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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 ssri s nari s snri s nassa s rima s etc to complement the dirty old tricyclics and irreversible unselective maoi s 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 in the longer run however irrespective of how clever our pharmacological interventions may one day be we d arguably be better off taking no drugs at all for if there were nothing fundamentally wrong with our default state of consciousness then we wouldn t now try so hard to change it thus our sophisticated descendants may opt instead to rewrite the vertebrate genome and allow themselves life long genetically pre programmed bliss they may naturally be animated by gradients of well being beyond the bounds of normal human experience as an everyday part of mental health 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 emotional and physical pain are primarily a disorder of the opioid system cf endogenous opioid system dysregulation existing opioid based treatments of mental and physical pain tend to activate the negative feedback mechanisms of the cns therefore the cycle of misery continues but in 2020 researchers at the department of infection and immunity of the luxembourg institute of health developed the novel agent lih383 the lih383 molecule binds to and blocks a previously unknown opioid receptor in the brain the atypical chemokine receptor ackr3 ackr3 functions as a scavenger receptor that sequestrates naturally secreted opioid peptides by binding and trapping the brain s endogenous opioids the ackr3 receptor reduces their mood brightening pain killing stress relieving and anxiolytic activity and darkens our default hedonic tone the novel lih383 molecule promises to dampen this sinister mechanism of feedback regulation so potentially lih383 could be used either alone or in conjunction with selective kappa opioid antagonists to revolutionise the treatment of pain disorders anxiety and depression and maybe elevate the default hedonic tone of the nominally well the therapeutic and societal implications are momentous for sure the history of psychopharmacology is littered with false dawns yet lih383 or its next generation successors combined with selective kappa opioid receptor antagonists could potentially revolutionise mental and physical health next 1 2 3 references and further reading opium people opium images opium timeline...