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 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" and "talk-therapy" alike must be neurochemically encoded to exert any effect 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 super-health 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 "better than well" 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 tortured non-human experimental animals, for instance, blandly get "used" and "sacrificed", certain socially taboo 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 (1925 – 2014) and David Nutt - 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. Some of the online literature, for instance Erowid, is first-rate. At its best, Wikipedia puts print publications to shame. Unfortunately, a lot of web-published material isn't much more objective in content or style than the professional journals it complements. Medical ghostwriting, unacknowledged conflicts of interest and publication bias are endemic to "peer-reviewed" academic journals; but methodological rigour is scarce in the scientific counter-culture too. 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 truly 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 perhaps 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 comparative controlled clinical trials are lacking. In "animal models", opioids reverse the depressed behaviour, learned helplessness and neuroendocrine responses associated with clinical depression. By contrast, opioid antagonists such as naloxone exacerbate them. To confuse matters further, sufferers from 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 opioid analgesics - even in the terminally ill. Yet we could all do with having our native endorphin systems enriched. Later this century and beyond, the customised site-selective successors to today's opioid drugs may play a critical role in promoting emotional super-health. For example, one potential breakthroughs in recent years was the synthesis and development of JDTic. JDTic exerts a sustained anti-anxiety and mood-brightening effect: it is the first orally active selective kappa opioid antagonist. Kappa is the "ugly" opioid receptor whose endogenous ligand is dynorphin. The dynorphin/kappa-opioid receptor system is implicated in the unpleasant states of mind caused by chronic uncontrolled stress. Repeated use of cocaine, heroin, ethyl alcohol and other euphoriant drugs induces a compensatory up-regulation of the dynorphin/kappa-opioid receptor system too, causing anxiety, anhedonia and dysphoria. Whereas mu receptor agonist opioids induce euphoria by enhancing dopamine release in the nucleus accumbens, activation of kappa opioid receptors inhibits dopamine release from the mesolimbic terminals. This deficiency is subjectively unpleasant because the mesolimbic dopamine system regulates hedonic tone and the capacity to experience (and anticipate) happiness. Dopamine also modulates the threshold of pain perception. In May 2012, the first human trial of JDTic was halted after worries about the incidence of asymptomatic and non-sustained ventricular tachycardia, casting a cloud of uncertainty over kappa therapeutics. But as of 2015, results in non-human "animal models" have been encouraging.
Unfortunately, all opioids in present-day human use 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, tolerance-inducing and 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 cannabinoids may be neuroprotective against the effects of stress. Conversely, cannabinoid CB(1) receptor antagonists/inverse agonists, like the formerly EC-licensed diet-drug rimonabant (Acomplia), may cause depression and anxiety. 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. Indeed the marijuana compound THC may actually be superior to commercially licensed products at blocking the formation of mind-rotting amyloid plaques of the memory-destroying Alzheimer's disease.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 prior 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 an intellectual 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. MDMA stimulates pro-social oxytocin release via activation of the serotonin 5-HT1A receptors. 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. Drug use 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 demonisation 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. It has a relatively low therapeutic index. 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. A report published in The Lancet in 2007 ranked alcohol and tobacco as more hazardous to human health than LSD. Their cumulative human death-toll to date is around 100 million and climbing. A WHO report published in 2008 projected that tobacco abuse may kill one billion people by the year 2100. 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 tobacco 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 BRIGHTENERSThe 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 aerobic 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 drug 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. Folic acid augmentation is advisable as well. 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. Several benzodiazepines are of natural origin: diazepam, for instance, can be found in the potato. Benzodiazepines act primarily on the GABA (gamma aminobutyric acid) receptor complex. GABA functions as the main inhibitory neurotransmitter in the central nervous system. GABA is made from the main excitatory neurotransmitter, glutamate. 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. In the meantime, currently licensed benzodiazepines tend to induce dependence, impair memory and psychomotor performance, dull consciousness and cloud the intellect. The saving grace of benzodiazepines is the weak tolerance of their anxiolytic effect. Yet 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, thereby modulating serotonin release and (sometimes) promoting a brightening of mood. Thus buspirone can be useful in anxious depressive states. Its active metabolite 1-PP is an anxiolytic 5-HT1A partial agonist too. Buspirone lacks the intellect-clouding effects of other clinical and alcoholic anti-anxiety agents. It's not a muscle relaxant. It's only mildly sedating. Yet buspirone's weak and equivocal effects on sub-types of dopamine function, while useful commercially for the purposes of touting its lack of "abuse-potential", mean buspirone isn't very exciting or popular. Crucially, unlike the benzodiazepines, it's not a fast-acting drug. Several weeks of use may pass before its dubious psychological benefits are felt. 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 and again in 2007, the FDA determined that Organon's gepirone (Ariza) was "not approvable".
Oxytocin is a natural anti-anxiety agent: the "cuddle hormone". Several drug companies, notably Wyeth, are investigating its patentable synthetic analogues. Enhanced oxytocin release contributes to the acute pro-social action of MDMA (Ecstasy). Oxytocin builds trust by reducing activity in the fear-processing circuitry of the amygdala. Taken off-label, oxytocin can be inhaled as an intranasal spray to combat social phobia. It reduces shyness and normal social anxiety. More controversially, oxytocin can be applied as an odourless body-spray to manipulate the responses of other people: "trust in a bottle". Nature's social peptide is also critical to pair-bonding. In future, mastery of the oxytocin system may allow us to control our degree of fidelity and attachment to each other far more effectively than marriage vows. The sociological implications of the widespread use and abuse of "social Viagra" would be far-reaching. It should be stressed that research into the safe and sustainable enrichment of human oxytocin function has barely begun.
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. In the second decade of the 21st century, older monoamine theories of depressive illness popular among researchers over the past 40 years have been eclipsed by other models. Thus the neurogenic hypothesis of depression and antidepressant action. The neurogenic model interprets depression, at least in its more severe forms, as a neurodegenerative and neuroinflammatory disorder disorder. Chronic uncontrolled stress causes oversecretion of gluocorticoid hormones, notably cortisol. Cortisol activates the glucocorticoid receptors that regulate metabolism, inflammation and immunity. An excess of glucocorticoid hormones reduces the rate of new brain cell-proliferation in the hippocampus. The hippocampus has the highest density of receptors for glucocorticoids in the brain. Stress-induced activation of the glucocorticoid receptors causes nerve cell death and dendritic atrophy in the hippocampus; by contrast, there is synaptic growth in the basolateral amygdala. The amygdala stores memories of emotional experiences - frequently fearful and unpleasant memories. Eventually, however, prolonged stress tends to atrophy the amygdala too. These long-term changes in brain morphology lower mood. They may result in anhedonia and depression in the genetically vulnerable. Antidepressants either diminish, prevent or (ideally) reverse stress-induced neural damage and impaired structural plasticity. How do they really work? Despite an explosive growth in neurobabble, 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 may 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 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. 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". Unpredictably, other users feel worse. 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 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 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; indeed, from 2013 the SSRI dapoxetine (Priligy) was licensed as an on-demand treatment for premature ejaculation. But SSRI-induced sexual dysfunction can still be a highly 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 vardenafil (Levitra); or a dopamine agonist, licit or otherwise, before bedtime action. Investigational drugs that heighten female sexual arousal (e.g. flibansein, or melanocortin agonists like PT-141/ bremelanotide (Vyleesi) are another option. Indeed, unlicensed use of the world's first aphrodisiac and inhalable sex-drug may herald a cultural revolution without precedent. Yet polypharmacy is scarcely an ideal solution for existing SSRI users. 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. In June 2015, the advisory committee to the FDA voted to approve flibanserin. The FDA is expected to announce whether flibanserin will be given a product license in August.
Second, though a few subjects may feel mildly euphoric, in other users the SSRIs serve more as mood-stabilisers and mood-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.
A backlash against SSRIs is now gathering pace. In 2008, a Public Library of Science meta-analysis of four commonly prescribed "second generation" antidepressants - using both published and withheld drug-company data - reported that SSRIs were scarcely more effective as antidepressants than placebos. The illustrious UK psychopharmacologist Professor David Healy delivers an even more damning verdict on contemporary psychiatry: "there is probably no other branch of medicine where the outcomes for a core disease are steadily worsening." [p. 95; Shock Therapy by Edward Shorter and David Healy (2007)]
THE DOPAMINE CONNECTION
What's missing, crucially, is the therapeutic enrichment of hedonic tone via a combination of mu opioid pathway enhancement and prolonged stimulation of meso(cortico-)limbic dopamine function.
This is really much more fun than it sounds. Yet the socially responsible use of reward pathway enhancements/remedial therapies is a technical, bioethical and medico-legal minefield. In the late twentieth century, experimental evidence 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 vital 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 the neuroprotective dopamine D3 receptor subtype selective 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 rostromedial shell of the nucleus accumbens is critical. Researchers into affective disorders can prematurely become 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 in antidepressant research. "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 Ecstasy-like empathogens and sociabilisers is at least 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 (RITALIN); MINAPRINE (CANTOR); NOMIFENSINE (MERITAL)
An 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 more benign version of cocaine, yet with a much longer half-life. Methylphenidate blocks the reuptake of, 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 Europe and 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's illicit and 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".
(Nomifensine (Merital) 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 différence!" 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); AMINEPTINE (SURVECTOR); TIANEPTINE (STABLON)
Bupropion (Wellbutrin) is possibly less effective than nomifensine. Yet bupropion is 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, though its development was discontinued GlaxoSmithKline in 2006. 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. In June 2006, the FDA licensed bupropion/Wellbutrin XL as the first preventive pharmacological treatment of Seasonal Affective Disorder (SAD).
Amineptine (Survector) is a cleanish, (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 amineptine onto the pharmaceutical grey market, discomfiting doctors and patients alike.Another "French" option is amineptine's cousin, tianeptine (Stablon). Tianeptine is a neuroprotective antidepressant that reverses the neuronal damage and lasting misery caused by uncontrolled stress. Chronic stress causes dysphoria by inducing corticotropin-releasing factor (CRF2) receptor stimulation of dynorphin release. The endogenous opioid peptide dynorphin activates the unpleasant kappa opioid receptors. Tianeptine acts both as a non-sedating anti-anxiety agent and a non-stimulating mood-brightener. Its use increases extracellular dopamine concentration in the nucleus accumbens and, at higher doses, in the frontal cortex. Uniquely in clinical medicine, tianeptine acts as a selective serotonin reuptake enhancer. Its puzzling efficacy as an antidepressant illustrates how little modern psychiatric medicine really understands about mind, mood and depression. Like other contemporary antidepressants, tianeptine's therapeutic action presumably depends on downstream adaptations both between and within neurons occurring over a period of several weeks. Chronic tianeptine use reverses stress-induced hippocampal dendritric atrophy and amgydaloid dendritic hypertrophy, which is just as nasty as it sounds. But the precise molecular mechanisms are obscure. Tianeptine/Stablon is not licensed in North America primarily because its patent has expired.
A breakthrough in tianeptine research was announced in July 2014 with the unexpected discovery that tianeptine is a full agonist at the mu and delta opioid receptors with negligible effect at the kappa opioid receptors. Selective mu opioid agonists in the brain's twin "hedonic hotspots" typically induce euphoria. Selective kappa agonists typically induce dysphoria. The role of central delta opioid receptors is poorly understood. Dual activation of the mu and, less potently, the delta opioid receptors may be critical to tianeptine's mood-brightening and anxiolytic effect - a therapeutic action seemingly unaccompanied by the physiological tolerance and dependence that have plagued traditional opioids. All previous research into tianeptine may need to be re-evaluated in this light. More research is urgently needed.
REBOXETINE (EDRONAX); ADRAFINIL (OLMIFON); MODAFINIL (PROVIGIL)
Reboxetine (Edronax) is a relatively well-tolerated, relatively 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. Multiple interactions between the different monoamine systems make it hard to target one neurotransmitter system without triggering a cascade of effects on the others. But 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. EMSAM, the transdermal selegiline patch, is probably the safest choice of MAOI.
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. 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. However, the significance of these prescribing indications is rapidly being eroded. Modafinil and adrafinil are now mainly used off-label as so-called lifestyle drugs.Of course, many millions of insomniacs suffer from the opposite problem. They simply want regular sleep. Supracor's 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.
MIRTAZAPINE (REMERON); NEFAZODONE (SERZONE); VENLAFAXINE (EFFEXOR) & DESVENLAFAXINE (PRISTIQ); DULOXETINE (CYMBALTA); ROLIPRAM; AGOMELATINE (VALDOXAN)
NARIs are normally activating. Anxious and depressive insomniacs, on the other hand, may benefit more from "dual-action" mirtazapine; 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 "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 altogether by its manufacturer Bristol-Myers Squibb under threat of litigation.
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". In February 2008, the FDA licensed its extended-release active metabolite desvenlafaxine as the antidepressant Pristiq after Weyth's venlafaxine patent expired. 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 augmentation-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 sometimes 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 wonderdrug for mental health 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.
Phosphodiesterase-inhibitors, 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.
Agomelatine (Valdoxan, Melitor, Thymanax) is a novel antidepressant and anti-anxiety agent developed by Servier and licensed in the European Union in February 2009. A synthetic analogue of the natural hormone melatonin, agomelatine is a potent melatonin receptor agonist and a serotonin 5-HT2C receptor antagonist. Blockade of the neural 5-HT2C receptors enhances frontocortical adrenergic and dopaminergic transmission, potentially improving cognitive performance. In "animal models", agomelatine also reduces the adverse effects of stress on memory. By acting as a melatonin receptor agonist, agomelatine improves sleep quality. When taken once daily before bedtime, agomelatine doesn't cause daytime drowsiness and sedation like the old tricyclics; nor does its use kill libido like the SSRIs. Agomelatine is typically well tolerated and remarkably free from adverse side-effects at therapeutic dosages. Drug giant Novartis acquired the US rights to agomelatine from Servier in 2006. In July 2009, Novartis announced it was delaying submission for US regulatory approval another three years while it conducted additional Phase III trials. Development for the US market was discontinued altogether in October 2011. American consumers must now order agomelatine online or from Europe.
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 low spirits. The only sort of remedy that they'll conceivably contemplate taking must carry a "natural" label and soothingly "herbal" description.
Unfortunately, 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 to consume. Other "natural" interventions such as bright light therapy combined with good sleep discipline may be of limited use. But two options 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. A Cochrane Review published in October 2008 found that hypericum extracts used to treat major depression had similar efficacy to standard antidepressants but fewer side-effects.INOSITOL
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
A further option involves using both some of the oldest and the newest drugs on the block, the monoamine oxidase inhibitors (MAOIs). The older irreversible MAOIs certainly shouldn't be combined with SSRIs. 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.Monoamine oxidase has two main forms, type A and type B. They are coded by separate genes. MAO may be inhibited with agents that act reversibly or irreversibly; and selectively or unselectively; these categories are not absolute. For instance, 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.
The 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.
Sadly, the role of MAO in deaminating tyramine (from the Greek word tyros, meaning cheese) wasn't at first understood. Certain MAOI-treated patients suffered hypertensive crises after eating varying amounts of tyramine-rich aged cheese; and several died. It is now recognised that the use of any MAOI which is both irreversible and unselective must be accompanied by dietary restrictions. But the adverse publicity of the initial inexplicable fatalities, combined with the introduction of a succession of dirty but sometimes tolerably effective tricyclic compounds, sent the use and reputation of MAOIs into a precipitous decline from which they still haven't fully recovered. The older non-selective and (more-or-less) irreversible inhibitors tranylcypromine (Parnate), phenelzine (Nardil) and isocarboxazid (Marplan) are nonetheless valuable antidepressants. Outside America, the selective and reversible MAOI moclobemide. is used too. 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 therapeutic opportunity.
SELEGILINE (l-deprenyl, ELDEPRYL, EMSAM)
A recent New York study showed that smokers had on average 40% less of the enzyme, monoamine oxidase type-B, in their brains than non-smokers. Levels returned to normal on their giving up smoking. Not merely is the extra dopamine in the synapses rewarding. The level of MAO-b inhibition smokers enjoy apparently contributes to their reduced incidence of Parkinson's and Alzheimer's disease. Unfortunately they are liable to die horribly and prematurely of other diseases first.
One option which the dopamine-craving nicotine addict might wish to explore is switching to the (relatively) selective MAO-b inhibitor selegiline, better known as l-deprenyl. Normally the brain's irreplaceable complement of 30-40 thousand odd dopaminergic cells tends to die off at around 13% per decade in adult life. 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. In future, the mood-enhancing transplantation of customized stem cells may restore a youthful zest for life in dopamine-depleted oldsters: such stem cell-derived monoaminergic grafts are currently on offer only to depressed rodents. 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.
Whatever the full explanation, deprenyl-driven MAOI-users, unlike cigarette smokers, are likely to be around to enjoy its distinctive benefits for a long time to come, possibly longer than their drug-naïve contemporaries. For in low doses, deprenyl enhances life-expectancy, of rats at least, by 20% and more. It enhances drive, libido and motivation; sharpens cognitive performance both subjectively and on a range of objective tests; serves as a useful adjunct in the palliative treatment of Alzheimer's and Parkinson's disease; and makes you feel good too. 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. In November 2004, Yale University researchers launched a study of deprenyl for smokers who want to quit tobacco. 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.L-deprenyl/selegiline can now 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. After various delays, in February 2006 the FDA granted EMSAM a product license for the treatment of major depressive disorder in adults. EMSAM's pharmacokinetic and pharmacodynamic properties promote the inhibition of MAO-A and MAO-B in the CNS while avoiding significant inhibition of intestinal and liver MAO-A enzyme. Three different strengths of EMSAM patch are currently marketed: 20mg/20cm2, 30mg/30cm2, and 40mg/40cm2, delivering daily doses averaging 6mg, 9mg and 12mg respectively. Use of the lowest dosage EMSAM 6 mg/24 hour patch calls for no dietary modification. At this dosage, MAO-A in the digestive tract is preserved at levels adequate to break down tyramine, while MAO in the brain is inhibited at levels adequate to induce an antidepressant effect. A restricted "MAOI diet" is prudently advised for the higher dosage EMSAM 9 mg/24 hr patch and the 12 mg/24 hr patch to avoid any risk of hypertensive crisis. But it's worth noting that (as of June 2015) no hypertensive crises following dietary indiscretions have been reported even in users of the high strength patches.
Unlike deprenyl, the novel irreversible selective MAO-B-inhibitor rasagiline (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. Azilect finally gained a US product license in May 2006. In August 2008, Teva announced promising results from a late-stage Phase III 18-month rasagiline trial. Parkinsonians who took a 1mg Azilect pill once a day from the start of the trial showed "significant improvement" over patients who started taking Azilect nine months later.
MOCLOBEMIDE (MANERIX, AURORIX)
Humans now have the capacity to choose their own individual level of activity or inhibition of the two primary monoamine oxidases. This does not quite enable the fine-tuning of personality variables with the functional equivalent of a graphic equaliser. It still represents a promising start. In MAO-inhibition, as in life, more is not always better. Excessive dosages of l-deprenyl, for instance, may actually shorten, not increase, life expectancy - at least in Parkinsonians if it's combined with l-dopa. And levels of above 80% inhibition of MAO-A may lead to a sharp and possibly unwanted fall in dopamine synthesis. Repairing Nature's niggardliness will be a priority for the decades ahead.
Moclobemide (Manerix, Aurorix), the "gentle MAOI", is both a selective and reversible inhibitor of MAO-A. It marks the first RIMA to win clinical acceptance. 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).
Gentleness doesn't suit everyone. Moclobemide isn't much good at lifting deep melancholy. Tranylcypromine (Parnate), on the other hand, is one of the older and non-selective MAOIs - and is often none the worse for it. Structurally related to amphetamine, 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. Tranylcypromine use increases trace amines, modulates phospholipid metabolism and up-regulates GABA(B) receptors. In fact, its nicest effects, as for all of the compounds cited here, will vary in nature and extent from person to person. To some extent, optimal dosage and long-term drug-regimen of choice can be discovered only by (cautious) empirical self-investigation.
Tranylcypromine is of course vastly preferable to the amphetamines and cocaine. Yet frequently and perversely, the more hazardous the drug, then the easier it is to get hold of in our society. The carcinogenic cocktail that carries off more people than all other toxins combined can be purchased quite legally and effortlessly at any tobacconist or newsagent. Obtaining the less lethal - but scarcely socially 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 using online pharmacies of uncertain reputation.
If 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 ethyl 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.
This freedom of choice isn't conventional wisdom. It will be suggested that the level of medical expertise required to make informed choices exceeds that of the average layperson. 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 largely incomprehensible.
BIOHAPPINESS PROSPECTS: 2019KETAMINE; RAPASTINEL(GLYX-13); APIMOSTINEL (NRX-1074)
What are the options for the chronic depressive who has tried everything? Diet, exercise and sleep discipline are good. Nothing works.
One last-resort option is ketamine. Ketamine is better known as a dissociative anaesthetic and painkiller. Taken at around a tenth of the anaesthetic dose, ketamine rapidly lifts "mental” pain too. Dosing can be repeated every three or four days as needed. A non-invasive nasal spray is a convenient home alternative to intravenous infusion. Higher dosing may increase efficacy and side-effects. Between 65% and 75% of even "treatment-resistant" depressives report rapid and sustained mood relief. Ketamine and its active metabolite hydroxynorketamine also banishes anxiety, intrusive traumatic memories and obsessive-compulsive symptoms. Ketamine's primary target is the N-methyl-D-aspartate (NMDA) receptor. NMDA is a glutamate receptor and ion channel protein critical to synaptic plasticity, memory function and abstract thought. Ketamine has weak agonistic effects on mu opioid receptors. Co-administration of naltrexone prevents immediate mood-elevation. But any acutely enjoyable opioidergic action cannot explain ketamine’s sustained mood-brightening effect. Longer-term down-regulation of depressogenic cytokines probably plays a role in mood improvement. So does ketamine-induced increased production of brain-derived neurotrophic factor (BDFN) and (indirectly) striatal dopamine release. Other researchers speculate that signalling via the AMPA glutamate receptor is key, mediated via ketamine's metabolite hydroxynorketamine. At present, neuroscience does not understand the downstream signalling cascade that explains ketamine’s therapeutic action, when it works. But used responsibly - and ideally under medical supervision - low-dose ketamine is a comparatively safe and effective mood-brightener. In March 2019, the FDA licensed esketamine, the S(+) enantiomer of ketamine, as a fast-acting antidepressant nasal spray under the marketing name of Spravato.
One pitfall with ketamine is transient "dissociative reactions". Full-blown out-of-body experiences are rare at the low therapeutic dose. Yet most depressives don't want to become psychonauts in any shape or form, just feel well. Another glutamate-modulating option is apimostinel, the orally active analogue of rapastinel. Apimostinel and rapastinel are glyxins - allosteric modulators of the glycine site of the NMDA receptor that typically lack ketamine's acute "psychotomimetic" effects. Both apimostinel and rapastinel are fast-acting, pain-killing, mood-brightening, neuroprotective smart drugs. Normally, neither apimostinel and rapastinel make users feel weird. Alas, the results announced in March 2019 of a Phase 3 trial of rapastinel as an adjunctive treatment of major depression were not encouraging. For a useful list of therapeutic mood-brighteners under commercial development, see Wikipedia's investigational antidepressants. "Health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity", says the World Health Organization (WHO) in its founding constitution. As so defined, can good health for all sentient beings be achieved without rewriting our genetic source code? Probably not, but gene therapy for sick Darwinian minds is still decades away from routine use. For now, we are stuck with drugs, and compassion.
BIOHAPPINESS PROSPECTS: 2020LIH383
Chronic mental and physical pain are primarily disorders of the opioid system (cf. Endogenous opioid system dysregulation in depression). Hence the impasse in the development of effective treatments for unhappiness. Human and nonhuman animals are all born addicts, dependent on endogenous opioids and engineered by natural selection to have no lasting way to satisfy their cravings. Our addiction might seem untreatable: exogenous opioid drugs can’t (responsibly) be used or commended as antidepressants or anti-anxiety agents. Tianeptine is an anomalous, partial, unexplained exception. Even relieving physical pain with opioids is fraught with problems, most notably tolerance. The acute therapeutic effects of mu opioid agonists can seem magical. Consumers feel well – sometimes for the first time in their lives. But then feedback-inhibition kicks in. Exogenous opioid users, through no fault of their own, can cause immense suffering to themselves, their friends and their families. Endogenous addicts often do likewise.
However, the bombshell discovery of a new opioid receptor in the CNS promises an entirely new class of drugs – and a therapeutic revolution. The atypical chemokine receptor ACKR3 binds to the brain’s natural opioids and traps them. In consequence, the pain-killing, mood-brightening and anti-anxiety activity of endogenous opioids is diminished, darkening mood and increasing feelings of pain, malaise and stress. Normally, the negative-feedback mechanisms of the brain are brutally efficient. Yet researchers at the Luxembourg Institute of Health have developed the novel molecule LIH383 to counteract this cruel negative regulation of hedonic tone.
LIH383 binds to and blocks the sinister ACKR3 receptor so it no longer traps the brain’s endogenous opioids. Taking LIH383 increases natural levels of opioid peptides in the CNS, thereby enhancing their pain-killing and mood-lifting properties on a long-term basis. Anxieties fade. Subjects feel happy. Therefore well-controlled clinical trials of LIH383 are vital. Will LIH383 work best with or without co-administration of a selective kappa antagonist to target the vicious dynorphin/kappa receptor system? LIH383 and its next-generation successors, perhaps used in conjunction with selective kappa antagonists, promise a revolution in mental health.
A wider societal revolution is conceivable too, if ACKR3 receptor blockade ever becomes the norm. Nominally well populations of endogenous opioid addicts could benefit from a sustainable uplift in hedonic range and hedonic set-points. Is medical science on the brink of creating "soma"? For sure, pitfalls and "unknown unknowns" abound. What is the optimal dosage-range of LIH383 and its successors? The risks? Possible immunological effects? Abuse potential? How should such agents be regulated? But 2020 may go down in medical history not just as the year of the coronavirus pandemic, but the dawn of a new era in mental health.
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 tragic aberrations. 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". Discontent is "adaptive". Everyday emotional pain is part of "what makes us human".
The 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.
Fortunately, 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 gradients of heavenly well-being become the genetically predestined norm of mental health, then the very notion of tampering with our newly 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.
Today's 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. Early in the 21st Century, "Just Say No" is frequently still 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.David Pearce
(last updated September 2020)
and further reading
Just For Chemists
The Wired Society
The Abolitionist Project
Resources on Depression
The Hedonistic Imperative
The Reproductive Revolution
The Biointelligence Explosion
MDMA: Utopian Pharmacology
Critique of Huxley's Brave New World
Online International Pharmacies 2020