respond well to this class of drug. Many depressed people suffer from poorly-defined
aches and pains, persistent fatigue, and shoulder-, neck- and back-pain. Duloxetine relieves both the somatic and emotional
symptoms of depression. Unlike venlafaxine, duloxetine exerts its more balanced serotonin and noradrenaline reuptake inhibition
throughout the dosage range. Duloxetine also weakly inhibits the reuptake of dopamine, and shows minimal affinity for the
histamine and cholinergic muscarinic receptors. Its side-effect profile appears to be relatively benign. Yet an authentic mental health wonderdrug remains elusive. Early expectations that duloxetine would
show superior efficacy in melancholic depressives have not yet been convincingly borne out in controlled clinical trials. Ill-served by mainstream
medicine, victims of melancholic and retarded depression may actually do better on dual noradrenaline-dopamine reuptake
inhibitors such as delicensed nomifensine (Merital) and/or mu opioid agonists/kappa opioid antagonists such as buprenorphine (Temgesic, Buprenex, Subutex). Duloxetine itself will probably prove a blockbuster product. It will most
likely be marketed for everything from stress urinary incontinence, social phobia and generalised anxiety disorder, diabetic
peripheral neuropathic pain and possibly irritable bowel syndrome. But alas it takes time to separate genuine therapeutic
advance from drug company hype, typically not until the patents expire.
both selective (e.g. the PDE type 4 inhibitor rolipram) and unselective, are another under-used option. The next few decades will take us much closer to the
downstream 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 that they'll conceivably contemplate taking must carry a "natural" label and soothingly "herbal" description.
most folk remedies are only marginally effective. Our drug-metabolising enzymes are the product of an evolutionary arms race
to counteract plant toxins. For plants tend to manufacture psychotropics because they poison or debilitate creatures tempted to eat them - not to heal our psychic woes. The Wisdom
Of Nature is a quaint piece of make-believe. Perversely, several of the natural remedies that sometimes actually work - notably
Cannabis sativa, Erythroxylon coca and Papaver somniferum - are now illegal. Other "natural" options are extremely limited. But two worth exploring are SAMe and St John's wort.
Hypericum, the active ingredient in St John's wort, appears to be an effective mood-brightener and anxiolytic -
by today's standards at least. Its side-effect profile and efficacy in mild-to-moderate depression compares 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, preferably not bankrolled by the makers of lucrative competing products. Thus a German trial published in the British Medical Journal in February 2005 reported that a proprietary standardised
extract of hypericum/St John's wort was more effective and a better tolerated treatment of moderate to severe depression than
the SSRI paroxetine (Paxil). This runs counter to the negative findings of the 2001 U.S. trial sponsored by the makers of the SSRI sertraline (Zoloft)
- which concluded that for moderate to severe depression, St John's wort was no better than a placebo. Faith in the integrity
of biological psychiatry would be greater if the single strongest predictive factor in the outcome of any published clinical trial wasn't the identity of the funding body.
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.
THE MAO INHIBITORS
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. It is inadvisable to combine them with stimulants or many other drugs. Yet both old and new, the MAOIs
do have some very interesting properties. MAOIs may be particularly useful for rejection-sensitive, so-called atypical depressives who have "reversed vegetative symptoms" i.e. overeating and oversleeping.
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. The beta-carboline alkaloids found in the world's most
popular drink, coffee, are competitive and reversible inhibitors of both MAO type A and type B. 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.
mood-elevating properties of the MAOIs were discovered quite by chance in a US veterans hospital early in the 1950s. 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 of old soldiers 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.
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
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 the neuroprotective antidepressant and anti-Alzheimer's drug TV3326 (ladostigil). MAOIs that lack the peripheral effects of currently explored drugs herald an exciting new window of
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.
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. Their death 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. Its use boosts levels of tyrosine hydroxylase, growth hormone, superoxide dismutase and the production of key interleukins. Deprenyl offers protection against DNA damage and oxidative stress by hydroxyl and peroxyl radical trapping;
and against excitotoxic damage from glutamate.
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. It is used successfully to treat canine cognitive dysfunction syndrome
(CDS) in dogs. At dosages of around 10 mg or below daily, deprenyl retains its selectivity for the type-B MAO iso-enzyme. At MAO-B-selective dosages,
deprenyl doesn't provoke 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.
2004, Yale University researchers launched a study of deprenyl for smokers who want to quit tobacco. Deprenyl can also be delivered via a transdermal patch. In December 2004, pharmaceutical firms Bristol-Myers Squibb and Somerset Pharmaceuticals announced they had entered into an agreement to distribute and commercialize EMSAM, the first transdermal treatment for major depression. If the FDA permits, the patch will be marketed early in 2006.
deprenyl, the novel irreversible selective MAO-B-inhibitor rasagiline (Agilect, Azilect) is not metabolized to methamphetamine or amphetamine. These trace amines are unlikely
to contribute to deprenyl's neuroprotective action. Rasagiline gained an EC product license as Azilect in mid-2005 for the symptomatic treatment of Parkinson's disease. The introduction of Agilect in the USA is currently stalled.
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, 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.
(Manerix, Aurorix), the "gentle MAOI", is both a selective and reversible inhibitor of MAO-A. It marks the first RIMA to win clinical acceptance. Moclobemide lacks anti-cholinergic side-effects. It promotes the healthy
growth of new neurons in the hippocampus. No dietary restrictions are needed. It is valuable as more than a mood-enhancer and
resilience-booster. 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).
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, tranylcypromine is 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 its use demands. In adequate doses, tranylcypromine 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)
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 - street 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. Many of the more beneficent drugs discussed here, on the other hand, are unlicensed, "investigational",
or 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.
the central principle at stake here 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 better off if we switched to enhancing receptor sub-type selective dopaminergic, opioidergic, serotonergic and cholinergic function
by the relatively safe if crude agents touched on here; and perhaps to the more exciting products under development. As a basic minimum, people shouldn't be legally robbed of the right to do so.
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. A quasi-priestly medical 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
WORKING FOR A DRUG-FREE FUTURE
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 animated by gradients of bliss. Unpleasant states of mind would be viewed as a tragic aberration. Bad thoughts and bad feelings could
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 served by the "natural" manufacture of some of the most vicious psychological adaptations imaginable. Sadness and anxiety are "normal". Everyday emotional pain is part of "what makes us human".
rot goes deeper. Selfish DNA can count on innumerable dupes to act as its distal representatives even today as the biotech revolution
unfolds. 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.
Actually, suffering exists only because it was good for our genes. Conditionally-activated negative emotions were fitness-enhancing in the ancestral environment. In the
current era, apologists for mental pain are serving as the innocent mouthpieces of the nasty bits of code which spawned them.
If pressed, primordial DNA's unwitting spokesmen would presumably disavow any such 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 stumbled upon; and then blindly exploited.
over 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 predestined norm of mental health, then the very notion of tampering with our new-won "natural" condition and feeling
"drugged" may come to seem immoral. It may also seem perverse. Why should anyone want to contaminate the divine ecstasy of
their spirituo-biological soul-stuff with chemical pollutants? No thanks.
twisted victims of the primordial genetic code, on the other hand, view the notion of sullying their natural state of being through psychoactive drugs with a much more deep-seated ambivalence. They adopt it as
a near-universal practice. Given the inadequacy of the third-rate pharmacological stopgaps on offer, and the lack of any 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. "Just Say No" is frequently a good rule-of-thumb. 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.