The Future of
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 of emotional well-being
may indeed surpass anything that human legacy wetware can even contemplate.
Right now, however, any future Post-Darwinian
Era of paradise-engineering can seem
an awfully long way off. Mainstream society today has a desperately underdeveloped
conception of mental health.
clearly a strong causal link between the raw
biological capacity to experience happiness
and the extent to which one's life is felt
to be worthwhile. High-minded philosophy treatises should
complicate but not confuse the primacy of the
pleasure-pain axis. So one very practical method of
life-enrichment consists in chemically engineering happier brains for all in the here-and-now. Yet how
can this best be done?
Any strategy which
doesn't subvert our inbuilt hedonic
treadmill of inhibitory feedback mechanisms in the
CNS will fail. Political and socio-economic
reforms offer at best a lame stopgap. To the scientific naturalist, all
routes to happiness must ultimately be biological: "culture" must be neurochemically
encoded to exert its effects on the psyche. Some of these routes to happiness involve
the traditional environmental detours. They are too technical, diverse and
futile to tackle here. If the quality of our lives is to be significantly
enhanced in the long term, then the genetically predisposed set-point of
our emotional thermostats needs to be recalibrated. The malaise-ridden norm
typically adaptive in
humanity's ancestral environment must be scrapped. So while we wait until
germ-line gene-therapy to promote mental 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
retaining one's sense of social and ethical
responsibility to other people and
information on this topic is extraordinarily difficult
for laity and professionals alike. The layman is more
likely to be given heavily slanted propaganda.
Unvarnished fact might confuse his supposedly uneducated and
functionally diminutive brain. Career-scientists, on
the other hand, are bedevilled by a different problem.
Access to funds, laboratories, raw materials, journal
publication, professional preferment,
and licenses to conduct experimental trials is all
dependent on researchers delivering results their
paymasters want to hear. The disincentives to
intellectual integrity could scarcely be greater; and they
are cloaked in such reputable disguise.
way of illustration, it's worth contemplating one
far-fetched scenario. How might an everlasting-happiness
drug - a drug which (implausibly!) left someone who tried it once living
happily-ever-after - find itself described in the
"Substance x induces severe, irreversible structural
damage to neurotransmitter subsystem y. Its sequelae include mood-congruent
cognitive delusions, treatment-resistant euphoria, and toxic affective
Eeek! Needless to say, no responsible adult would mess around with a potent neurotoxin under this
researchers play the game by the rules. They keep their heterodox opinions
to themselves. Others find such cognitive
dissonance too unpleasant. So they gradually internalise the puritanical
role and tendency to warped scientific prose expected of them. [Whereas
horribly-tortured experimental animals,
for instance, blandly get "used" and "sacrificed", certain
drugs always get "abused" by "drug-abusers"] On the
other hand, some of the most original and productive minds in the field
- 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 web-published material isn't much more objective
in content or style than the professional journals it complements. Devising
one's own system of filtering and quality-control to drown out the noise
is a challenging task for anybody.
SOME DEAD ENDS
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
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 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 controlled clinical trials are lacking. In "animal models", opioids
reverse the depressed
helplessness and neuroendocrine
responses associated with clinical depression. By contrast, opioid antagonists
such as naloxone exacerbate
them. To confuse matters further, sufferers of depression typically share
an increased sensitivity to pain; and modern "antidepressants" can themselves
act as "physical" painkillers.
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. Next century and beyond, the customised site-selective
successors to today's opioid drugs will play a critical role in promoting
opioids are flawed. Taken at fixed dosage, they lose some of their euphoriant and analgesic effect
as tolerance sets in; opioid drugs are physiologically addictive. Overdoses can cause respiratory depression; by contrast, physical pain is a potent respiratory stimulant. When taken recreationally, opioids inspire a dreamily contented disengagement
from the problems of the world. Their use diminishes our drive to
constructive activity as consumers in today's competitive global marketplace. More insidiously, excess consumption of narcotics inhibits the release
of endogenous opioids normally induced by social interaction with friends
and family. By diminishing
the craving for human companionship, the addict substitutes one form of
opioid addiction for another. Thus junkies are usually "selfish".
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, 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.
of posterity will surely weed out such adulterants from their elixirs
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 new 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 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 a revolution without precedent. Until then, psychedelic drugs are too unpredictable - and our dark, Darwinian minds are too poisoned - to responsibly 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. In consequence, distrust, suspicion
and jealousy evaporate. They are replaced by a serene sense of universal love.
The sensorium remains clear. Emotion is intensified. Much recreational
drug-use tends to be self-centred. It is often branded as selfish. Yet here
is a "penicillin of the soul" which promises to subvert our DNA-driven
tendency to self-aggrandisement.
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
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
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
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
- the traditional date-rape drug of choice - and, most insidiously of all,
the really sinister mass-killers. A report published in The Lancet in March 2007 ranked alcohol and tobacco as more hazardous to human health than LSD. Their total human death-toll to date is around 100 million and climbing. With that poker-faced Alice-In-Wonderland
logic popular amongst the world's sleazier governments, not merely do the
authorities preserve the legal status of cigarette sales here in the UK
on grounds of upholding personal liberty. The slickly expensive marketing
and glamorisation of tobacco
products to potential victims is sanctioned on similar grounds too. We ought
to be as shocked at tobacco promotion as we'd certainly feel if instead
the billboards urged kids to try heroin because it's cool. Yet familiarity
breeds moral apathy. Youngsters are typically hooked before they are in
any position to make an informed choice of their preferred poison - or even to abstain altogether.
Meanwhile a state-supported export drive targets the poor in vulnerable
Third World countries. With a cynicism that almost beggars belief, one celebrated
British ex-Prime Minister accepted a million-dollar bribe from a leading
member of the drug-cartels for her services. Her party's Home
Secretary then delivered himself of blood-curdling calls for a crack-down
on evil drug-pushers(!). He went on to increase the draconian penalties
already available for personal users 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.
DIRTY MOOD BRIGHTENERS
The commonly recognised legal and illegal recreational
drugs offer poor prospects for sustained biological mood-enhancement. So what
about the heterogeneous group of compounds uninvitingly labelled as anxiolytics
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 exercise will increase the efficacy
of all the potential life-enhancers touted here. A rich supply of precursor
chemicals (e.g. l-tryptophan,
the rate-limiting step in the production of serotonin)
can also reduce their effective dosages. By choosing to eat an idealised
"stone-age" diet rich in organic
nuts, seeds, fruit and vegetables, and drastically reducing one's consumption
of saturated fat (red meat, fried foods), sugar (sweets etc) and hydrogenated
oils (found in margarine and refined vegetable oils), then one's baseline
of well-being - or at least relative ill-being - can be sustainably lifted. There is mounting evidence too that an omega-3 fatty acid-rich diet or supplementation is protective against depression and other psychiatric disorders. Visitors to HedWeb probably don't expect
to be assailed by sermons on the benefits of exercise any more than food-faddism.
Yet regular and moderately vigorous physical exertion releases endogenous
opioids, enhances serotonin
function, stimulates nerve growth factors, promotes cell proliferation in the hippocampus,
and leads to a livelier, better-oxygenated
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,
such as diazepam
(Valium), chlordiazepoxide (Librium), alprazolam (Xanax), lorazepam (Ativan), clonazepam (Klonopin) and the shorter-acting sedative-hypnotic temazepam (Restoril),
are useful but still dreadfully crude anti-anxiety agents. They
act primarily on the GABA
(gamma aminobutyric acid) receptor complex. GABA functions as the main inhibitory
neurotransmitter in the central nervous system. GABA is made from the main excitatory neurotransmitter, glutamate. The progress of molecular
biology and neurogenetics in unravelling the fiendish complexity of GABA's
should eventually allow more targeted compounds to be developed. Ideally, these more
selective and site-specific drugs will lack the sedative, amnestic and hypnotic properties
of today's brands. Activation of GABA(A) receptors containing the alpha 1 subunit is responsible for benzodiazepine-induced sedation and memory deficits. It is hoped that newly-synthesised agonists selective for the alpha 2 GABA(A) receptor subtype may finally deliver a non-sedating antianxiety drug. Merck's investigational L838,417 is one such candidate. Human trials are eagerly awaited. The first non-benzodiazepine, non-sedating/amnesiac drug of its class to reach the market may prove to be DOV Pharmaceutical's ocinaplon. Ocinaplon is a GABA alpha-2 modulator. It exerts its anti-anxiety effect at doses (allegedly) substantially lower than doses that induce measurable sedation, amnesia, muscle relaxation and incoordination. Ocinaplon is in phase III clinical trials for anxiety (summer 2005; temporarily suspended August 2005). In the meantime, currently licensed benzodiazepines tend to induce dependence, impair memory and psychomotor performance, dull
consciousness and cloud the intellect. So there's not much chance of radical
life-enrichment here, for now at least.
(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, the FDA determined that Organon's gepirone (Ariza) was "not approvable". In February 2007, GlaxoSmithKline and Fabre-Kramer Pharmaceuticals announced an exclusive worldwide agreement for the development and commercialisation gepirone ER. A FDA review of its use for major depressive disorder is anticipated later this year.
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 prosocial 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,
re-regulation, activation of specific transcription factors regulating gene expression, and new nerve-cell growth in the hippocampus. In the first decade of the 21st century, older monoamine theories of depressive illness popular among researchers over the past 40 years have been eclipsed by the neurogenic hypothesis of depression and antidepressant action. The neurogenic model interprets depression, at least in its more severe forms, as a neurodegenerative 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
and their allies are relatives of the neuroleptic drug chlorpromazine.
Chlorpromazine is also known as Largactil, the notorious "chemical
cosh". Tricyclics block to varying degrees the reuptake of serotonin
and noradrenaline into the nerve cell terminals from where they are released. The consequent changes in pre- and post-synaptic receptor sensitivity lighten the spirits of 60-70% of the depressives who take them.
Perhaps unsurprisingly given their parentage, the tricyclics are all dirty drugs,
though some are dirtier than others. Their anti-cholinergic
effects harm memory, concentration and intellectual performance. Their anti-histamine
action induces drowsiness and sedation. Their adverse effect on cardiac
function makes them dangerous in overdose. Most "euthymic" volunteers
on whom they have been tested don't like their dulling effects of consciousness.
Unlike chlorpromazine, the tricyclic antidepressants don't noticeably block
the dopamine receptors. But with one notable exception,
they do precious little to stimulate dopamine
function either. Hence they're not much fun even for the severely depressed
people who can benefit from taking them. For three decades they were the
mainstay of the treatment of clinically-acknowledged depression.
They contributed to the widely-held medical opinion that anything classed
as an antidepressant won't help "normal" people; unless of course
they were "really" depressed. Basically, tricyclics are cheap,
nasty and usually best avoided.
but still in some ways deeply flawed, are the selective serotonin reuptake
inhibitors [SSRIs]. Serotonin,
"the civilising neurotransmitter", plays a vital role in mood, memory, appetite,
sleep, pain perception and sexual desire.
(Luvox, Faverin), paroxetine (Paxil,
Seroxat), sertraline (Zoloft,
Lustral), and citalopram
(Cipramil, Celexa) are currently licensed and marketed. More of their
tweaked and enhanced relatives are on the way from pharmaceutical companies
eager for a lucrative piece of the action. In a triumph of marketing hype and creative use of patent law if not clinical need, citalopram's S-enantiomer was FDA-licensed in 2002 as "Lexapro". The SSRIs all differ in their half-lives,
chemical structure and precise specificities. Their functional effects are
broadly similar, though Prozac is the most activating, longest-lasting, least selective and most likely to provoke dose-related akathisia; paroxetine has anticholinergic and sedating antihistaminergic effects; fluvoxamine most commonly induces nausea and has the shortest half-life; and citalopram is the most serotonin-selective. The
mood-brightening, resilience-enhancing and anti-anxiety properties of the SSRIs really
can make a (very) modest percentage of the population feel "better than well".
As a class, SSRIs (mostly) don't have the physically unpleasant and cognitively debilitating
anticholinergic effects of the tricyclics. SSRIs don't demand the dietary restrictions of the MAOIs. Their dependence potential and withdrawal reaction is usually milder than the opioids.
The (sometimes) beneficent properties
of the SSRIs are celebrated in Peter Kramer's contemporary classic Listening
to Prozac. Kramer has written a remarkably honest book. It's a discursive
memoir by a therapist who is forced to admit that many of his clients seemed
rapidly to fare far better on a pill than on his industrial-strength regimen
of caring talk-therapy. Kramer's discussion of "cosmetic psychopharmacology"
and "designer personalities", however, enraged traditionalists.
For chemical Calvinist orthodoxy finds the notion that people should have
a right to choose pharmacologically who and what they want to be profoundly
offensive. In Against Depression, published in May 2005, Kramer argues that depression should be eradicated altogether.
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 the currently unlicensed SSRI dapoxetine may shortly be marketed 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
the alpha2-adrenergic antagonist yohimbine; a phosphodiesterase type-5 inhibitor like sildenafil
(better known as the sexual rocket-fuel Viagra), long-acting tadalafil (Cialis) or newly licensed vardenafil (Levitra);
or a dopamine agonist, licit or otherwise,
before bedtime action. Investigational drugs that heighten female sexual arousal (e.g. flibansein, or melanocortin agonists like PT-141/bremelanotide) 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.
Second, though some 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
the "balance of power" in personal relationships - for good or ill.
In some cases, SSRIs may even act as thymoanaesthetisers
which diminish the intensity of felt emotion; by contrast, a mood-brightening
serotonin reuptake-enhancer like tianeptine (Stablon)
may intensify emotion instead. Affective flattening may be welcome to
someone in the pit of unmitigated clinical depression. It is scarcely
a life-enriching property for "normal" people who lack any convenient
diagnostic category which acknowledges their malaise.
THE DOPAMINE CONNECTION
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 - investigators that the mesolimbic dopamine system serves
as the final common pathway for
pleasure in the brain. Enhanced responsiveness of post-synaptic dopamine
D2/D3 receptors is
crucial to long-term emotional well-being. Insofar as they work, all "serotonergic" and "noradrenergic"
mood-brighteners eventually act on the mesolimbic
dopamine pathway, albeit in differing degrees and with varying delay. Even SSRIs depend on sensitization of the mesolimbic dopamine D2 receptors for their (modest) mood-lifting effect. New anti-Parkinsonian agents, notably the neuroprotective dopamine D3 receptor subtype selectve 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 readily get over-attached
to one particular neurotransmitter system, its receptor sub-types and their signal-transduction
cascades. Traditionally, serotonin
and noradrenaline have attracted
the fiercest rival partisans. "Dopaminergic" (and opioid) agents, by contrast,
are suspect. They are politically incorrect since they are potentially "abusable".
Moreover it can be argued that the research and development of safe and sustainable Ecstasy-like empathogens
and sociabilisers is as morally urgent as the license of safe and sustainable euphoriants. At
any rate, enhanced mesolimbic dopamine release, exclusively or otherwise,
enriches the intensity of experience; increases pleasure and libido, and potentially
boosts cognitive performance.
Even better, whereas some dopaminergics are potentially toxic, some dopamine-enhancing agents may have neuroprotective properties as well.
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, but doesn't significantly
release, the catecholamines noradrenaline and dopamine. If it is taken in sustained-release
form or combined with an SSRI,
all of which have anti-obsessive-compulsive
properties too, then the likelihood of dose-escalation is minimised. In North America, students sometimes take Ritalin to gain a competitive edge in exams. However, its long-term effect on the developing brain is poorly understood.
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".
great promise as a pleasantly stimulating dopaminergic
that also potently inhibits the reuptake of noradrenaline and - to a much lesser extent - serotonin. It was marketed by its manufacturers Hoechst with the slogan "vive la difference!" Merital was withdrawn from licensed use after the discovery of its rare side-effect
of precipitating a serious blood-disorder.
For retarded melancholics,
however, it was typically a very effective and well-tolerated
mood-brightener with minimal side-effects.
The risk/reward ratio of its carefully-monitored use may have been misjudged. Nomifensine is now obtainable only as a research chemical too.
BUPROPION (WELLBUTRIN); AMINEPTINE (SURVECTOR); TIANEPTINE (STABLON)
is possibly less effective than nomifensine. Yet it's useful because it
lacks the adverse effects on sexual
function characteristic of the SSRIs. In some subjects - particularly women - libido,
arousal, and the intensity and duration of orgasm may actually increase.
Bupropion weakly blocks the reuptake, but diminishes the release, of dopamine.
This may account for reports of its diminished propensity to induce mania
in the genetically susceptible. Bupropion's active metabolites
inhibit the reuptake of noradrenaline. Radafaxine, one of these metabolites, also blocks the dopamine transporters; radafaxine may in future be marketed as a slimming drug as well as an antidepressant. Bupropion itself, branded as Zyban,
may help in giving up smoking.
Scandalously, bupropion isn't licensed and marketed as an antidepressant in Europe - though doctors may prescribe Zyban to non-smoking depressives "off-label". Bupropion plus an SSRI is sometimes more effective than either agent alone. In June 2006, the FDA licensed bupropion/Wellbutrin XL as the first preventive pharmacological treatment of Seasonal Affective Disorder (SAD).
(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 it 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 chronic, uncontrolled stress. 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.
REBOXETINE (EDRONAX); ADRAFINIL (OLMIFON); MODAFINIL (PROVIGIL)
(Edronax) is a relatively well-tolerated,
relatively selective "noradrenergic" agent. Crudely, whereas serotonin
plays a vital role in mood,
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.
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 new sleep-aid eszopiclone (Lunesta) can be taken on a nightly basis indefinitely. It will be the first sleeping pill not to carry an FDA warning against long-term use.
MIRTAZAPINE (REMERON); NEFAZODONE (SERZONE); VENLAFAXINE (EFFEXOR); DULOXETINE (CYMBALTA); ROLIPRAM
NARIs are normally activating.
Anxious and depressive insomniacs, on the other hand, may benefit more from "dual-action" mirtazapine; or from newly-licensed duloxetine.
(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.
(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". 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
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.
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
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"
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"
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. Other "natural" interventions such as bright light therapy are of limited use. But two options worth exploring are SAMe and St John's wort.
the active ingredient in St John's wort, appears
to be an effective mood-brightener and anxiolytic - by today's standards at
least. Its side-effect profile and efficacy
in mild-to-moderate depression compares favourably with its synthetic counterparts.
Hypericum's blend of serotonin-reuptake inhibiting and (mild) MAO-inhibiting
properties (not a combination otherwise to be explored with potent
synthetics: the risk of the potentially fatal serotonin syndrome
is too great) contributes to - without wholly explaining - its generally benign
effects. Once again, much more research is needed, preferably not bankrolled by the makers of lucrative competing products. Thus a German trial published in the British Medical Journal in February 2005 reported that a proprietary standardised extract of hypericum/St John's wort was more effective and a better tolerated treatment of moderate to severe depression than the SSRI paroxetine (Paxil). This runs counter to the negative findings of the 2001 U.S. trial sponsored by the makers of the SSRI sertraline (Zoloft) - which concluded that for moderate to severe depression, St John's wort was no better than a placebo. Faith in the integrity of biological psychiatry would be greater if the single strongest predictive factor in the outcome of any published clinical trial wasn't the identity of the funding body.
One further remedy, albeit
at "unnatural" doses, is worth noting. Inositol levels tend
to be low in depressives and high in euphoric
people. Taking myo-inositol as a food supplement in doses of 12g and more
per day represents perhaps the first successful use of the precursor
strategy for a second messenger rather than a neurotransmitter in the search
for long-term mood-brightening agents. Inositol and its derivatives serve
as messenger molecules within the nervous system. The molecule itself is a
naturally occurring isomer of glucose. It is a key intermediate of the phosphatidyl-inositol
cycle. This is a second-messenger system used by several noradrenergic, serotonergic
and cholinergic receptors. Adult westerners typically consume about one gram
of inositol per day in their food. The richest dietary sources are fruits,
nuts, beans and grains. The mood-darkening ("stabilising") effect
of lithium in manically
euphoric people may be explicable in terms of its inositol-depleting effect.
Potentially, if taken in high doses, inositol seems to be a good way of lightening
the spirits and diminishing anxiety in "euthymic" and depressed people alike.
Dosages of even 50g and more reportedly produce no toxic side-effects. This
regimen shouldn't be attempted unsupervised by people with a history of bipolar
disorder. As usual, much more research is in order. One "problem"
is that naturally-occurring compounds - such as inositol and SAMe - can't be patented.
So the scope for high profit-margins is diminished. Progress is unlikely to
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.
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
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
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
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
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. Deprenyl has an anti-oxidant, immune-system-boosting
and dopamine-cell-sparing effect. Its use boosts levels of tyrosine
hydroxylase, growth hormone,
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
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 December 2007) 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.
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
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).
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
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
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.
WORKING FOR A DRUG-FREE FUTURE
Suppose, for a moment, that the reproductive success of our DNA had been
best served by coding for ecstatically happy vehicles rather than malaise-haunted
emotional slum-dwellers. If this had been the case, then none of the pharmacological
interventions discussed in The Good Drug Guide would be necessary.
Life-long well-being would seem only "natural". We would all enjoy gloriously
fulfilled lives. Each day would be animated by gradients of
bliss. Unpleasant states of mind would be viewed as a tragic aberration.
Bad thoughts and bad feelings could be diagnosed as a freakish but clinically treatable type of psychopathology.
Of course, it didn't work
out that way. Instead, the inclusive
fitness of our genes has been served by the "natural" manufacture
of some of the most vicious
psychological adaptations imaginable. Sadness and anxiety are "normal". 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 new-won
"natural" condition and feeling "drugged" may come
to seem immoral. It may also seem perverse. Why should anyone want to contaminate
the divine ecstasy of their spirituo-biological soul-stuff with chemical
pollutants? No thanks.
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. "Just Say No" is frequently a good rule-of-thumb. Yet with the right new genes and
designer-drugs, there's no reason why mature Post-Darwinian
life shouldn't just get better