Reboxetine (Edronax) is a well-tolerated , highly selective "noradrenergic" agent. Crudely, whereas serotonin plays a vital role in mood, noradrenaline is essential to maintaining drive and the capacity for reward. There's a fair bit of evidence that chronically depressive people have dysfunctional and atypical noradrenergic systems - particularly their alpha 2 and beta-adrenoceptors. Reboxetine itself doesn't have the disruptive effects on cognitive function or psychomotor performance so annoyingly typical of older clinical mood-brighteners. Indeed the new NorAdrenaline Reuptake Inhibitors (NARIs) are probably under-used and under-hyped. NARIs - and dopaminergics like amineptine (Survector) - may be especially good for drive-deficient "anergic" states where the capacity for sustained motivation is lacking; and for melancholic depressives with a poor ability to cope with stress. Perhaps surprisingly, preliminary studies suggest reboxetine can actually reverse tranylcypromine-induced hypertensive crises. The "cheese effect" is usually triggered by ingesting tyramine-rich foods. Thus NARIs plus MAOIs may prove a potent form of combination-therapy.
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; more adventurous souls may wish to combine the two. Alpha-1 adrenergic agonists like adrafinil and modafinil are centrally-acting stimulants which can brighten mood and sharpen mental focus. They stimulate the noradrenergic post-synaptic receptors and thereby boost alertness, activity and energy. At sensible dosages, they are remarkably free of side-effects. However, the approval process in the USA is so slow, costly and bureaucratic, and the marketing hurdles typically so formidable, that foreign companies are often deterred from seeking FDA acceptance. [modafinil was licensed by the FDA as Provigil for the treatment of narcolepsy in Dec 1998 ] So elderly people continue to suffer the prescription of mildly dementing anticholinergics like the dumb-drug tricylcic imipramine. Adrafinil, by contrast, is at least as successful as hepatotoxic Anglo-Saxon products at treating the cognitive and memory impairments of incipient senility.
Fortunately, a "French" drug like adrafinil can now be ordered over the Net; but it ought to be available at the local corner store. It has the commercial disadvantage of being very cheap.
Sunday, August 16, 2009
Bupropion; Amineptine
Bupropion (Wellbutrin) is possibly less effective than nomifensine. Yet it's useful because it lacks the adverse effects on sexual function characteristic of the SSRIs. In some subjects, in fact, libido, arousal, and the intensity and duration of orgasm may actually increase. Bupropion mildly 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. Its active metabolites block the reuptake of noradrenaline. Chewed as a gum, bupropion is good for giving up smoking. Scandalously, it isn't licensed and marketed in Europe.
Amineptine (Survector) is a clean-ish, (relatively) selective dopamine reuptake blocker. Higher doses promote dopamine release too. Amineptine is liable occasionally to cause spontaneous orgasms. It is a mild but pleasant psychostimulant and a fast-acting mood-brightener. Unlike 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".
Amineptine (Survector) is a clean-ish, (relatively) selective dopamine reuptake blocker. Higher doses promote dopamine release too. Amineptine is liable occasionally to cause spontaneous orgasms. It is a mild but pleasant psychostimulant and a fast-acting mood-brightener. Unlike 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".
Sunday, August 9, 2009
Methylphenidate; Minaprine; Nomifensine
A SSRI can be combined ("augmented"; sounds more soothing to the official medical ear) with a dopaminergic such as methylphenidate. As "Ritalin", methylphenidate is prolifically dispensed to American schoolchildren for different purposes altogether. In spite of its structural relationship to amphetamine, methylphenidate resembles in many ways a benign version of cocaine, yet with a much longer half-life. It blocks the reuptake, but doesn't significantly release, the catecholamines noradrenaline and dopamine. If it is combined with an SSRI, all of which have anti-obsessive-compulsive properties too, the likelihood of dose-escalation is minimised.
Chewing coca leaves with a dash of powdered lime is a nutritious and energising way to sustain healthy mood.
Unfortunately, it is not very good for one's teeth.
A more cautious but still interesting option might be minaprine. 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.
Nomifensine (Merital) showed great promise as a pleasantly stimulating dopaminergic which also inhibits the reuptake of noradrenaline and - to a much lesser extent - serotonin. It 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.
Chewing coca leaves with a dash of powdered lime is a nutritious and energising way to sustain healthy mood.
Unfortunately, it is not very good for one's teeth.
A more cautious but still interesting option might be minaprine. 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.
Nomifensine (Merital) showed great promise as a pleasantly stimulating dopaminergic which also inhibits the reuptake of noradrenaline and - to a much lesser extent - serotonin. It 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.
Dopamine function
What's missing, crucially, is vigorous and prolonged stimulation of meso(cortico-)limbic dopamine function.
This is really much more fun than it sounds. The currently available experimental evidence has persuaded many - but not all - researchers that the mesolimbic dopamine system serves as the final common pathway for pleasure in the brain. Enhanced responsiveness of post-synaptic dopamine D2/D3 receptors is crucial to long-term emotional well-being. The otherwise anomalous mood-brightening effects of the serotonin-reuptake accelerator tianeptine, for instance, are probably explained by its tendency to increase extracellular concentrations of dopamine in the nucleus accumbens. All "serotonergic" and "noradrenergic" mood-brighteners eventually act on the mesolimic dopamine pathway, albeit in differing degrees and with varying delay. And new anti-Parkinsonian and anti-Alzheimer's agents, notably roxindole and pramipexole, owe their exciting potential role as fast-acting antidepressants to their dopaminergic action.
The full story is inevitably complex. Dopamine isn't itself the magic pleasure-chemical, though its functional role is crucial. Researchers into affective disorders readily get over-attached to a particular neurotransmitter, its receptor sub-types and their signal transduction cascades. Traditionally, serotonin and noradrenaline have attracted the fiercest rival partisans. "Dopaminergic" (and opioid) agents, by contrast, are suspect. They are politically incorrect since they are both potentially "abusable". Moreover safe and sustainable empathogens are arguably as morally urgent as safe and sustainable mood-boosters. At any rate, mesolimbic activation, exclusively or otherwise, enhances the intensity of experience; increases pleasure and libido, and boosts cognitive performance. Even better, certain dopamine-enhancing drugs may have neuro-protective properties too.
So what are the other contemporary options for chemical life-enhancement?
This is really much more fun than it sounds. The currently available experimental evidence has persuaded many - but not all - researchers that the mesolimbic dopamine system serves as the final common pathway for pleasure in the brain. Enhanced responsiveness of post-synaptic dopamine D2/D3 receptors is crucial to long-term emotional well-being. The otherwise anomalous mood-brightening effects of the serotonin-reuptake accelerator tianeptine, for instance, are probably explained by its tendency to increase extracellular concentrations of dopamine in the nucleus accumbens. All "serotonergic" and "noradrenergic" mood-brighteners eventually act on the mesolimic dopamine pathway, albeit in differing degrees and with varying delay. And new anti-Parkinsonian and anti-Alzheimer's agents, notably roxindole and pramipexole, owe their exciting potential role as fast-acting antidepressants to their dopaminergic action.
The full story is inevitably complex. Dopamine isn't itself the magic pleasure-chemical, though its functional role is crucial. Researchers into affective disorders readily get over-attached to a particular neurotransmitter, its receptor sub-types and their signal transduction cascades. Traditionally, serotonin and noradrenaline have attracted the fiercest rival partisans. "Dopaminergic" (and opioid) agents, by contrast, are suspect. They are politically incorrect since they are both potentially "abusable". Moreover safe and sustainable empathogens are arguably as morally urgent as safe and sustainable mood-boosters. At any rate, mesolimbic activation, exclusively or otherwise, enhances the intensity of experience; increases pleasure and libido, and boosts cognitive performance. Even better, certain dopamine-enhancing drugs may have neuro-protective properties too.
So what are the other contemporary options for chemical life-enhancement?
Sunday, August 2, 2009
Recreational drugs
The commonly recognised legal and illegal recreational drugs offer poor prospects for sustained biological mood-enhancement. So what about the heterogeneous group of compounds uninvitingly labelled as anxiolytics and antidepressants? Have they potentially anything significant to add to most people's quality of life? Official medical doctrine says no. Allegedly, only sufferers from clinically-sanctioned psychiatric disorders will benefit from such agents; though in recent years it has at last been formally recognised that depressive disorders are under-diagnosed and under-treated even by the twentieth century's abjectly poor standards of acceptable ill-being. Most of humanity, however, still doesn't fit any of the official diagnostic boxes. Can "diagnostic creep" triumph over therapeutic minimalism and enhance their quality of life? Yes. Must the goal of pharmacotherapy be as limited as Freud's aspiration for psychotherapy: "to transform hysterical misery into common unhappiness"? No.
First, the boring but crucial preliminaries. Optimal nutrition and exercise will increase the efficacy of all the potential life-enhancers touted here. A rich supply of precursor chemicals (e.g. tryptophan, the rate-limiting step in the production of serotonin) can also reduce their effective dosages. By choosing to eat an ideal "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. 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 opiates, enhances serotonin function, stimulates nerve growth factors, 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, the benzodiazepines such as diazepam (Valium) and the shorter-acting temazepam, are sometimes useful but still dreadfully crude anti-anxiety agents. They act primarily on the GABA (gamma aminobutyric acid) receptor complex. GABA functions as the main inhibitory neurotransmitter in the central nervous system. The progress of molecular biology and neurogenetics in unravelling the fiendish complexity of GABA's receptor sub-types should eventually allow more targeted compounds to be developed. These more selective and site-specific drugs will lack the sedative and hypnotic properties of today's marketed brands. In the meantime, benzodiazepines in current use tend to induce dependence, dull consciousness and impair the intellect. So there's not much chance of radical life-enrichment here.
Buspirone (Buspar), is somewhat more promising. It acts on an autoreceptor subtype of serotonin. This means it has mood-brightening properties too; and hence it is useful in anxious depressive states. Buspirone lacks the intellect-clouding effects of other clinical and alcoholic anti-anxiety agents. Yet its weak and equivocal effects on sub-types of dopamine function, while useful for the purposes of commercially touting its lack of "abuse potential", mean it isn't very exciting or especially effective.
The so-called anti-depressants fall into several categories. Their mood-brightening effect is correlated with alterations in the concentration of catecholamines and/or serotonin in the central nervous system and the long-term receptor re-regulation these changes provoke.
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. Perhaps unsurprisingly given their parentage, they are all dirty drugs, though some are dirtier than others.
Their anti-cholinergic effects harm memory 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 best avoided.
Much better, but still in some ways deeply flawed, are the selective serotonin reuptake inhibitors.
Serotonin, "the civilising neurotransmitter", plays a vital role in mood, memory, appetite, sleep, pain perception and sexual desire.
Fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), and citalopram (Cipramil, Celexa) are currently licensed and marketed. More of their "me-too" relatives are on the way from pharmaceutical companies eager for a lucrative piece of the action. The SSRIs all differ in their half-lives, chemical structure and precise specificities. Their functional effects are broadly similar. Their mood-brightening, resilience-enhancing and anti-anxiety properties really can make a modest percentage of the population feel "better than well". As a class, they don't have the physically unpleasant and cognitively debilitating anti-cholinergic effects of the tricyclics. A much larger section of the community - folk who daily knock back huge quantities of ethyl alcohol in the socially accepted fashion - could surely gain from the durably enhanced serotonin function SSRIs can yield. Such a switch would necessitate a big change in marketing strategy.
The beneficent properties of the SSRIs are celebrated in Peter Kramer's contemporary classic Listening to Prozac. Kramer has written a remarkably honest book. It's a discursive memoir by a therapist who is forced to admit that many of his clients seemed rapidly to fare far better on a pill than on his industrial-strength regimen of caring talk-therapy. Kramer's discussion of "cosmetic psychopharmacology" and "designer personalities", however, enraged traditionalists. For chemical Calvinist orthodoxy finds the notion that people should have a right pharmacologically to choose who and what they want to be profoundly offensive.
Two common problems limit the usefulness of SSRIs, at least when taken on their own. The problems stem from the indirect inhibitory effect of Prozac-style drugs on dopamine function, a consequence of deliberate selective targeting on the functional enhancement of subtypes of serotonin pathway.
First, SSRIs can compromise libido and sexual performance. This isn't always a disadvantage in over-excitable young males. It can still be a very distressing phenomenon for people too embarrassed to talk about it. Technical performance difficulties can sometimes be counteracted by taking (the alpha-2 adrenergic agonist) yohimbine; the phosphodiesterase inhibitor sildenafil (better known as the sexual rocket-fuel Viagra); or a dopamine agonist, licit or otherwise, before bedtime action. Yet this is scarcely an ideal solution.
Second, though some subjects may feel mildly euphoric, in other users the SSRIs serve more as mood-stabilisers and -flatteners in their lives. By increasing the user's emotional self-sufficiency, too, SSRIs may subtly change the "balance of power" in personal relationships - for good or ill. In some cases, SSRIs may even act as thymoanaesthetisers which diminish the intensity of felt emotion; by contrast, a mood-brightening serotonin reuptake-enhancer like tianeptine 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.
First, the boring but crucial preliminaries. Optimal nutrition and exercise will increase the efficacy of all the potential life-enhancers touted here. A rich supply of precursor chemicals (e.g. tryptophan, the rate-limiting step in the production of serotonin) can also reduce their effective dosages. By choosing to eat an ideal "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. 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 opiates, enhances serotonin function, stimulates nerve growth factors, 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, the benzodiazepines such as diazepam (Valium) and the shorter-acting temazepam, are sometimes useful but still dreadfully crude anti-anxiety agents. They act primarily on the GABA (gamma aminobutyric acid) receptor complex. GABA functions as the main inhibitory neurotransmitter in the central nervous system. The progress of molecular biology and neurogenetics in unravelling the fiendish complexity of GABA's receptor sub-types should eventually allow more targeted compounds to be developed. These more selective and site-specific drugs will lack the sedative and hypnotic properties of today's marketed brands. In the meantime, benzodiazepines in current use tend to induce dependence, dull consciousness and impair the intellect. So there's not much chance of radical life-enrichment here.
Buspirone (Buspar), is somewhat more promising. It acts on an autoreceptor subtype of serotonin. This means it has mood-brightening properties too; and hence it is useful in anxious depressive states. Buspirone lacks the intellect-clouding effects of other clinical and alcoholic anti-anxiety agents. Yet its weak and equivocal effects on sub-types of dopamine function, while useful for the purposes of commercially touting its lack of "abuse potential", mean it isn't very exciting or especially effective.
The so-called anti-depressants fall into several categories. Their mood-brightening effect is correlated with alterations in the concentration of catecholamines and/or serotonin in the central nervous system and the long-term receptor re-regulation these changes provoke.
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. Perhaps unsurprisingly given their parentage, they are all dirty drugs, though some are dirtier than others.
Their anti-cholinergic effects harm memory 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 best avoided.
Much better, but still in some ways deeply flawed, are the selective serotonin reuptake inhibitors.
Serotonin, "the civilising neurotransmitter", plays a vital role in mood, memory, appetite, sleep, pain perception and sexual desire.
Fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), and citalopram (Cipramil, Celexa) are currently licensed and marketed. More of their "me-too" relatives are on the way from pharmaceutical companies eager for a lucrative piece of the action. The SSRIs all differ in their half-lives, chemical structure and precise specificities. Their functional effects are broadly similar. Their mood-brightening, resilience-enhancing and anti-anxiety properties really can make a modest percentage of the population feel "better than well". As a class, they don't have the physically unpleasant and cognitively debilitating anti-cholinergic effects of the tricyclics. A much larger section of the community - folk who daily knock back huge quantities of ethyl alcohol in the socially accepted fashion - could surely gain from the durably enhanced serotonin function SSRIs can yield. Such a switch would necessitate a big change in marketing strategy.
The beneficent properties of the SSRIs are celebrated in Peter Kramer's contemporary classic Listening to Prozac. Kramer has written a remarkably honest book. It's a discursive memoir by a therapist who is forced to admit that many of his clients seemed rapidly to fare far better on a pill than on his industrial-strength regimen of caring talk-therapy. Kramer's discussion of "cosmetic psychopharmacology" and "designer personalities", however, enraged traditionalists. For chemical Calvinist orthodoxy finds the notion that people should have a right pharmacologically to choose who and what they want to be profoundly offensive.
Two common problems limit the usefulness of SSRIs, at least when taken on their own. The problems stem from the indirect inhibitory effect of Prozac-style drugs on dopamine function, a consequence of deliberate selective targeting on the functional enhancement of subtypes of serotonin pathway.
First, SSRIs can compromise libido and sexual performance. This isn't always a disadvantage in over-excitable young males. It can still be a very distressing phenomenon for people too embarrassed to talk about it. Technical performance difficulties can sometimes be counteracted by taking (the alpha-2 adrenergic agonist) yohimbine; the phosphodiesterase inhibitor sildenafil (better known as the sexual rocket-fuel Viagra); or a dopamine agonist, licit or otherwise, before bedtime action. Yet this is scarcely an ideal solution.
Second, though some subjects may feel mildly euphoric, in other users the SSRIs serve more as mood-stabilisers and -flatteners in their lives. By increasing the user's emotional self-sufficiency, too, SSRIs may subtly change the "balance of power" in personal relationships - for good or ill. In some cases, SSRIs may even act as thymoanaesthetisers which diminish the intensity of felt emotion; by contrast, a mood-brightening serotonin reuptake-enhancer like tianeptine 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.
Monday, June 29, 2009
Some dead drugs
One spectacularly incompetent route to a lifetime of happiness involves taking illegal 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 catecholamines (noradrenaline; dopamine), amphetamine triggers to a much greater extent their synaptic release as well. It is thus more potent.
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.
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. Hence their use is best discouraged.
The depressant opioids are marginally more benign. They can be extremely pleasurable. Next century, their customised and site-selective successors may play a valuable role in promoting emotional superhealth. We could all do with having our native endorphin systems enriched. Unfortunately, the present crop are physiologically addictive They lose quite a bit of their euphoriant effect as tolerance sets in. Typically, they inspire a dreamily contented disengagement from the problems of the world. They diminish any drive to constructive activity. Sadly, too, their use impairs the release of endogenous opioids normally induced by social interaction with friends and family.
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 exogenous opioids in contemporary society. Yet even if they were legal and given away in cereal packets, they wouldn't make a good choice of mood-booster - or at least not in their present, crudely non-specific guise. kappa- agonists, for instance, have dys phoric 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, however be habit-forming. It has euphoriant, psychedelic and sedative properties. Experiments with stoned rats suggest the drug reduces the amount of corticotrophin-releasing factor 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 is associated with increased vulnerability to stress and a withdrawal-reaction; arguably one good reason not to stop in the first instance.
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, it just leaves the user pleasantly and harmlessly stoned. It's fun. Sleepiness, pain relief and euphoria are typical responses. 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. It seems that 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 self-development of the species. This does not, one ought scarcely need to add, suggest users should be persecuted and criminalised.
The empathogen "hug-drug", ecstasy (methylenedioxymethamphetamine; MDMA) offers a wonderfully warm, sensuous, loving, and empathetic peak experience to the first-time user. Distrust, suspicion and jealousy evaporate. They are replaced by a serene sense of universal love. The sensorium remains clear. Emotion is intensified. Much recreational drug-use tends to be self-centred. It is often branded as selfish. Yet here is a "penicillin of the soul" which promises to subvert our selfish-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 experience is a mere 90 minutes. So taking ecstasy scarcely amounts to a full-scale strategy for life either. It 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-hydroxybutyric acid (GHB). GHB usually takes the form of a clear, odourless, slightly salty-tasting liquid.
It's 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 naive 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. The intensity of orgasm is heightened. Hence GHB is potentially useful in relieving the psychopathologies of prudery and sexual repression. Unfortunately, its therapeutic value has been eclipsed by its demonization in the mass-media. Stories of chaste virgins turning into sex-crazed nymphomaniacs make great copy and poor medicine. Moreover GHB is sometimes confused with the amnestic "date-rape" benzodiazepine, flunitrazepam - better-known as the potent and fast-acting sedative-hypnotic "forget pill", Rohypnol. Bought on the street, GHB may be confused with all sorts of other substances too.
Yet even pure GHB is no magic elixir. Not everyone likes it. GHB's psychological effects are unpredictable and poorly understood. Nausea, dizziness, inco-ordination are common; reaction-time is slowed. GHB does not usually promote great depth of thought. Its very status as "an almost ideal sleep inducing-substance" makes it of limited use to those who aspire instead to be more intensely awake. The lack of any discernible body-count to fuel the periodic moral panics its use induces may allow a partial rehabilitation. Yet GHB evokes - at best - only a faint and fleeting parody of the life-long chemical nirvana on offer to our transhuman successors.
Alcohol - the traditional date-rape drug of choice - and, most insidiously of all, cigarettes are the really sinister mass-killers. 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 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 ex-British Prime Minister accepted a million-dollar bribe from a leading member of the drug-cartels for her services. Her party's ineffable Home Secretary then delivered himself of blood-curdling calls for a crack-down on evil drug-pushers(!). He went on to increase the draconian penalties already available for personal users of cannabis.
So long as our governments collude with the organised drug cartels to share out the billions of dollars of tax revenues mulcted from nicotine-addicts - thereby keeping direct taxes visibly down and themselves visibly in office - there seems little hope of a more intelligent approach to psychoactive drugs as a whole.
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.
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. Hence their use is best discouraged.
The depressant opioids are marginally more benign. They can be extremely pleasurable. Next century, their customised and site-selective successors may play a valuable role in promoting emotional superhealth. We could all do with having our native endorphin systems enriched. Unfortunately, the present crop are physiologically addictive They lose quite a bit of their euphoriant effect as tolerance sets in. Typically, they inspire a dreamily contented disengagement from the problems of the world. They diminish any drive to constructive activity. Sadly, too, their use impairs the release of endogenous opioids normally induced by social interaction with friends and family.
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 exogenous opioids in contemporary society. Yet even if they were legal and given away in cereal packets, they wouldn't make a good choice of mood-booster - or at least not in their present, crudely non-specific guise. kappa- agonists, for instance, have dys phoric 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, however be habit-forming. It has euphoriant, psychedelic and sedative properties. Experiments with stoned rats suggest the drug reduces the amount of corticotrophin-releasing factor 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 is associated with increased vulnerability to stress and a withdrawal-reaction; arguably one good reason not to stop in the first instance.
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, it just leaves the user pleasantly and harmlessly stoned. It's fun. Sleepiness, pain relief and euphoria are typical responses. 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. It seems that 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 self-development of the species. This does not, one ought scarcely need to add, suggest users should be persecuted and criminalised.
The empathogen "hug-drug", ecstasy (methylenedioxymethamphetamine; MDMA) offers a wonderfully warm, sensuous, loving, and empathetic peak experience to the first-time user. Distrust, suspicion and jealousy evaporate. They are replaced by a serene sense of universal love. The sensorium remains clear. Emotion is intensified. Much recreational drug-use tends to be self-centred. It is often branded as selfish. Yet here is a "penicillin of the soul" which promises to subvert our selfish-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 experience is a mere 90 minutes. So taking ecstasy scarcely amounts to a full-scale strategy for life either. It 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-hydroxybutyric acid (GHB). GHB usually takes the form of a clear, odourless, slightly salty-tasting liquid.
It's 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 naive 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. The intensity of orgasm is heightened. Hence GHB is potentially useful in relieving the psychopathologies of prudery and sexual repression. Unfortunately, its therapeutic value has been eclipsed by its demonization in the mass-media. Stories of chaste virgins turning into sex-crazed nymphomaniacs make great copy and poor medicine. Moreover GHB is sometimes confused with the amnestic "date-rape" benzodiazepine, flunitrazepam - better-known as the potent and fast-acting sedative-hypnotic "forget pill", Rohypnol. Bought on the street, GHB may be confused with all sorts of other substances too.
Yet even pure GHB is no magic elixir. Not everyone likes it. GHB's psychological effects are unpredictable and poorly understood. Nausea, dizziness, inco-ordination are common; reaction-time is slowed. GHB does not usually promote great depth of thought. Its very status as "an almost ideal sleep inducing-substance" makes it of limited use to those who aspire instead to be more intensely awake. The lack of any discernible body-count to fuel the periodic moral panics its use induces may allow a partial rehabilitation. Yet GHB evokes - at best - only a faint and fleeting parody of the life-long chemical nirvana on offer to our transhuman successors.
Alcohol - the traditional date-rape drug of choice - and, most insidiously of all, cigarettes are the really sinister mass-killers. 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 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 ex-British Prime Minister accepted a million-dollar bribe from a leading member of the drug-cartels for her services. Her party's ineffable Home Secretary then delivered himself of blood-curdling calls for a crack-down on evil drug-pushers(!). He went on to increase the draconian penalties already available for personal users of cannabis.
So long as our governments collude with the organised drug cartels to share out the billions of dollars of tax revenues mulcted from nicotine-addicts - thereby keeping direct taxes visibly down and themselves visibly in office - there seems little hope of a more intelligent approach to psychoactive drugs as a whole.
Drugs for mental health
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 breathtakingly 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 base-line of emotional well-being may indeed exceed anything today's legacy wetware can even contemplate. Right now, however, a 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 neurobiological 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 in-built hedonic treadmill of inhibitory feedback mechanisms in the CNS will fail. Political and socio-economic reforms offer at best a lame stopgap. To the scientific naturalist, all routes to happiness must ultimately be biological: "culture" must be neurochemically encoded to exert any effect.
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 for germ-line gene-therapy to become standard, it's worth considering instead how ordinary late twentieth-century Homo sapiens can sustainably maximise emotional well-being with only present-day pharmacology to rely on. No less importantly, how is it possible to combine staying continuously high - one's embarrassment at using the frisson-charged term from the vernacular is revealing - 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 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 sub-system y. Its sequelae include mood-congruent cognitive delusions and several chronic and intractable cases of toxic affective psychosis".
Eeek! Needless to say, no sensible adult would wish to mess around with such 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. They gradually internalise the puritanical role and tendency to warped scientific prose expected of them. [Whereas horribly-tortured experimental animals, for instance, blandly get "used" and "sacrificed", certain drugs always get "abused" by "drug-abusers"] On the other hand, some of the most original and productive minds in the field of psychopharmacology - pre-eminently Alexander Shulgin - have already been silenced. Many more careers have been intellectually strangled at birth or consigned to professional oblivion. The danger of poisoning the wells of information, for whatever motives, is straightforward. When young people discover they have been lied to or deceived, over cannabis for instance, they will pardonably assume that they have been lied to or deceived over the dangers of other illegals too. And this, to put it mildly, would be exceedingly rash.
Most recently, the Internet daily delivers up an uncontrollable flood-tide of fresh ideas to counter official misinformation. Unfortunately, a lot of it isn't much more objective in content or style than the professional journals it complements. Devising one's own system of filtering and quality-control to drown out the noise is a challenging task for anybody.
It's all very well being told our descendants will experience every moment of their lives as a breathtakingly 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 base-line of emotional well-being may indeed exceed anything today's legacy wetware can even contemplate. Right now, however, a 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 neurobiological 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 in-built hedonic treadmill of inhibitory feedback mechanisms in the CNS will fail. Political and socio-economic reforms offer at best a lame stopgap. To the scientific naturalist, all routes to happiness must ultimately be biological: "culture" must be neurochemically encoded to exert any effect.
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 for germ-line gene-therapy to become standard, it's worth considering instead how ordinary late twentieth-century Homo sapiens can sustainably maximise emotional well-being with only present-day pharmacology to rely on. No less importantly, how is it possible to combine staying continuously high - one's embarrassment at using the frisson-charged term from the vernacular is revealing - 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 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 sub-system y. Its sequelae include mood-congruent cognitive delusions and several chronic and intractable cases of toxic affective psychosis".
Eeek! Needless to say, no sensible adult would wish to mess around with such 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. They gradually internalise the puritanical role and tendency to warped scientific prose expected of them. [Whereas horribly-tortured experimental animals, for instance, blandly get "used" and "sacrificed", certain drugs always get "abused" by "drug-abusers"] On the other hand, some of the most original and productive minds in the field of psychopharmacology - pre-eminently Alexander Shulgin - have already been silenced. Many more careers have been intellectually strangled at birth or consigned to professional oblivion. The danger of poisoning the wells of information, for whatever motives, is straightforward. When young people discover they have been lied to or deceived, over cannabis for instance, they will pardonably assume that they have been lied to or deceived over the dangers of other illegals too. And this, to put it mildly, would be exceedingly rash.
Most recently, the Internet daily delivers up an uncontrollable flood-tide of fresh ideas to counter official misinformation. Unfortunately, a lot of it isn't much more objective in content or style than the professional journals it complements. Devising one's own system of filtering and quality-control to drown out the noise is a challenging task for anybody.
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