"If we could sniff or swallow something that would, for five or six hours each day, abolish our solitude as individuals, atone us with our fellows in a glowing exaltation of affection and make life in all its aspects seem not only worth living, but divinely beautiful and significant, and if this heavenly, world-transfiguring drug were of such a kind that we could wake up next morning with a clear head and an undamaged constitution - then, it seems to me, all our problems (and not merely the one small problem of discovering a novel pleasure) would be wholly solved and earth would become paradise." ALDOUS HUXLEY

1894 - 1963



THE BIRTH OF A NEW GENERATION

It would indeed be extraordinary if - alone among the neurotransmitter systems of the brain - the endogenous opioid families were immune from dysfunction. Enkephalins are critical to "basal hedonic tone" i.e. whether we naturally feel happy or sad. Yet the therapeutic implications of a recognition that dysfunctional endogenous opioid systems underlie a spectrum of anxiety-disorders and depression are too radical - at present - for the medical establishment to contemplate. In consequence, the use of opioid-based pharmacotherapies for "psychological" pain is officially taboo. The unique efficacy of opioids in banishing mental distress is neglected. Their unrivalled efficacy in treating "physical" nociceptive pain is grudgingly accepted.

Later this century and beyond, however, the development of highly selective, site-specific designer drugs and innovative gene-therapies may enhance our native opioid function and revolutionise mental health. Therapeutic intervention targeted on the opioid pathways will potentially enrich the quality of life of even the nominally "well", not least because - by the more enlightened health standards of posterity - we may all be reckoned mentally ill.

Today, by contrast, immense energy is devoted by the authorities into persecuting "illicit" narcotic users. Many drug-"abusers" feel well thanks only to the "non-therapeutic" use of opioids. They are stigmatised, pilloried and criminalised in a futile War Against Drugs. In the "Inquisition against pleasure", victims of medically-sanctioned human-rights abuses - e.g. the hundreds of thousands of drug "offenders" incarcerated in the Amerikan gulag - are officially supposed to believe their malaise-ridden drug-naïve states were "normal", "natural" and mentally healthy. In the course of our ill-conceived Drug War, vast resources are dissipated by the state-apparatus in an effort to choke off narcotic production and supply. When these efforts are temporarily successful, drug-deprivation makes the habitual opioid user feel ill; [s]he "cold-turkeys" with characteristic irritability, anhedonia, depression, sickness behaviour and sometimes raw physical pain. The ill-effects felt from involuntary deprivation of opioids are taken to demonstrate the likely ill-effects of legalised access, a paradox that might be thought laboured were its human costs not so tragic.

When caught up in the criminal justice system, users may be pressured into taking opioid antagonists like naltrexone (Trexan). Such drugs can induce dysphoria and suicidal despair. At best, their use subtly diminishes the victim's capacity ever to feel well. Meanwhile Chinese military surgeons have developed (2003) a new treatment weapon against narcotic users: surgical destruction of the pleasure centres. Western doctors are said to be following these procedures with interest, but are more likely to achieve their functional equivalent by non-surgical means.

Even where it is acknowledged that many opioid users have a pre-existing anxiety or depressive disorder in urgent need of relief, those so afflicted are fobbed off with often third-rate psychotropics instead. For a start, the monoamine hypothesis of depression - and the new classes of drug it has spawned (SSRIs, NARIs, SNRIs, NaSSAs, RIMAs etc to complement the dirty old tricyclics and irreversible unselective MAOIs) - is radically incomplete. A minority of people, admittedly, find such drugs effective. Often taking a licensed antidepressant is better than nothing at all - perhaps in part because of their positive effects on endogenous opioid peptide release. Yet even in the context of controlled clinical trials with relatively high dosage-regimens and artificially good rates of patient-compliance, it's rare for response-rates to reach more than 70%. Rates of full remission of depressive symptoms are far lower, perhaps 25-30%. Out "in the field", the picture is worse still. Adverse side-effects are common. Response may take weeks. Withdrawal reactions can be unpleasant.

A recognition of the crucial role of dopamine, and selective dopamine reuptake blockers, in sub-types of depressive mood-disorders might push response and remission rates higher. The mesolimbic dopamine system is critical to vitality, motivation, libido and a capacity to anticipate reward. Dopaminergics can also act as analgesics. They can also reverse the apathetic sedation induced by some antidepressants and opioid agonists. Yet the FDA stymies the licensing of effective dopamine reuptake-blocking mood-brighteners at home; and applies pressure to deny access to them abroad. This is because of worries about their (sometimes) faster efficacy - and mild psychostimulant effect - raise the spectre of "abuse-potential"; and proscription, persecution and indiction are favoured over consumer education. For Big Brother knows best.

More controversially, adding customised opioids, enkephalinase-inhibitors and kappa-antagonists to our therapeutic armamentarium may prove critical to boosting response- and remission-rates towards 100% in the decades ahead. Crudely, whereas dopamine mediates "wanting", mu opioid agonists mediate "liking". Both systems can be fruitfully enhanced. Depressive and dysthymic people often suffer from a dysfunctional opioid system and anhedonia - an incapacity to experience pleasure. Sometimes orthodox "antidepressants" may even make them feel worse. Yet controlled clinical trials of designer narcotics for refractory and/or melancholic depression, let alone their use by "normal" people with "ordinary" mood-disorders, are not imminent. Opioid use isn't inherently life-shortening: for instance, chronic morphine administration extends longevity in vertebrate and invertebrate species alike.

So what is to be done? Even in the context of today's crude agents, would some of us be better off as legalised junkies?

No, usually not, at least in contemporary society. Self-medicating users with enough resources to maintain a regular supply may indeed find they can function as well as, or better than, their drug-naïve state. Popular mythology aside, users don't seek to escalate dosage indefinitely: both humans and laboratory monkeys with unlimited access tend slowly to increase injection-frequency until eventually they self-administer a stable and subjectively optimal amount of the drug. Most users take heroin, not primarily to stave off the abstinence syndrome, but because they find life on heroin better than their pain-ridden life without it. Yet the existence of a typical heroin addict in prohibitionist society can still be exceedingly unpleasant at times. Contemporary opioid drugs, natural and synthetic alike, are flawed. The problem is not the euphoric well-being they can induce - an ill-named "adverse side-effect" - but their tendency to induce a financially ruinous tolerance; perhaps insidiously to dull the intellect; trigger nausea; slow digestive processes; and sometimes induce a parodoxical hyperalgesia. Most seriously, when taken in acute excess, today's opioids can cause respiratory depression. This is a consequence of their stimulation of the mu-2 receptors in the medullary respiratory centres of the brain. These problems are exacerbated a thousandfold, however, by the illegal status of narcotics in contemporary society. Dosage, purity and regularity of supply cannot be guaranteed; prices are inflated; quality-control is negligible; good hygiene is difficult. Pharmacological education is non-existent, whereas it ought to be part of the core curriculum. Opioid users are frequently forced into crime to pay for pharmacotherapies that should be cheaply and safely available; and damned for seeking a state of mind which will one day be their birthright: invincible happiness.

To promote emotional superhealth both durably and effectively, designer-opioids must be synthesised that are also subjectively nicer, richer and cleaner than today's product-line. For one of our three major endogenous opioid families is implicated in profoundly dysphoric psychological effects: a cruel negative-feedback system exists between the mu and kappa systems that "corrects" any "excess" tendency to well-being. Thus dynorphin activity at the kappa receptors tonically inhibits the release of dopamine from the mesolimbic terminals. By contrast, the mu-opioid receptor selective endomorphins, especially endomorphin 1, are potent antidepressants: they enhance mu opioid receptor-mediated dopamine release in the nucleus accumbens. If our well-being is to be sustainably enhanced, the balance between the two opposing opioid systems must be shifted.

The role of the mu receptors appears to be crucial in another respect. Today, people vary hugely in their sensitivity to pain. This sensitivity is genetically regulated. Pain perception - and, conversely, emotional well-being - is closely linked to the number of neuronal mu receptors. This number is controlled by a single gene, the mu opioid receptor gene. Pain-sensitivity is diminished when the receptors are present in relative abundance. When the receptors are reduced in number or missing altogether, relatively minor noxious stimuli may be perceived as painful.

In the short-to-medium term, then, we need better-targeted opioids, safer and more site-specific than the present crop. Smarter opioids can potentially be combined with cholecystokinin antagonists (e.g. proglumide); nitric oxide (NO) synthase inhibitors; peroxynitrite-blockers; and also, perhaps, better-designed NMDA receptor antagonists - co-analgesics with potential antidepressant efficacy that inhibit the onset of tolerance. Although mu receptor agonists are the best analgesics and euphoriants, selective delta receptor agonists and enkephalinase inhibitors may prove clinically valuable antidepressants. The development of centrally active and more selective kappa antagonists - which block the endogenous excess production and reuptake of dynorphin underlying many depressive and anxiety disorders - is also a priority. Orally active JDTic, a potent, exceedingly long-acting selective kappa antagonist, underwent preclinical testing until detection of asymptomatic ventricalar tachycardia halted further trials. Kappa Therapeutics, the world's first conference dedicated to the kappa opioid receptor, was held in Seattle July 2011. CERC-501, a potent, selective, short-acting kappa antagonist, is currently (late 2016) undergoing trials as an antidepressant and potential treatment for alcoholism and nicotine dependence. In the meantime, Buprenorphine (Buprenex, Temgesic, Subutex), for instance, is certainly no panacea; but it would probably benefit a far wider section of the population than its current restriction to use in "detoxifying" heroin-addicts. Its role as a mixed mu agonist reduces buprenorphine's addictive potential as a euphoriant while increasing its safety in overdose. Buprenorphine's kappa receptor antagonism may contribute to its superior efficacy as an antidepressant. Even the humble codeine analogue tramadol (Ultram), a selective partial mu agonist analgesic with noradrenaline and serotonin reuptake inhibiting properties, can serve as a useful mood-brightening stopgap. Weak but non-negligible kappa agonism limits its therapeutic benefit. But contemporary medico-legal opiophobia ensures such usage remains strictly off-label.





THE QUEST FOR A DRUG-FREE SOCIETY

Wouldn't lifelong happiness make us stagnate? No. In our genetically-enhanced post-human successors, the functional analogues of aversive experience can potentially perform an analogous functional role to mental and physical pain in our Darwinian past, but without its textures of phenomenal nastiness. Our descendants' enriched dopamine function will enhance their drive, energy and will-power, not just hedonic capacity. Thus outright abolitionism is not technically infeasible - just ideologically problematic.

Tomorrow's bioscientists face another challenge. Taken in excess, opioid-based drugs of today tend to dull consciousness, inducing a dreamy warm contentment. The name "narcotic" derives from the Greek word for stupor. Indeed smacked-out bliss is typically used as the archetype of what any drug-or-gene-underwritten chemical utopia would be like. Most notably, soma in Aldous Huxley's Brave New World is depicted as a cross between a non-addictive opioid and a hangover-less tranquilliser. Thus Huxley's utopians enjoy only an empty imbecilic happiness, not life-enriching peak experiences. Unlike dopaminergics, soma doesn't increase incentive-motivation, nor does it heighten the felt intensity of experience. You can use soma to drift off to sleep.

Yet this negative stereotype of synthetic bliss is profoundly misleading. Addictive tranquillity is only one option among many. It reflects a poverty in our conception of the range of options for paradise-engineering that biotechnology puts on offer. In reality, the quality of our consciousness can be intensified, sharpened and radically diversified by creative psychopharmacology. Intellect and empathy, and not just mood, can be prodigiously enhanced when the ideology of Better Living Through Chemistry finally enters mainstream culture.

Better still, when a wholesale genomic rewrite - and not just piecemeal genetic tinkering - unfolds in the millennium ahead, then any chemical manipulation of our descendants' emotionally- and intellectually-enriched superminds may be redundant. At most, lifestyle drugs will offer an optional fine-tuning for the parameters of their well-being - set against a backdrop of native-born bliss. In the wake of any such Post-Darwinian Transition, a wide variety of social interactions will "naturally" trigger a far richer endogenous opioid release than occurs today; and do so from a much higher baseline of emotional well-being.

However, our present restrictive definitions of mental illness, and the technical challenges posed by large-scale genetic-rewrites, make germline gene-therapy seem a pipe-dream for now. In the present era, lifetime pure dysthymia afflicts far too many people; and periods of "mild" anxiety, malaise and depressive episodes blight the lives of hundreds of millions more. Meanwhile countless victims of chronic pain-disorders are condemned to a life of needless suffering by institutionalized opiophobia. Victims of the most unspeakable, spirit-crushing neuropathic or central pain are liable to be fobbed off with pain-management courses - "helping you to manage your pain" - rather than given the potent pain-relief they deserve. For with a bit of creative psychopharmacology, both the tolerance and adverse side-effects of chronic opioid use are manageable even with today's crude agents. Thanks to tomorrow's biotechnology, the real obstacles to curing the nasty side of life are set to become doctrinal, not technical. Suffering of any kind is due to become optional. It remains to be seen how quickly the ideological baggage of the past can be overcome.

THE 2020 REVOLUTION