Some 1-benzylpiperazine users report that low-dose BZP is itself mildly E-like. So-called Party Pills, Social Tonics, Legal Party Drugs, Legal Herbal Highs and the like are marketed under numerous brand names, commonly mixed with various amino acids, vitamins, herbs and other agents designed to modulate the core BZP experience and minimise side-effects. Over 20 million such tablets and capsules have reportedly been sold in New Zealand, currently the world leader in BZP consumption and export. BZP use is now spreading world-wide. Consumption is mostly by clubbers seeking a safer legal alternative to MDMA or amphetamines. BZP is relatively safe if used in moderation. No fatality has yet been recorded from BZP use alone. Many BZP-based preparations contain black pepper, a tribute not to BZP's wholesome natural origins (it's synthetic), but to discourage thrill-seekers who might otherwise snort rather than swallow it. The Social Tonics Association of New Zealand (STANZ) has developed a Code of Practice to encourage responsible use. Inevitably, the FDA has now banned BZP on grounds of abuse potential. In 2002 the drug was made Schedule 1 and its US users criminalised. Sale in the UK was banned in 2007. BZP was originally (1944) synthesised, developed and manufactured by Wellcome as a potential anti-parasitic. Many piperazine drugs tend to paralyse intestinal parasites, allowing unwanted fauna to be flushed from the body. In the 1970s, BZP was investigated as an antidepressant. Used experimentally, BZP proved effective in reversing melancholic/retarded/hypersomnolent depression. The BZP analogue N-ben-zyl-piperazine-picolinyl fumarate was even briefly marketed in Hungary under the brand name Trelibet as an antidepressant, though no clinical trials have been conducted into its long-term efficacy. Development was halted after BZP was discovered to have amphetamine-like properties. Amphetamine, methamphetamine and BZP alike do indeed release dopamine from non-vesicular pools; and the subjective effects of high-dose BZP cross-generalise to amphetamines in drug discrimination studies. However, the subjective effects of BZP are more subtle than crude speed; BZP promotes the release and (to a lesser degree) inhibits the reuptake of the monoamine neurotransmitters dopamine, noradrenaline and serotonin with different relative potencies. BZP also acts as a relatively non-selective serotonin agonist. The affinity of BZP for the serotonin 5-HT2A receptor is quite low, so psychedelic effects are comparatively minor at sensible doses. Taking BZP doesn't give rise to the inner serenity, emotional release or extraordinarily empathetic compassion of MDMA; but nor is BZP a classic dopaminergic power-drug like amphetamine. Moderate behavioural activation, sensory enhancement and a low-key euphoria are typical. Dry mouth, appetite suppression and insomnia are common adverse side-effects. Unlike, say, cocaine, BZP use tends to be self-limiting, a critical advantage for a recreational drug. Yet subjects who hope to replicate the full richness of the MDMA experience will be disappointed.
There are further subtleties in the way of replicating MDMA's acute effects; and even more obstacles to sustaining the magic indefinitely. The serotonergic system has both 5-HT1B autoreceptors and post-synaptic 5-HT1B heteroreceptors; they play different functional roles. 5-HT1B receptors acting as autoreceptors regulate serotonin release via inhibitory feedback at the presynaptic terminals of serotonergic neurons; turnover and release of serotonin are typically increased under conditions of acute stress. 5-HT1B heteroreceptors are located on the terminals of nonserotonergic neurons. Thus 5-HT1B heteroreceptors regulate the release of other neurotransmitters. A single serotonin neuron can modulate different brain functions and multiple cellular targets in virtue of the thousands of non-synaptic varicosities on its axonal branches that project to multiple areas and neurotransmitter systems. 5-HT1B receptors within the ventral tegmental areas (VTA), for instance, function as heteroreceptors to inhibit GABA release. Since the GABA terminals in the VTA and substantia nigra exert a tonic inhibitory influence on dopamine function, inhibition of GABA by inhibitory 5-HT1B heteroreceptors leads to the disinhibition of dopamine activity. Thus agents acting directly or indirectly as 5-HT1B agonists can cause the release of dopamine in the striatum and nucleus accumbens. Indirectly again, dopamine release is also regulated by 5-HT1B heteroreceptors within the glutamatergic hippocampo-accumbens pathways. Regulation of 5-HT1B receptor function itself is under the control of 5-HT-moduline, an endogenous tetrapeptide that controls 5-HT1B receptor efficacy. 5-HT-moduline is a so-called allosteric modulator. Allosteric modulators bind to a different binding site from the natural agonist and can, potentially, circumvent the development of tolerance. 5-HT-moduline is released from adrenal medulla in response to acute stress. 5-HT-moduline plays a pivotal role in synchronising the serotonergic signalling activity of the different terminals of individual neurons, coordinating their effects on a variety of different cerebral functions. Rationally designed synthetic drugs that recognize the 5-HT-moduline binding-site on the 5-HT1B receptors, and act on the 5-HT1B receptors as allosteric modulators themselves, may potentially exert long-term serenic, anxiolytic and mood-brightening effects by increasing serotonin release.
In general, however, care must be taken in describing serotonin 5-HT1 agonists as "serenics", even if such agents induce a syndrome outwardly suggestive of inner tranquillity. The demeanour that an animal exhibits after "serenic" administration may indeed be submissive, passive and timid - in contrast to the fierce, assertive and aggressive behaviour of 5-HT1B knockouts. Yet "serenity" tends to connote an inner E-like peace that may be lacking - and not just in the unfortunate laboratory rodent. In fact some so-called "serenics" may enhance fear/anxiety reactions: it's only their use in combination with dopamine-releasing euphoriants that makes such agents especially interesting to the psychonaut. Indeed supersensitive 5-HT1B autoreceptors are implicated in depression and obsessive compulsive disorder. By introducing extra copies of the gene for 5-HT1B receptors into serotonin neurons, researchers can breed passive and depressive rats that show signs of abject misery [i.e. "learned helplessness" and "behavioural despair"]. The syndrome of learned helplessness is associated with excess production of 5-HT1B receptors that are churned out in greater profusion by the depressive brain. This isn't to deny that 5-HT1B agonists may have therapeutic potential, whether in bipolar disorder, autism, alcoholism or disorders of impulse-control and aggression. Thus the triptans, serotonin 5-HT1B/1D receptor agonists, are clinically effective for treating migraines; they can also curb aggression. But 5-HT1B antagonists and inverse agonists such as SB-236057-A are under investigation for possible clinical use as long-term and relatively fast-acting antidepressants. Acute 5-HT1B autoreceptor blockade can increase serotonin release. Cognitive function is affected by their use too. Whereas 5-HT1B agonists may adversely affect memory via inhibition of acetylcholine release in the hippocampus, antagonists and inverse agonists of the 5-HT1B receptor can improve the consolidation of learning. This simplified outline of the neurobehavioural role of a single family of serotonin receptor subtype illustrates how inducing lifelong E-like states - as distinct from "mere" raw bliss - is going to pose a formidable technical challenge. In this case, the possible existence of multiple subpopulations of 5-HT1B autoreceptors and heteroreceptors makes inadequate selectivity of ligands even more of a problem, especially for seekers of precision-tools rather than chemical coshes.
Whereas serotonin 5-HT1B receptor knockout animals are aggressive by nature, 5-HT1A knockouts are timid, anxiety-ridden creatures. Whereas serotonin 5-HT1B receptors are found mainly on terminal processes, 5-HT1A receptors are located solely on serotonergic nerve cell bodies within the dorsal raphé nucleus. Intriguingly, 5-HT1A receptor density is reported to be inversely correlated with susceptibility to spiritual experience, opening up the possibility of genetically amplifying our capacity for spirituality beyond anything humanly accessible today: it may be premature to assume that our descendants will be secular rationalists. Density of the 5-HT1A autoreceptors is also inversely correlated with the reactivity of the amygdala to threatening stimuli. However, the role of the 5-HT1A receptors in MDMA's acute subjective effects still isn't clear. Pretreatment with a serotonin (5-HT1A) receptor antagonist apparently reduces MDMA's pro-social effect, in rats at least. Taken over a prolonged period, selective 5-HT1A receptor agonists typically exert a delayed-onset anxiolytic as well as (sometimes) a mood-brightening activity. Their (modest) therapeutic efficacy relies on an adaptive neuronal response. Acute activation of the presynaptic 5-HT1A receptor on the raphé nuclei tends to reduce both the rate of firing of serotonin neurons and the corresponding release of serotonin from the nerve terminals; chronic activation causes the receptors to desensitise, leading serotonergic neuronal activity to rebound. Clinically, buspirone (Buspar), a 5-HT1A partial agonist, is licensed for generalised anxiety disorder. Similar agents like gepirone (Ariza), flesinoxan, tandospirone and ipsapirone are under investigation. Alas taking them doesn't remotely engender the extraordinary sense of inner peace induced by MDMA. In rats at least, 5-HT1A agonists facilitate male sexual behaviour, hypotension, increased food intake and produce hypothermia, none of which are prominent sequelae of MDMA use. In general, 5-HT1A agonists are well tolerated. But they may also on occasion induce dizziness, nausea, and headaches, probably linked to their postsynaptic receptor action rather than presynaptic anxiolytic effect. Buspirone itself is also a dopamine D2 antagonist, albeit a weak one. This may explain why it's never been wildly popular with patients. It's also very slow to work. Gepirone, on the other hand, allegedly lacks significant activity at the dopamine D2 receptors. Gepirone acts as an agonist at the presynaptic 5-HT1A receptors and a partial agonist at the post-synaptic 5-HT1A receptors. Hopefully, gepirone will prove a clinically useful anxiolytic and antidepressant. However, though 5-HT1A antagonists reduce discrimination of MDMA in animal models, the role of 5-HT1A receptor activation in MDMA's effects needs elucidation via more first-person experimental studies.
Recent research from Sydney University neuropharmacologist Iain McGregor suggests that post-synaptic serotonin 5-HT1A receptors contribute to MDMA's acute pro-social action via the enhanced release of oxytocin. Oxytocin in turn reduces activity and weakens connections in the fear-processing circuitry of the amygdala. MDMA activates post-synaptic 5-HT1A receptors of the paraventricular nucleus and supraoptic nucleus of the hypothalamus. The paraventricular nucleus and supraoptic nucleus contain oxytocin neurons. Oxytocin is a nine amino-acid peptide hormone and neurotransmitter that promotes pair-bonding, trust and social recognition. Commercially, oxytocin is marketed by Verolabs as a spray: so-called trust-in-a-bottle: "Liquid Trust Spray - the first Oxytocin product, formulated to enhance people's trust in you!"[sic]. In future, MDMA analogues may conceivably be marketed with similar restraint. MDMA typically causes its users to trust each other to an exceptional degree, confiding intimate personal feelings and secrets they would never otherwise share. Such drug-induced intimacy may partly be mediated by an increased release of oxytocin via MDMA-activated 5-HT1A receptors. Co-administration of MDMA and an oxytocin antagonist would test this hypothesis in humans. There are methodological problems with the use of rats as test subjects in this context; but the evidence is suggestive.
The MDMA molecule, especially the dextrorotatory "+" isomer, has only a low affinity for the serotonin 5-HT2 receptor. This is why taking the drug within the normal dose-range typically induces only minor perceptual changes. If prompted, many Ecstasy users report altered time perception, but any visual distortions are usually mild: the N-methyl group of the MDMA molecule prevents it from fitting as comfortably into the 5-HT2A receptor as does the trippier (-)-MDA enantiomer of its structural parent. Experiments with human as well as non-human animals show a correlation between a drug's psychedelic potency and 5-HT2A receptor binding affinity. Activation of the 5-HT2A receptors is a prerequisite of the "classic" hallucinogenic effects exerted by tryptamine psychedelics such as LSD and phenethylamine psychedelics like DOM. Conversely, 5-HT2A receptor inverse agonists act as antipsychotics. Despite the low affinity of MDMA for the 5-HT2 receptor, pharmacological blockade or genetic knock-out of the 5-HT2B receptor abolishes MDMA-induced hyperlocomotion and serotonin release in the nucleus accumbens and ventral tegmental area of the brain.
None of this neurobabble should disguise the fact that psychedelia is still scientifically uncharted. It's often too weirdly exotic for words. Materialistic neuroscience has failed to close the ontological gulf between neural porridge and consciousness - whether "ordinary" or "altered" states. Some psychonauts, understandably enough, feel the neurobabblers have lost the plot. Most of today's storytelling about altered states and the chemistry of mind will doubtless seem no less archaic to our descendants than the Greek humoral psychology of classical antiquity strikes the contemporary molecular biologist. Yet fortunately for the engineering purposes of inducing sustainable E-like bliss, we need manufacture only the sufficient neural conditions for beautiful states of consciousness. We don't need a deep understanding of how and why consciousness is generated (or alternatively, some philosophers allege, its fundamental immanence in the world). We can guess even less about the possible altered states of consciousness of our redesigned successors. We don't know whether the "explanatory gap" between the physical facts and phenomenal mind can ever be closed. But either way, our emotionally invincible descendants should be able to explore entheogens, and map out even the most outlandish reaches of psychedelia, in safety. Unlike us, our genetically enriched descendants may revel in the assurance that bad trips are inconceivable, and psychological damage is impossible. This is because their obnoxious molecular substrates will have been edited out.
Alas our own less robust minds are psychologically vulnerable to even "physically" harmless psychedelics that aren't also euphoriants. Dual-action dopamine- and serotonin-releasers like MDMA are the latter, though they aren't always harmless. With MDMA, as with so many psychoactive drugs, very often "less is more". This piety is easy to intone but hard to practise, especially when taking fast-onset euphoriants. The lucidity of the entactogenic effect of MDMA may be especially pronounced at low-to-moderate dosages. "Optimal" dosage of psychotropic agents taken for "non-approved" purposes is most often empirically determined by the user investigating what level induces maximal enjoyment. Yet the effects of lower, "sub-optimal" dosages that more subtly modulate consciousness may be of greater value for facilitating personal growth. Low-to-moderate dosage E-experience may be easier to integrate into the rest of one's E-less life. Nonetheless at higher, quite possibly neurotoxic doses of 200mg or so, MDMA can itself sometimes deliver psychedelic euphoria, entheogenic rapture, and some very interesting exotica indeed. Alas the unique effects of such doses [and likewise higher doses of other stellar phenethylamines] cannot safely be investigated in depth until the neurotoxicity of MDMA's metabolites and/or toxic free radicals can be prevented.
In the meantime, if the user desires a completely clear sensorium, then perceptual alterations might seem eliminable altogether, in principle, by taking only the (+)-MDMA enantiomer rather than the standard racemate. Sadly, pure (+)-MDMA is scarce; it's also hard to prepare at home. Thus one unintended consequence of scheduling MDMA has been to widen youthful exposure to psychedelia, albeit psychedelia in its warmest and most gentle introductory guise. (-)-MDMA at normal doses is only minimally active at the "psychedelic" 5-HT2A receptor owing to its (comparatively) bulky methyl group. By contrast, MDA (which lacks it) is an all-in-one cocktail that can be hallucinogenic as well as empathetic and slightly speedy.
Alternatively, if uncomplicated perceptual clarity is sought then a 5-HT2 antagonist such as ketanserin or the 5-HT2A selective MDL-11939 might help preserve total lucidity. 5-HT2A antagonists have the additional advantage of preventing MDMA-induced hyperthermia that exacerbates toxicity. Neurotoxic hydroxyl radical formation is temperature-mediated; conversely, hypothermia-inducing agents enhance neuroprotection.
However, there are complications. Stimulation of the serotonin 5-HT2A receptors contributes to the rewarding effects of MDMA, or at least plays a permissive role in dopamine release. So trying to eliminate perceptual alterations completely while retaining the full-blooded E-magic may be difficult. MDMA is often reckoned a "serotonergic" drug. Compared to amphetamine this is true: MDMA's affinity for the serotonin transporter is greater, and its ratio of serotonin to dopamine release is higher, than amphetamine. Even MDMA's extra release of dopamine partly depends on its activation of the 5-HT2A receptors. But serotonin-releasing agents [e.g. the halogenated amphetamine appetite-suppressant fenfluramine (Pondimin)], taken on their own, aren't notably rewarding or entactogenic/empathetic, at least at ordinary dosages. The enhanced release and reuptake inhibition of dopamine is essential to MDMA's tendency to promote blissful well-being and to colour its entactogenic-empathetic effect.
Convergent strands of evidence indicate that dopamine release is critical to the MDMA magic. Dopaminergic activity in the brain and motor behaviour may be crudely interpreted as under the inhibitory control of the serotonin system. Yet the multiple serotonin pathways play functionally different roles. According to one hypothesis, the extra serotonin released by MDMA stimulates 5-HT2A receptors located on inhibitory gamma-aminobutyric acid (GABA) striatonigral neurons. VTA dopaminergic neurons in the brain's reward centres are under continuous inhibition by GABA. Stimulation of the 5-HT2A receptors inhibits these GABA neurons, thereby allowing the disinhibition of dopamine biosynthesis. Post-E levels of dopamine in the mesolimbic reward circuitry are far higher than would be explained by MDMA's relatively weak additional release of dopamine via the uptake carrier.
Animal drug discrimination studies, and the human behavioural evidence, tend to support this dopaminergic account. Although some MDMA users prefer reflective tranquillity and intimate group hug-ins, many loved-up clubbers opt to dance for hours at raves - a form of hyperlocomotion one would expect from Peruvian marching-powder rather than a serotonergic agent.
However, this account is still simplistic. The release of serotonin following an MDMA-induced reversal of the reuptake pump results in a stimulation of the 5-HT1B receptors and, at higher doses, increasingly of the 5-HT2A receptors as well. Such receptor stimulation can trigger marked hyperactivity, especially in young MDMA users who rave. At lower doses, MDMA-induced locomotor activity is caused mainly by the released serotonin's preferential activation of the 5-HT1B receptor. This is because serotonin has a somewhat higher affinity for the 5-HT1 receptors than the 5-HT2 receptors. The greater flood of serotonin in the synapses triggered by higher doses of MDMA promotes locomotor activity via 5-HT2A receptor-mediated dopamine stimulation as well. To complicate matters, MDMA may itself bind, albeit weakly, to the 5-HT2A receptor. A further complicating factor is that MDMA-induced release of serotonin stimulates the 5-HT2C receptors. Activation of the 5-HT2C receptors serves to mask expression of MDMA-induced hyperactivity, sometimes evidently more effectively than others. The various subpopulations of 5-HT2C receptor located on GABAergic neurons in the ventral tegmental area and the substantia nigra tend to exert a tonic inhibitory influence over the mesolimbic dopamine system. Thus 5-HT2C receptors tonically inhibit dopamine release in the nucleus accumbens, mostly it seems in virtue of their constitutive activity i.e. entering the activated receptor state in the absence of an agonist. Other things being equal, activation of 5-HT2C receptors is anxiogenic, demotivating and generally unpleasant. Certainly the stimulant effects of MDMA are greatly enhanced following treatment with a 5-HT2C antagonist. Sustained antagonism of the 5-HT2C receptors might well we harnessed to intensify the hedonic properties of long-lasting E-like consciousness. Less speculatively, 5-HT2C antagonists such as agomelatine (Valdoxan) are under investigation as potential clinical antidepressants.
As usual, there are complications: all 5-HT2C receptors are not the same. Numerous 5-HT2C receptor isoforms are produced as a result of RNA editing, and their individual roles in modulating the MDMA effect aren't properly understood. In general, the receptor story illustrates at the molecular level that being blissful isn't the same as being blissed out. To sustain empathetic love, simply banishing all capacity for social anxiety isn't going to work. Specific and selective 5-HT2C receptor antagonism may well prove a worthwhile goal; but it's too early to say what the MDMA experience may gain or lose in consequence, whether socially or subjectively. Empathy entails caring about others, not lacking a care in the world. Thus the MDMA-induced disinhibition from social anxiety, and the lowering of psychological defensive barriers, is radically distinct from the sort of anxiolysis induced by SSRIs or the benzodiazepines - or indeed by alcohol or opiates. With none of these drugs or drug categories is a reduction in the user's social anxiety matched by an E-like upwelling of empathy or sensitivity to the feelings of others - in fact quite the reverse. There are subtleties of the MDMA experience that haven't yet been explored.
If acute serotonin-mediated enhanced dopamine-release is indeed essential to the magic of MDMA, then a wide range of safe long-acting dopaminergics are already on offer to augment any hypothetical subtype-selective "serotonergic" therapies. Compared to our descendants, we're probably all anhedonic. So some form of dopaminergic augmentation is a therapeutic step in the right direction. "Dual-deficit" models of everyday E-less malaise are plausible; and they naturally invite dual-action remedies. Clearly, inhibition of glutamate-evoked firing in the nucleus accumbens is an ingredient of the E-magic: it is known that firing-inhibition depends on both dopamine and serotonin release; and this process is mediated by both dopamine and serotonin receptors. But beyond these superficial generalities, working out how to replicate sustainably at the molecular level the precise neurochemical signature of peak experiences will be hard. Until the dawning of the era of wholesale genomic rewrites and true designer babies, using a cocktail of subtype selective serotonin agonists and gentle dopaminergic psychostimulants still looks like the easiest way to mimic and enhance the entactogenic-empathogenic effect induced by MDMA-like compounds. However, there are many pitfalls in choosing the right dopaminergic for the job.
In contrast with intracranial electrical stimulation, a direct chemical assault on the hedonic treadmill rarely works. This failure is witnessed by the unsatisfying and usually counterproductive effects of using catecholamine-depleting psychostimulants. Darwinian-era mood and motivation is regulated via a multitude of indirect mechanisms of feedback-inhibition. So it's worth reviewing how and why the substrates of human well-being are held in check; and what can be done about it. First, an unavoidably fast-and-furious tour of the dopamine system is in order. The CNS has three main dopaminergic pathways. They regulate movement, hormonal secretion, and emotion. Each projects from dopaminergic cell groups in the midbrain. 1) The nigrostriatal pathways extend from the substantia nigra pars compacta to the striatum. This pathway is critical to the control of involuntary motor movement; its dysfunction is implicated in the tremor, rigidity and akinesia of the "dopamine deficiency disorder" Parkinson's disease, and several other neuropsychiatric disorders such as Tourette's Syndrome. 2) The tuberoinfundibular system extends from the hypothalamus to the pituitary gland. It's involved in prolactin- and growth hormone-secretion, and the regulation of lactation and fertility. 3) The mesocorticolimbic pathway extends from the ventral tegmental area to the nucleus accumbens and the medial prefrontal cortex. The mesocorticolimbic system is central to emotion, motivation, willed action and, more subtly, the modulation of thought-processes. In crude terms again, dopamine is critical to sensorimotor integration; appetitive behaviour of all kinds; the capacity to switch from one course of behaviour to another; and the orchestration and activation of the motor output system. Dopamine has also traditionally been described as the brain's "pleasure chemical", cueing potentially (Darwinian) fitness-enhancing stimuli so they can acquire control over an organism's behaviour. Certainly, consistent with the dopamine theory of reward, electrically or pharmacologically stimulating microcircuits in the rostromedial shell of the nucleus accumbens produces intense pleasure in the absence of any goal-seeking behaviour. But this formulation can be misleading. The mesolimbic dopamine system mediates "wanting" more than "liking"; and its drug-induced or electrical stimulation may increase incentive-salience rather than the raw intensity of pleasure itself. Dopaminergic neurotransmission is critical to incentive-motivation and all forms of purposeful behaviour. Dopamine levels tend to rise if one is anticipating a rewarding event; and levels then tend to fall if the anticipated reward fails to materialise. Couched in the language of psychology rather than neuroscience, enhanced dopamine release in the pleasure centres imparts a sense of urgency, significance and a feeling of things-to-be-done. The molecular substrates of pure pleasure are still elusive.
At the cellular level, the dopamine system doesn't quite rival the molecular, pharmacological and functional diversity of the serotonin system; but the two "classic" types of dopamine receptor (D1-like and D2-like receptors) have several subtypes and alternate splice-forms. Further, the number of different messenger RNA and dopamine binding sites substantially exceeds the five dopamine receptor genes of the human genome, a diversity that reflects the genetic polymorphism and alternative splicing events in normal dopamine gene-expression. However, each type of dopamine receptor belongs to the superfamily of G-protein-coupled receptors that activates or inhibits different forms of adenylyl cyclase inside the cell. Intriguingly, the presence or absence of variant alleles of dopamine receptor subtypes and their signal-transduction mechanisms is correlated with variants of human behaviour and personality. For example, individuals with genotypes containing the seven-repeat allele of the dopamine D4 16-amino acid repeat polymorphism tend to exhibit the personality trait of "novelty-seeking". This trait is characterised by a tendency to impulsiveness, risk-taking, exploration, excitability, and an optimistic mood, though alas not a loving, E-like temperament. For better or worse, within a few decades prospective parents will be able to select such alleles and their rationally redesigned enhancements when choosing the parameters of their future offspring. Such naturally loved-up kids may prove more easily adorable than today's Darwinian default-models.
Like the other catecholamine neurotransmitters, dopamine itself is synthesised from the non-essential amino acid L-tyrosine. L-tyrosine is transported across the blood-brain barrier into the dopaminergic nerve cell. L-tyrosine is converted to L-dopa by the enzyme tyrosine hydroxylase. L-dopa is then rapidly converted to dopamine by L-amino acid decarboxylase. Next dopamine is sequestered in synaptic vesicles by a dopamine transporter. At the synapse, the dopamine nerve terminal displays high-affinity uptake sites. They rapidly terminate the action of the neurotransmitter on the receptors if it isn't metabolised by the MAO or COMT enzymes. Depending on concentration gradient, the dopamine carrier can transport dopamine back into the nerve cell, recycling it as normal, or alternatively, after a user has taken a classic amphetamine, the carrier can transport dopamine from the cell terminals into the synaptic cleft. In common with amphetamine, MDMA inhibits the neuronal reuptake of dopamine, albeit more weakly than MDA. Further, increased post-E administration activity of the serotonin 5-HT1B and 5-HT2A receptors causes the dopaminergic neurons themselves to fire more rapidly. This higher impulse-frequency causes increased dopamine-release via exocytosis of the dopamine-containing vesicles in the normal manner.
So what leaves so many "normal" Darwinian people - who are neither clinically depressed nor loved-up on MDMA - comparatively anhedonic and hypodopaminergic? The dopamine neurotransmitter is under powerful homeostatic control. So is the density and signal-transduction efficiency of the receptors to which it binds. Feedback-inhibition of dopamine synthesis, dopamine release and spontaneous action-potential generation in dopamine-producing cells is modulated by a variety of functionally distinct dopamine autoreceptors that regulate membrane excitability. The dopamine neurotransmitter itself functions as an end-product inhibitor of tyrosine hydroxylase, the rate-limiting step in dopamine production. Dopamine plays this role by competing with a tetrahydrobiopterin co-factor for a binding site on the enzyme. Dopamine synthesis is also modulated by the rate of impulse-flow from the nigrostriatal pathway. In addition, presynaptic dopamine receptors modulate the rate of tyrosine hydroxylation; and most mesolimbic dopamine neurons possess cholecystokinin-autoreceptors and neurotensin-autoreceptors that regulate dopamine function as well. Indeed activity of the mesocorticolimbic dopamine system is regulated by multiple neuronal pathways containing different neurotransmitters, notably serotonin, opioids, GABA and glutamate. Precisely what dopamine actually does in the all-important dopamine-sensitive shell of the nucleus accumbens is unclear. The main effect of its release seems to be the inhibition of the GABAergic medium spiny projection neurons (MSNs). These neurons come in two types. One subtype expresses dopamine D2 receptors and enkephalin. This sort of GABAergic medium spiny cell projects from the nucleus accumbens to the ventral pallidum. It is activated by "reward stimulation" of the ventral tegmental area. The other subtype of GABAergic medium spiny projection neuron co-expresses substance P, dynorphin and dopamine D1 receptors. This subtype projects directly back to the ventral tegmental area. It regulates motivation and pleasure, or our deficit thereof.
So how can this cruel and complex web of inhibitory feedback mechanisms best be modified? If our aim were pure-and-simple cloud nine euphoria, then better drugs to decrease glutamate and GABA currents in the critical medium spiny neurons of the nucleus accumbens might be adequate - at least until new genes and gene networks can be more readily inserted in the genome, and the regulation of old ones improved. But well-controlled, high-functioning euphoria is more elusive than mind-blowing rapture. Crude "natural" interventions to enrich dopamine function aren't effective. For instance, some psychonauts, clubbers and alternative therapists alike have explored taking free-form amino acid supplements of L-tyrosine and L-phenylalanine in a bid to boost native dopamine levels or reanimate a drug-frazzled brain. But tyrosine hydroxylase is normally saturated. So unlike tryptophan-loading and/or 5-HTP-loading to increase neural levels of serotonin production, this "dopaminergic" precursor strategy typically doesn't work. On the other hand, taking L-dopa does increase synaptic dopamine levels. This is especially so when L-dopa is combined (as in Sinemet for Parkinsonians) with a peripheral decarboxylase inhibitor such as carbidopa to prevent its metabolism outside the brain, At least for a minority of "normal" subjects, taking L-dopa can be an effective motivator, libido-enhancer and mood-brightener. In a more controlled setting, rodents engineered so they can't synthesize dopamine initially develop quite normally, only to die miserably a few weeks after birth following a failure to eat, drink or do very much in this world at all. Yet when such dopamine knock-out mice are abundantly maintained on L-dopa, they can flourish. Indeed L-dopa-maintained dopamine knock-out mice become hyperactive and sexually vigorous. This manipulation has not yet been attempted in dopamine knock-out humans. Augmentation should in any case be tried only cautiously and in controlled-release preparations (e.g. Sinemet SR) since high levels of L-dopa may increase oxidative stress. Whatever the mechanism, simply increasing raw dopamine levels per se is not enough. For instance, an agent such as alpha-methylparatyrosine that inhibits tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis, might be expected to produce a state of melancholic depression; but in non-depressives it doesn't reliably do so. This complicates any simplistic catecholamine-depletion theory of retarded depression. Nevertheless, dopamine-releasing agents demonstrably tend to induce euphoria. By contrast, dopamine receptor antagonists like haloperidol are dulling and dysphoric. All the classical dopamine D2-blocking neuroleptics blunt will-power and flatten emotion. Administering dopamine D2-blockers tends to induce apathy and anhedonia, and ruins the MDMA magic. Nasty but instructive, such magic-prevention experiments are an important pointer to what's needed to sustain the MDMA spectrum of consciousness. It's known that stimulation of the dopamine D2-like receptor causes an increase in phosphatidylinositol hydrolysis by activating enzyme phospholipase C. Enhanced phosphatidylinositol hydrolysis is implicated in euphoric mania. Conversely, the lithium used to treat "uncontrolled" euphoria inhibits the phosphatidylinositol second messenger system and darkens mood in nondepressed "euthymic" people. Understanding the principles behind the pharmacological induction of controllable non-stop euphoria will be a first step on the route to designing lifelong variations of the subtler forms of magic.
In the meantime, dopamine antagonists like amisulpride (Solian) can be used at low doses preferentially to antagonise the synthesis-, release- and impulse-modulating presynaptic dopamine D2/D3 autoreceptors. Thus a regimen of low-dose amisulpride may potentially enhance dopamine release and boost mood and motivation, whereas many dopamine reuptake inhibitors [e.g. vanoxerine, bupropion, nomifensine] "adaptively" diminish the neuronal release of dopamine over time, even though their action on reuptake inhibition increases the neurotransmitter's synaptic availability. Unfortunately, pre-treatment with high doses of dopamine reuptake inhibitors blunts MDMA-induced release of dopamine, though not to the same degree as SSRIs blunt MDMA-induced release of serotonin. Other crude strategies to augment dopamine function involve taking dopaminergic agents such as the dopamine agonists pergolide (Permax) and bromocriptine (Parlodel); the potent, pro-sexual, long-acting D2 agonist cabergoline (Dostinex); selective D2/D3 agonists such as pramipexole (Mirapex) or ropinirole (Requip); catechol-o-methyltransferase (COMT) inhibitors such as tolcapone (Tasmar); selective MAO-B inhibitors such as selegiline (Eldepryl) or rasagiline (Azilect); adenosine 2A receptor antagonists; and centrally active nicotinic receptor agonists. Oral, centrally-active dopaminergic "pro-drugs" with higher bioavailability and fewer adverse side-effects are also under investigation. But there are obvious problems. For instance, dopamine-release promoting agents, if fast-acting and taken in the absence of anything subtype selectively "serotonergic", may not induce serenely motivated well-being as distinct from compulsive pleasure-seeking, thought disturbances or manic excitement. Any tendency to cause uncontrolled dose-escalation is likely to cause toxicity, florid psychoses and abuse. Regrettably, these worries about the "abuse-potential" of psychostimulants frequently generalise in mainstream wisdom to an unwarranted fear of all "dopaminergic" antidepressants/mood-brighteners.
This taboo against "excessive" well-being can have serious medical consequences. Even victims of melancholic or retarded depression are widely denied access to clinically effective catecholaminergic antidepressants. This is one reason why so many remain depressed or "partial responders"; another is opiophobia. MDMA itself rapidly banishes all kinds of depression, albeit not for long. In spite of its relatively powerful indirect dopaminergic activity, MDMA is sometimes likened in the media to the much more commonly prescribed selective serotonin reuptake inhibitors; fluoxetine (Prozac) was the first and most famous SSRI. In reality there are profound differences between MDMA, the SSRIs and other "serotonergic" antidepressants. Like an SSRI, MDMA occupies the serotonin transporter and prevents serotonin from binding, increasing its availability in the synapse. However, MDMA is small enough to be taken up by the serotonin reuptake transporter into the serotonergic cell. The serotonin transporter pulls the MDMA molecule up into the axon, where its release from the transporter allows the transporter to bind to intracellular cytoplasmic serotonin, which it releases into the synapse before taking back more MDMA into the terminal. Quite aside from their different molecular mechanisms of action, however, there are striking differences in subjective effect between MDMA and "serotonergic" centrally active psychiatric medicines. Clinically-licensed SSRIs [fluoxetine/Prozac; sertraline/Zoloft; fluvoxamine/Luvox; paroxetine/Paxil; and citalopram/Celexa] may make a small minority of people feel durably "better than well". More typically, SSRIs are mood-blunters and even, for some people, psychic anaesthetisers. SSRIs commonly make those who take them more resilient and less anxious. But they don't promote depth of feeling, intellectual dynamism or clarity of thought. SSRIs can also diminish the intensity of love. MDMA, by contrast, is a veritable love-potion, what Claudio Naranjo aptly christened a "feeling intensifier". On MDMA, emotions are heightened as well as enriched. Compared to loved-up ecstatics on MDMA, the rest of us have the emotional intensity of zombies; and zombies have no real insight into what they're lacking, even if some of us can talk as though we do. Ironically, at a time when the loss of personal liberty entailed by prohibitionist drug laws is justified by the societal costs of illicit drug-taking, "psychiatric" drugs are clinically prescribed by physicians regardless of the likely effect of a medication on the personal relationships of the patient. SSRIs, by enhancing the user's emotional self-sufficiency, can either save marital relationships or wreck them. By reducing "neediness", SSRIs also diminish what today passes for love. SSRIs are prone to impair romantic ardour as well as libido. One technical (and ideological) challenge of the pharmacogenomic revolution in prospect at the interface between genetics and drug-design will be to investigate how the emotional honesty and extraordinary depth of feeling induced by MDMA can be sustained over a period of months, years and decades rather than for two-hour bursts.
There are further complications to overcome if any bid to replicate and sustain full-spectrum E-like consciousness is to succeed. MDMA triggers the release of the neurotransmitter acetylcholine via a histaminergic H1 mechanism. MDMA is also a weak agonist of the acetylcholine muscarinic M1 receptors. MDMA's modest cholinergic activity may contribute to the exquisite lucidity of consciousness characteristic of pure MDMA taken in a therapeutic setting. For the cholinergic system is vital to memory, higher thought-processes and verbal fluency. Cholinergics such as piracetam (Nootropil) are used as nootropics or "smart drugs"; and acetylcholinesterase inhibitors like galantamine (Reminyl), rivastigmine (Exelon), tacrine (Cognex) and donepezil (Aricept) are used as palliative treatments of Alzheimer's disease. Acetylcholine-release and muscarinic receptor activation probably play no direct role in the rewarding hedonic effects of MDMA. Yet their subtle contribution to the texture of the magic can't be discounted. "Dumb-drug" antimuscarinic agents commonly induce mild euphoria via their indirect enhancement of dopamine function. Their mood-brightening effect stands in contrast to many cholinergic (e.g. muscarinic M4 receptor) agonists and cholinesterase inhibitors which have a tendency to subdue mood. A wide range of cholinergics is now under development for the palliative treatment of Alzheimer's disease, a progressive neurodegenerative disorder characterised by profound cholinergic deficits. Some depressives, however, may actually benefit from the antimuscarinic anticholinergic effects that more intellectually fastidious clinicians would call an adverse side-effect of the older tricyclics. While a great many depressed people report intellectual sluggishness and poverty of thought, other melancholic and introspective depressives endure "hypercholinergic frenzy", possibly owing to dysregulation of the cholinergic-adrenergic axis. Sadly, innumerable depressives among life's walking wounded today find the examined life scarcely worth living: they cope with life only by "just getting on with it". By contrast, MDMA allows introspection to become insightful and enjoyable even to the naturally angst-ridden. On MDMA, both philosophising and emotional self-honesty can be illuminating and fun. It's a shame that such self-insight can't more readily be prolonged.
Another enigma is the role of DHEA. MDMA causes a rise in the adrenal corticosteroid dehydroepiandrosterone (DHEA). DHEA is the precursor to testosterone, progesterone, estradiol and other steroids. The rise and peak physiological values of DHEA between around 1 to 2½ hours post-MDMA administration is correlated with user-reported euphoria, though DHEA's precise contribution to the mood-elevation is unclear. In general, levels of DHEA decline with age after early adulthood. Long-term supplementation with DHEA seems to have beneficial effect on libido, immune function and some forms of cognition. However, in spite of a wealth of research, no firm conclusions have yet been reached on the advisability of taking DHEA supplements, or an optimal dosage if taken. Nor is it known what role enhanced DHEA might play in sustaining enriched quality of life over the longer term. Taken on its own, DHEA may brighten mood; but it's scarcely an E-like effect.
One unwanted effect of MDMA, especially when taken at higher doses, is its tendency inhibit to tryptophan hydroxylase by triggering a rapid oxidation of the enzyme's sulphydryl sites. Tryptophan hydroxylase is the rate-limiting enzyme in serotonin synthesis. Even though the acute functional loss of tryptophan hydroxylase in the cell terminal is reversible, the axon's vulnerability to oxidative stress is increased. In order sustainably to enhance our capacity for empathetic bliss, and certainly to prevent any functional serotonergic deficit, tryptophan hydroxylase function must be enhanced, not inhibited. However, to date no stimulator (or inhibitor) of the biosynthesis of serotonin has been commercially marketed. Interestingly, the use of interventions to increase the biosynthesis of serotonin prior to MDMA use tends to trigger an increased synaptic release of dopamine, thereby enhancing the user's euphoria. Unfortunately, increased serotonin synthesis also aggravates post-E neurotoxicity. The two mechanisms are separable in principle. In the meantime, restraint is prudent.
Ultimately, we may be able to generate sublime MDMA-like states - at will, to order, and indefinitely - only when the intracellular signal-transduction mechanisms, and regulation of genetic switching beyond the post-synaptic cascade, are better understood. The orchestrated "overexpression" of some genes and the receptor proteins they code, the redesigned "under-expression" of others, and perhaps the selective silencing of gene expression via RNA-mediated interference of anything really nasty, can amplify desirable facets of our consciousness and suppress its darker and more poisonous variants. Thus at one terrible extreme, suicide victims, for instance, tend to show heightened levels of serotonin 5-HT2A receptors. Before death, they show a greater activity in the genetic machinery churning out the 5-HT2A receptor itself. So as well as developing gene-therapy to prevent suicidality - and forestall the whole spectrum of deeply unpleasant para-suicidal and self-destructive states - it should be possible, conversely, to engineer an unimaginably richer love of life, of ourselves and each other by genetically enhancing our own minds. Freedom to optimise (or at least improve) one's genome should prove at least as personally liberating as the freedom to optimise one's drug-regimen. Doubtless a regulatory minefield lies ahead.
One momentous development is perhaps only a decade or so away. In the imminent era of genomic healthcare, we may each enjoy access to a read-out of our own individual genotype i.e. the set of particular forms of genes - alleles - peculiar to each individual who isn't a monozygotic twin [triplet etc]. Harnessed to pharmacogenetics, the study of how an individual's distinctive genetic inheritance affects the body's response to drugs, such intimate genetic self-knowledge should allow the design and prescription of a drug-regimen tailored to each unique person, whether for medical, social, research or "recreational" purposes. At first, only the crudest stratification of patient populations by genotype may be the medical norm. This is because commercial drug companies prefer large markets. Yet eventually we should all have optional access to the gene-expression profile of each neurotransmitter-specific neuronal subtype in the mind-brain. Such access offers scope for fine-grained manipulations of the chemistry of our souls inconceivable in the Dark Ages of pre-genomic medicine.
Genetically personalised medicine offers another bonus. It should eliminate the possibility of idiosyncratic drug reactions caused by genetic abnormalities - for example rare polymorphisms of the cytochrome P450-2D6 system critical to drug metabolism. Owing to genetic polymorphisms in drug-metabolising enzymes, receptors and transporters, a range of drugs beneficial to c.99% of the population can't get regulatory approval. In some cases, valuable licensed medicines are pulled after post-marketing surveillance. This therapeutic opportunity is wasted because, say, 1%, 0.1%, or even 0.01% of people who take such agents suffer severe adverse reactions. The advent of genetically personalised medicine should mean that these atypical cases can be excluded; and given other medication instead. Useful older drugs can be dusted off the shelves and re-licensed. New agents can be developed and given faster regulatory approval.
Psychoactive drug users in particular should benefit from the prospect of genetic self-knowledge. Cytochrome P450 forms a superfamily of hepatic enzymes with hundreds of different isoforms that catalyse the oxidative metabolism of a huge diversity of substrates, including MDMA. The duration of action and/or intensity of the effect of numerous drugs are determined by their rate of metabolism by cytochrome P450. Whereas some "housekeeping" enzymes are expressed constitutively i.e. they are perennially active, other enzymes are expressed essentially only when triggered by the presence of the exogenous chemical. Inducible enzyme isoforms increase both in amount and activity in response to drugs.
The precise role of CYP2D6 in MDMA pharmacology is still unclear. MDMA is not merely a substrate for CYP2D6; it also binds to the enzyme, forming an inhibitory complex. The CYP2D6 enzyme is soon saturated even in efficient metabolisers. Other human cytochromes P450 such as CYP-1A2, CYP-3A4 and CYP-2bB are critically involved in the oxidative metabolism of MDMA. It is possible these other metabolic pathways play an important role in everything from idiosyncratic responses to MDMA to the notorious "loss of magic". If enzyme induction accounts wholly or in part for the loss, then the roots of disenchantment can be investigated and prevented, whether for MDMA or perhaps its still imperfect successors. If, however, central processes of neuroadaptation are at work, either instead or as well, then longitudinal neuroimaging studies comparing the brain-scans of, say, drug-virgins ninety minutes or so after dropping their first magical E (or perhaps its safer successor(s)) with brain-scans taken during their hundredth-odd trip should allow the neurochemical basis of any loss of magic to be pinpointed and reversed. Indeed the magic itself can presumably be amplified, probably more delightfully than an unenchanted Darwinian mind can grasp.
More broadly, genomic medicine will deliver the freedom to choose who or what we want be, both as individuals and collectively as a species. In the long run, a spectrum of mental superhealth that is orders of magnitude richer than anything accessible today can be genetically pre-programmed. "Phenotypic plasticity" (the nearest analogue to free will a molecular geneticist will recognise) can be both vastly extended to enhance personal autonomy and, no less importantly, constrained where it's cruel and unwanted. Thus better designed gene-and-drug combinations can perpetuate truly sublime modes of consciousness whereas, conversely, a predisposition to such ancient Darwinian horrors as sociopathy or suicidality can be genetically cured. A rewritten genome can potentially liberate us from all trace of psychopathy and depression - the enemy from without and, all too often, the enemy within. When taken today, MDMA rapidly banishes the horrors of both. Alas they soon return; the acute effects of MDMA are mostly all too reversible. Prediction is always a hazardous business, but to our descendants, breeding kids with anything like our own corrupt code may seem like wanton child abuse.
Post-Darwinian Medicine
Decoding the human genome offers the promise of lifelong emotional health via somatic or germline therapy. Such well-being may be modulated at will via entactogens-empathogens akin to MDMA; by entheogens, psychedelics, nootropics; or agents from categories currently too exotic to imagine. Or alternatively, our descendants may opt to abandon psychotropic drugs as pollutants of their genetically-enriched minds.The biotechnology revolution throws up darker scenarios too. The spectre of biowarfare, bioterrorism, and perhaps totalitarian state control over our reproductive decisions tends to loom larger in the contemporary imagination than utopian visions of boundless love and joy. Clearly genetic engineering and designer-drugs, like the printing press, can be put to unethical use. Nightmarish dystopias make spine-chilling science-fiction and, maybe more plausibly, better futurology than wide-eyed technophilia. The near future may indeed be bleak. Those of us who aren't morbidly interested in pain and suffering probably underestimate how dreadful primordial Darwinian life can be at its worst. Some mental and physical torment is so bad its victims would snuff out the whole world to end it. Disturbingly, the sense in which its victims could be deluded in evaluating its dreadfulness is unclear.
Yet human nature as encoded in our DNA isn't immutable. Mankind's barbaric track-record to date is an unreliable guide to our post-human future. If Homo sapiens' nastier alleles and their more sinister combinations can be silenced or edited out of the genome, and new improved code-sequences inserted instead, then the pessimists will be confounded. A major discontinuity in the development of intelligent life lies ahead. Providentially, we've learned that the DNA-driven world isn't written in God-given proprietary code it would be hubris to tamper with, but in bug-ridden open source amenable to improvement.
Given our current design-limitations, any planning for a post-human population endowed with invincible mental health sounds ambitious in scope if not messianic in spirit. Even granted that paradise-engineering is technically feasible, the abolitionist project still amounts, by today's lights, to a breathtakingly bold strategic move for our species. It may never happen. Most philosophers assume that suffering will endure as long as life itself. Only the horrific, purposeless cruelty of a living world evolved by natural selection makes an abolitionist agenda of "unnatural" selection so morally urgent. That said, any mental health plan aimed at underwriting lifelong emotional well-being for the world's population no more entails developing a millenarian blueprint for a post-human Utopia, or prophesying the imminent End Of History à la Francis Fukuyama, than the still radically incomplete conquest of "physical" pain dictates specifying the particular kinds of pain-free lives we should all lead. The lifestyle options following success in either case are effectively limitless. Thus any fleshed-out examples of possible post-Darwinian forms of life are purely illustrative. If mental superhealth does become the societal norm, then gradients of genetically predestined bodily and emotional well-being can constitute the presupposed backdrop to the diversity of everyday life, not its focus. Gradients of lifelong happiness can enrich our autobiographical narratives, not supplant them. Ecstasy needn't be orgasmic; though it can be.
As contemplated today, scenarios of a post-Darwinian era of lifelong bliss demand a greater effort of imagination than the possibility of lives spent "merely" without "physical" suffering. The futuristic scenarios feel "unreal". The prospect of lifelong happiness strikes us as far more utopian in conception than the prospect of lifelong bodily health. Yet in both cases, gradients of well-being can play a role informationally analogous to their nastier Darwinian counterparts while shorn of their unpleasant (and sometimes harrowing) subjective textures. Assuming here without argument a functionalist model of computational mind, what's indispensable to intelligence in the broadest sense of the term are the triple processes of information, computation and feedback. The "raw feels" of unpleasantness are neither necessary nor sufficient for intellectual progress. Thus our silicon robots don't suffer anguish, even when we recode their "affect programs"; and it seems they're getting smarter a lot faster than we are.
The existence of lives animated by gradients of well-being should be distinguished from lives spent in a state of uniform well-being. Chronic heavenly bliss, like chronic pain and despair, is a condition that's technically possible to implement in the vertebrate CNS. For good or ill, such uniformity would be a recipe for stasis. The intra-cranially self-stimulating rat or monkey - or human wirehead - isn't going anywhere. By contrast, if a predisposition to gradients of ecstatic well-being is ever genetically encoded as our default mood-spectrum, then critical discernment can be functionally retained, and self-motivation enhanced, without sacrificing the humane ethic of a cruelty-free world. This conjecture isn't idle. Some bioethicists would argue a world without suffering is the precondition for any civilised society. Plausible or not, the lack of any inevitable tradeoff between happiness and critical insight undercuts one ideological obstacle to global mood-enrichment.
Predicting the dial-settings on the emotional thermostats of our descendants is unavoidably speculative. But if (very controversially) post-Darwinian humans will innately feel superwell, albeit in varying degree, precisely what modes might their genetically enhanced and perhaps pharmacologically modulated well-being most plausibly take? Will such well-being be the egoistic happiness of amoral, emotionally self-reliant ubermenschen? Or could being loved-up on Ecstasy, or perhaps long-acting brands of entactogen-empathogen cleaner and safer than MDMA, offer a better model of social life in centuries to come?
This sort of crystal-ball gazing clearly demands scepticism as well as a lively imagination. As Dr Shulgin reminds us elsewhere, any prediction is hopelessly entangled with the wishes of the predictor. Such bias might seem to defeat the enterprise from the start. Fortunately (or otherwise), however, some scientific prophecies can become self-fulfilling if ever their makers acquire the power to implement them. In this instance, technically at least, Homo sapiens will soon have the collective scientific expertise to redesign our own nature. So if we ever aspire to enjoy, say, lifelong ecstasy for our minds and bodies, then we can have it. If we're so minded, then apes can become angels. The ultimate stumbling-block, if there is one, will be traditional Darwinian-era ideologies, not scientific ignorance of how to redesign the molecular machinery of emotion. For sure, the vision of a whole civilisation, and not just an all-weekend rave, founded on the neural substrates of an E-like "Peace, Love, Understanding and Respect" sounds sociologically naïve and (socio-)biologically impossible. Stated so bluntly, the loved-up edition of scientific utopianism is perhaps the most implausible (and unreadable) premise for a sci-fi novel one can imagine. The non-specific prediction of genetically preprogrammed well-being for our descendants is contentious enough as it stands. Any more detailed explorations of the possibility that such enriched well-being might be, say, E-like rather than egoistic are therefore hugely more speculative; and quite probably mistaken. But for the following reasons, a civilization based on relationships of, say, mutual loving empathy and intensified E-like consciousness is not impossible, just far-fetched. At a minimum, it's worth sketching out an extended family of E-like scenarios as a corrective to a routine but unargued assumption that underlies rival predictions. This assumption is that societies based on the behavioural genetics of primate-style dominance-and-submission hierarchies will endure indefinitely. Thankfully, both the reproductive biology and mode of selection pressure at work in the new era of genomic medicine will be different from the evolutionary past. Our genetic programming will no longer be "blind", even if its early (re-)programmers will be only partially sighted. Varieties of (post-)human genotype won't just be quasi-randomly generated via sex, genetic crossing-over and mutation. Instead, genotypes will be purposely (re)designed - even if the early designers barely know the ramifications of what they'll be doing.
For we're presently on the brink of the era of "unnatural" selection. Throughout the living world, a regime of blind natural selection acting on effectively random mutations has governed the evolution of information-bearing self-replicators since the origin of life itself. The Darwinian Era has lasted for over four billion years. Most recently, in the aftermath of the post-Cambrian explosion of multicellular animal life and the evolution of central nervous systems, selection pressure has created suffering beyond belief. Mercifully, a regime change is imminent. Within a few centuries at most, intelligent life will be able to rewrite the vertebrate genome and redesign the planetary ecosystem. Sooner still, if we want our genetically enriched (grand-)children to be happy, then in the impending reproductive era of preplanned designer babies we will also have to choose - either actively or by default - whether the kinds of heritable well-being our offspring enjoy will tend to be solipsistic or social, orgasmic or intellectual, hypomanic or serene, loving or self-centred, or perhaps ultimately take forms that can't be grasped by the contemporary Darwinian mind. Whatever criteria are used, an increasing range of genotypes will soon be chosen in deliberate anticipation of their phenotypical effects. Needless to say, no such calculated sets of genetic decisions can be taken by prospective breeding couples at present. "Genetic choice" in the early 21st century usually means nothing more ambitious than choosing the gender of one's child, often in less than ideal circumstances. Yet as the human genome is deciphered, and eventually the "transcriptome" and proteome beyond, a staggering extension of freedom of choice will be thrust upon us. As wiring up the neural reward centres with microelectrodes shows, the practicalities of inducing - and then sustaining - the neural substrates of bliss are technically quite easy. Viewed as an engineering problem, no one needs to suffer; suffering is an unnecessary evil. This is true even with today's embarrassingly clumsy interventions. Modulating bliss in controllable ways is trickier - whether by drugs, microelectrodes or gene-therapy. Short-term technical snags aside, our state-space of life-enriching options is poised rapidly to expand. Of course even with utopian biotechnology and mature nanotechnology, constraints won't be absent. The menu of practical choices on offer to our enriched descendants isn't entirely limitless. For instance, decades spent in unceasing, paroxysmal super-orgasms, or perhaps immersion in fantasy wish-fulfilment in virtual reality software, may well be viable lifestyle options one day for individuals. They are technically feasible to implement. Yet it's hard to imagine parents wanting such modes of existence for their kids, or to devise evolutionary game-theoretic models where the prevalence of genotypes that permit such lifestyles could be globally stable. In any post-Darwinian reproductive era ahead, "unnatural" selection pressure will still be at work, at least until the abolition of senescence brings the throwaway era of traditional DNA mortals to a close. Thus any currently foreseeable civilisation will be social in character, not quasi-solipsistic. If so, then one urgent challenge will be to make our social interactions less emotionally costly. Today, for a few hours, MDMA offers perhaps the richest chemical tool for social intimacy in existence. If nothing else, the MDMA experience demolishes the conventional wisdom that "artificially"-induced happiness must be amoral and selfish - hedonistic, one-dimensional and shallow. More generally, the sense of heightened authenticity, love and self-insight induced by entactogen-empathogens will no longer seem an escapist holiday from Real Life when entactogenic-empathogenic states can be sustained indefinitely - whether by gene-therapies or soul-medicines or varieties of both. In theory, at least, mental superhealth can become the new benchmark of consensus-reality against which any departures are defined, not drug-induced psychotic episodes.
It's safe to say MDMA itself isn't going to change the world. Yet as a taster of what's feasible in post-prohibitionist culture and a possible genetically-enriched future beyond, the MDMA experience shows social life at its best. MDMA promotes a more altruistic mode of consciousness than has maybe ever existed on the planet, certainly among testosterone-driven young males. On MDMA, one can love thy neighbour as thyself; and the lion can lie down with the lamb. Feelings of hostility, bigotry and intolerance evaporate. Competitiveness is replaced by love, tolerance and respect. Such social harmony seems "unnatural" if not miraculous when viewed from the poisonous miasma of mainstream society. For outside the embraces of loved-up ecstatics, we tend to pay a terrible price for the benefits of group living. The costs of social existence are attested by the grisly chronicles of human history, Gibbon's "register of the crimes, follies, and misfortunes of mankind". It's not as though we have much choice about living together. Even in the absence of MDMA, human beings are still compulsively sociable. This compulsion to socialise is generally seen as healthy rather than dangerously addictive, despite the traumas it brings. In abnormal conditions of social isolation, the personality starts to deteriorate: solitary isolation, whether real or figurative, is rightly viewed as a cruel and unusual punishment. Our genes, via the reward pathways and the neural projections they code, make us chronically hooked on the company of others. Our very identities are bound up with our social roles. We are physiologically dependent on the opioidergic, oxytocinergic, dopaminergic and serotonergic mechanisms that friends, family and colleagues may trigger within us.
At its best, this chronic dependence on human company gives short-term highs and even warm afterglows. But dependency, craving, and withdrawal-reactions are common when significant others are taken away from us or adulterated. Purity varies; supply is erratic; and adverse reactions are common. Cue-elicited craving readily triggers relapse. Our sociability can spin out of control into a financially ruinous habit. We spend lots of time and effort thinking about how to get more of whoever stimulates our mesolimbic reward circuitry most vigorously, possibly romanticised under more poetic descriptions. Without friends, lovers or family, most people tend to become lonely, sometimes agonisingly so. In extreme cases, loneliness and lovesickness can induce suicidal despair. Bereavement and abandonment can be as traumatic as heroin-withdrawal; and they share similar neural substrates.
Alas given a Darwinian genome the compulsion to socialise is all too often a dangerous, self-destructive addiction. Living without Ecstasy, we are predisposed by our genes to conflict with each other: mothers and children, men and women, brothers and sisters, friends and relatives - all have different and often conflicting genetic interests. Only monozygotic ("identical") twins may hope to be spared this insidious rivalry. Camouflaged genetic conflict underlies our disposition to squabble and fight amongst ourselves, even though we compulsively need each other's company too. Thus testosterone-driven males find themselves enacting decades-long competitive rituals to attract and retain genetically superior mates. Competitive status-seeking in its subtle - and not-so-subtle - guises is a cross-cultural universal, deeply rooted in our biology. Conflict to the point of warfare is genetically predisposed in our make-up. It's endemic to human society. Right from conception and the implantation of the conceptus in the womb, genetically-driven conflict plays itself out, often leading to trauma (e.g. preeclampsia etc.) for mother and unborn child alike. Later on, even the noblest of human sentiments are fragile. Love all too easily turns into hatred, admiration into contempt. By way of illustration, consider, say, proverbial "lover's quarrels". There are innumerable "proximate" explanations of why star-crossed lovers often argue so painfully and vehemently. But the "ultimate" evolutionary explanation seems to be, at least in part, that tempestuous rowing and its consequences serve as a brutal but effective way for prospective breeding couples to test each other out. Evolutionary psychology suggests that, from a gene's eye view, it's better to discover if a prospective partner will let you down sooner, when (s)he's goaded under conditions of stress, rather than later after you've sunk a substantial investment of time and resources in the partnership. Arguing can be traumatic; but the capacity to do so is [genetically] adaptive.
Human relationships can bring psychological rewards too. Anyone having fun right now would find this drumbeat of misery, heartache and emotional squalor all a bit overblown. Yet if anything the nastiness alluded to here is understated; the worst pains in life are inexpressible. Under the genetic status quo, most of us are condemned at different stages of a lifetime to re-enact the messy - and sometimes desperately sad - personal dramas of our ancestral past. TV soap-operas and teledramas serve to sanitise just how emotionally unpleasant Darwinian life can be. For as human generation succeeds human generation, we replay the age-old sagas of sexual betrayal, jealousy, loneliness, and rejection. We are forced to endure the savage competition of lookism - an inadequate, frivolous term for a cruel and omnipresent phenomenon in human society. Less colourfully, a multitude of pettier but still wounding frustrations, humiliations and misunderstandings can mar daily social life and sour personal relationships.
The genetic rot goes deeper. Evolutionary psychiatry suggests that the cross-culturally ubiquitous phenomenon of depression, and the wider spectrum of depressive and dysthymic disorders, is not a genetically dysfunctional anomaly. Counter-intuitively, a conditionally activated tendency to depression may represent a fitness-enhancing adaptation to group living. The (involuntary) capacity for depression is one of a number of ancient, genetically adaptive mechanisms and strategies for dealing with "social defeat" in a tribal environment. Group living conferred advantages on otherwise vulnerable individual primates on the African savannah. Embracing tribal life forms a valuable defence for a puny "naked ape" against big predators. But thanks to the pressure of sexual selection, human tribal society imposes a cruel pecking-order of subordination relationships among members of the tribe. For sure, depression has many proximate causes; there are many subtypes of depression; and not all depressive moods and behaviours are genetically adaptive. Yet viewed in evolutionary perspective, a syndrome of sustained melancholy, behavioural suppression, and a preoccupation with personal failure and inadequacy is the internalised correlate of the yielding or "losing" behavioural sub-routine. On this "rank theory" hypothesis, the involuntary activation of submissive and depressive states is an unpleasant but effective defence-mechanism for weaker individuals where any tendency to initiate or escalate conflict with a powerful dominant rival might easily be disastrous. Thus states of depression or low mood ensure the weak "keep their heads down" and don't overreach themselves. By contrast, the (hypo-)manic spectrum of mood and behaviour is a manifestation of the "winning subroutine". Clearly, not all submissive people are unhappy, and not all dominant and/or aggressive people are (hypo-)manic. So there are complications to the hypothesis and a legion of exceptions. A capacity to switch mode can sometimes be adaptive too; hence the probable evolutionary origins of bipolarity. Yet down at the bottom of the social heap, there are proportionately far more crushed and wounded spirits than there are at the top. Socially dominant Alpha males tend to be temperamentally expansive and optimistic. Conversely, even life's "winners", if deposed and defeated, may become depressed themselves, and slink away to die, metaphorically or otherwise. Depression in human societies is far more prevalent than (hypo-)mania, albeit far less visible. This greater prevalence probably reflects conditions in the evolutionary environment of adaptation where the spectrum of depression, mania and bipolarity first arose. But whatever the ultimate evolutionary roots of mood variation and affective disorders as interpreted by rank theorists, contemporary humans in all known societies are obsessively status-conscious. Status-competition corrupts personal relationships in societies stratified by caste, class and money alike. Even apparent counter-examples don't challenge the generalisation. Thus societies based around the potlatch, the Pacific Coast Native American custom of conspicuous gift-giving rather than wealth-accumulation, reflect a disguised expression of competitive power relationships. Indeed the tradition of rival displays of gift-giving finds echoes today in the competition between billionaire American plutocrats to endow the biggest charitable trust foundations.
The poison of competitive status-seeking might seem incurable. ["If everybody is somebody, then nobody is anybody"; "It's not enough to succeed. Others must fail"] Yet short-term symptomatic relief for this syndrome already exists; and its long-acting analogues may one day offer complete remission. Taken communally, MDMA induces an almost miraculous transformation in the structure and relationships of any social group. At MDMA-animated raves, no one who's loved-up is trying to "diss" anyone else. MDMA abolishes the desire to put anyone down. On MDMA, primate dominance hierarchies dissolve in an egalitarian love-in. A lifetime's inferiority-feelings, snobberies, and status-anxieties dissipate in a flood of augmented serotonin and dopamine release. Intriguingly, the euphoria experienced by MDMA users doesn't take the form of uncontrolled manic excitement, even where the drug induces "behavioural activation". MDMA's indirect, serotonin-mediated enhanced dopamine-release produces psychostimulant, emotional and perceptual effects that feel very different from crude dopamine-releasing amphetamine. Even the most animated ravers taking pure MDMA tend to experience a profound sense of inner calm, a "peace that passeth all understanding". Identifying the neurochemical signature of states combining inward serenity and outer dynamism presents a wonderful therapeutic opportunity. The contrast between raves packed with loved-up clubbers on hugdrugs and parties fuelled by alcohol or cocaine is striking.
Back in the harsh, E-less world, inferior social status is associated with low serotonin function and low mood. Thus dominant males tend to have far higher serotonin function, as measured by CSF 5-HIAA levels, than subordinate males. The neurological basis of social rank order can be investigated by various manipulations. Experimentally boosting or depleting the serotonin levels of social animals enhances or sabotages an individual's place in the pecking-order. Revealingly, there are also gender differences in serotonin activity. The mean rate of serotonin synthesis in men is over 50% higher than the mean rate of serotonin synthesis in women. Women are more sensitive than men to both the MDMA magic and MDMA's adverse side-effects. Women are also more likely to suffer from the post-E serotonin dip; more prone to depression; and more likely to benefit from Prozac. Yet such comparisons are invidious. Men and women alike of any social status at all can flourish far better in E-like states - while they last. Unfortunately, communal E-like consciousness simply isn't sustainable via chronic MDMA use. In wider E-less society, "winners" probably don't do [serotonin-depleting] drugs, though idealistic E-users might suggest that zero-sum status-games are best not played at all. For better or worse, a heavy, serotonin-depleting E-regimen can disrupt the user's social status in the competitive urban jungle - and probably elsewhere. Admittedly, there are too many confounding variables to test this hypothesis in methodologically rigorous studies on humans. Even so, a proposed "E-users are losers" research proposal is more likely to gain official funding than a well-controlled trial of, say, the health benefits of MDMA-assisted psychotherapy.
Of course the aspiration for a civilisation founded on relationships of shared love and respect sounds impossibly idealistic. A society based on "winners" and "losers" intuitively strikes us as natural. With today's genes and the kinds of culture they promote, adversarial social relationships are probably inevitable. Like depression, the evolutionary roots of everyday sociopathy run deep. For speculatively, applying here Richard Dawkins' "extended phenotype" theory, not merely has it been genetically adaptive for weaker social primates to have an inbuilt conditionally-activated capacity for depression, it can also be genetically adaptive for Alpha males (and aspiring Alpha males) to subdue potential rivals by making them depressed too. Perennially chastened, socially anxious and chronically depressive potential competitors are less likely to be sexually active and promiscuous. Crushed, anhedonic and submissive, they are less of a challenge to the inclusive fitness of one's genes. Happy, dominant, extroverted males, by contrast, are potential sexual rivals who directly or indirectly threaten one's reproductive success. Thus we witness their downfall with equanimity. Even within the bounds of holy wedlock, too much happiness for one's nearest and dearest doesn't always suit one's genetic interests. A cowed and depressive wife, whose only solace in life is looking after the kids, can be less threatening to one's genetic prospects than an exuberant, sociable and possibly sexually adventurous bundle of joy. If we are looking for an evolutionary perspective on why we often behave so vilely to each other - sometimes seemingly gratuitously so - then this kind of sexual selection pressure offers one possible explanatory framework. If it is adaptive to have others exhibit a spectrum of behaviour characteristic of low mood or high social anxiety, then other things being equal, alleles and allelic combinations may flourish if they conditionally promote the capacity to induce such anxiety and depression whether in strangers or tribe members who aren't allies or close kin - and if occasion demands, even in those who are both. Depending on a lot of other factors too, the (behavioural effects of the) happiness of others, male or female alike, can indirectly detract from our own Darwinian fitness. Consequently their perceived happiness doesn't tend to give us as much joy as moralists might wish. Sad to say, reports of good fortune befalling our fellows do not always inspire a warm glow of vicarious satisfaction. On the contrary, news of another person's lottery-win, for instance, or its traditional counterpart on the African savannah, is liable to trigger involuntary feelings of jealousy and resentment, or at best an envious ambivalence. Of course, it's worth stressing that natural/sexual selection doesn't care about the subjective textures of misery or happiness per se. Selection pressure works on the spectrum of behaviour such mood traits engender. What was selected for [as distinct from adventitiously selected] in the ancestral environment of adaptation wasn't the capacity to make others feel miserable as distinct from behave miserably. To selfish DNA, our suffering itself is incidental. The distinction, however, is of limited comfort to its victims.
Fortunately we're not systematically spiteful, even though we're not naturally loved-up. If human malice were really genetically hardwired, then any nostrums for social reform, life-enriching lovedrugs or improving the vertebrate genome would be futile. Thankfully, a malignant streak of human nastiness is matched by a common if ineffectual desire to improve ourselves and help others. This good-will just needs genetic and pharmacological amplification.
So granting human beings no more than a minimal and diffuse benevolence, what can be done to make us temperamentally nicer to each other as well as happier and smarter? Would we individually and collectively be better off if perpetually loved-up on more advanced and sustainable analogues of E? Or are loved-up ecstatics just too vulnerable to genetic invasion by "defectors" and wolves in sheep's clothing for such genes or allelic combinations to flourish? Vulnerability to predatory and Machiavellian genetic rivals is presumably the reason why sweetheart suckers living in blissfully E-like states are thin on the ground in the drug-free Darwinian world. What reasons are there, if any, for predicting that the nature of adaptive traits in the era of genetic engineering will change in ways that make beautiful minds more widespread?
If genetic engineering or rational drug design are to deliver us from the Darwinian rat-race into everyday states of ecstatic grace, or anything at all like it, then there are short-term and wider evolutionary constraints to be overcome. Truly far-sighted genetic re-programming is a formidable challenge. Some genetic manipulations may involve computing the interactions between dozens or ultimately hundreds of alleles. Often their contributions to mental and behavioural traits won't be additive but dependent on a plethora of environmental contingencies. This Problem of Conditional Activation threatens a combinatorial explosion of possibilities to calculate. It presents a daunting task of prediction and control. Other interventions, however, might seem (comparatively) more straightforward. For instance, the action of testosterone, and its hormonally active dihydrotestosterone metabolite, is in large part responsible for war, social violence and competitive dominance behaviour, territoriality, sexual aggression, reduced male life-expectancy, and going bald. The genetic and/or pharmacological manipulation of testosterone may play a vital role in undercutting the darker horror scenarios for the future so popular in the science-fictional literature.
Yet first there are many problems to be resolved here too. Testosterone can't, realistically, just be edited out of the genome, as distinct from edited and re-regulated. The eradication of testosterone would indeed spell a world without war. But androgenic hormones can't be deleted altogether, even if the option of rearing functionally emasculated or chemically castrated offspring were an idea palatable to prospective parents, an unlikely prospect right now. Testosterone is the stereotypical "male hormone". Yet testosterone is present in women too, albeit in smaller amounts: it's important to female sexual response, just as it's responsible for spontaneous nocturnal erections in males. Testosterone plays a role in female bone-strength, muscle-mass and a general sense of well-being. Moreover, expository convenience aside, androgenic hormones are no more intrinsically evil than the MDMA molecule is intrinsically good. Thus testosterone promotes what might be described as "strong-mindedness". Today the trait of strong-mindedness fosters what's often little more than callousness in pursuit of unworthy ends. But not always. Even in a mature post-Darwinian civilisation, most of us may well prefer to cultivate "strong personalities". The popularity of performance-enhancing anabolic steroids with athletes and bodybuilders stems only in part from the way such drugs enhance strength, power, speed, endurance and muscle-mass. For anabolic steroids are popular because they can also act as mood-elevating, mind-toughening personality-pills. Taking anabolic steroids induces a sense of well-being sometimes amounting to euphoria, an increased tolerance of stress, and a sense of competitive "edge". The price of using such drugs can be hypermasculine aggressiveness ["roid rage"], increased dominance behaviour and even a propensity to sexual violence. Normal endogenous male production of their native anabolic counterparts is risky enough already. If our species is to survive its newfound capacity to build weapons of mass-destruction, and tackle the genetic origins of male violence and all-round nastiness, then we must somehow curb the biological roots of masculine aggression. This particular intervention strikes us as a disconcerting prospect. Darwinian sexual and gender identities are central to social existence today, and usually integral to who we think we are. However, the long-term role of the Y chromosome in the evolution of intelligent life is uncertain; and the ethical value of testosterone-driven masculinity is unproven at best. The phenomenon of sexual reproduction itself has only persisted and evolved as a defence against parasitism; an additional mechanism that promotes genetic variability is a powerful weapon in the evolutionary arms race against pathogens. In the new reproductive era ahead, however, genetic diversity can be intelligently pre-planned. So at the very least, enlightened biomedicine should be able to edit out a predisposition to the more sociopathic forms of masculinity from the genome. More far-reaching strategies can be contemplated too. On the other hand, recalling H.G. Wells' The Time Machine (1898), we don't want to turn into enfeebled and weak-minded Eloi, even if we live in a world without Moorlocks. It's good to wake up each morning feeling ready to take on the world and win, even if we eventually discover that the rest of the world is on our side; and some day it may be conspiring to help us.
Today the world generally isn't on our side. Low testosterone function is associated with social defeat, passivity and subordination. Low testosterone levels are also implicated in depressed mood. The syndrome of depression has both proximate and evolutionary roots. Depression is popularly viewed as a sign of weakness; and folk-wisdom is right. Such a perception leads to its systematic underreporting, especially among males, thereby painting a falsely rosy picture of (male) mental health. Depressive illness is reported to be twice as common among women as men. Conversely, it's sexy for men to be cool, confident and 'sussed' - the sort of personality often faked if you aren't, though for evolutionary reasons depressives find it harder to bluff. Therapists and sensitive physicians may take determined steps to reassure their clients that depression isn't a sign of weakness. Alas this assurance typically isn't true. Depressives characteristically tire quickly, act ineffectually and give up too easily. Potential new antidepressants are correspondingly tested for their capacity to reverse the learned helplessness and behavioural despair induced by chronically "stressing" [torturing] non-humans in "animal models". Whereas exuberant hypomania is a signal of strength and resolve, albeit a risky signal, depressives can't pursue their projects with fanaticism, nor can they work indomitably to pursue what they believe to be morally right. For their capacity to anticipate reward is blunted. Life for depressed people too easily seems meaningless, absurd and pointless - the nihilistic polar opposite to a hyperdopaminergic sense of urgency and significance. For the mesocorticolimbic dopamine system mediates not just the salience and intensity of anticipated reward; it also determines strength of will. By contrast, the spirit of depressives is easily broken; and there's no natural remedy for weakness of will.
This grim diagnosis isn't a counsel of despair. On the contrary: well-designed genetic and pharmacological interventions should in principle allow weaker spirits to be invigorated and frailer personalities empowered. With better drugs and better genes, one's idealised persona can be made flesh. We'll soon have the option of making ourselves stronger, better-motivated and more steely-minded in character than even the bravest palaeo-Darwinian primitive or Nietzschean ubermensch. It's an open question whether such strength of character will be egoistic or empathetic, cocaine-like or E-like, or something different altogether. Yet with the right gene-and-drug combos, we can be superheroes, even if the need for heroism may shortly pass. In the meantime, innovative pharmacotherapy and/or genetic medicine will be vital if the weak-mindedness and weak willpower blighting so many lives today is to be overcome.
Weak-mindedness takes many forms. One effect of administering MDMA is the way it eliminates jealousy. Even anti-abolitionists, normally so eager to hymn the character-building virtues of suffering stoically borne, rarely find many positive words to say about the ennobling attributes of the green-eyed monster. Jealousy is a persistently nasty, vicious, and pervasive feature of Darwinian human social relationships. It's also about as voluntary as sneezing; and far harder to cure. Like MDMA, SSRIs tend to diminish jealousy. SSRIs also act more sustainably than short-acting clubdrugs. But SSRIs also tend to diminish the intensity of being in love. On MDMA, by contrast, people of either sex can and frequently do spontaneously embrace and caress each other - complete strangers as well as intimate friends. On MDMA, everyone naturally tends to love each other, almost as if we were clones rather than genetic rivals.
Such behavioural effects present a bizarre and perhaps disturbing spectacle to the E-less Darwinian outsider. Yet the lessons to be drawn from the use of today's crude hugdrugs and lovedrugs extend far wider than the recipe for a good weekend out clubbing. One way to put the world to rights invokes the tired nostrums of socio-economic and political reform. Such social engineering hasn't proven effective at curbing the frightfulness of life to date. Pursued in a biological vacuum, so to speak, any kind of environmental approach to building a world without cruelty, fear and pain is bound to fail. The other, biologically based strategy for saving the world will involve treating our, say, congenital androgenic, serotonergic, opioidergic, dopaminergic, PEA and endocannabinoid dysfunction via gene-therapy and rationally designed pharmaceuticals. Critically, it entails choosing kinder genotypes for our offspring. This option doesn't amount to a very soul-stirring prospect. Like our notions of psychoactive drugs, the concept of "eugenics" is horribly tainted. The word itself, originally a coinage of Sir Francis Galton (1822-1911), is indelibly tarred with the pseudoscientific quackery of the Third Reich - though it's worth recalling that Nazi "race-hygienists" didn't use happiness as their touchstone of genetic excellence. Yet the lethal dangers posed by the genetic status quo coupled with advanced military technology are far greater than the risks of a genetic reform program predicated on the goal of world-wide personal happiness. Warnings from history aside, unless the Darwinian masculine identities of our evolutionary past are superseded, then jealousy, conflict and warfare will go on for ever (or kill us off); and the prophets of doom will be right.
Alas Ecstasy itself is something of a false prophet. MDMA-induced love is no more everlasting than its older and fitness-enhancing counterpart. Two days after taking the magic lovepill(s), the drug-catalysed outpouring of affection has subsided. "Natural" love sometimes lasts longer; but Darwinian love is still ephemeral, eventually killed off by receptor desensitisation and down-regulation no less effectively than E-induced love is ended by serotonin depletion. For the fickleness of Darwinian affection has hitherto been genetically adaptive. It's an adaptation that remains a shabby substitute for genetically-underwritten true love. Only by subverting some exceedingly cruel feedback-inhibition mechanisms can the depth and range of our affection for each other be enriched and sustained. As it is, most Darwinian social life is soulless and loveless. But our genes do allow their vehicles to fall in and out of love with a small percentage of prospective mates in ways that tend to serve our reproductive success. In a largely anonymous mass-society, love and affection are in even shorter supply than among tribal hominids in African prehistory. Where love does sporadically flicker or flare up among us, its expression is tightly regulated. E-less love is rarely all-embracing: such Darwinian love tends to be jealous, possessive and exclusive. The law and social sanction impose penalties for loving too much or too little, loving the wrong person at the wrong age or the wrong gender. "He who is rational about love is incapable of it"; but this isn't true in the eyes of the law or of our peers.
At MDMA-driven raves, by contrast, women can feel safe in public, gay people feel truly at ease, and sexually straight or bisexual clubbers can express love and affection for each other free from overt or internalised homophobia. Taboos on touching and the whole gamut of tactile experience are relaxed. The body no longer feels like a prison for the soul but an extension of it. The classic dopaminergic psychostimulants like cocaine promote a hard-edged, don't-touch-me egoism. MDMA promotes intimacy, warmth, and an empathetic sense of other humans beings as fellow subjects rather than objects.
Of course, after a weekend of being "loved-up", mood-congruent post-E "reality" soon sets in. Did one really let slip those gushing effusions to strangers one barely knew? Did one really hug that hateful brute of a rival for the affections of one's heart's desire? Viewed from [state-dependent] "reality" again a few days later, being nice to everyone, truly loving oneself, and feeling (and being) wonderful all seem faintly embarrassing, perhaps even a chemically-fuelled madness. "It was the just the E talking". One may recall from English literature the effect of taking soma, the "ideal pleasure drug" featured in Aldous Huxley's uncannily prescient Brave New World (1932). After John the Savage threatens to disrupt their soma supply, the angry low-caste Deltas riot. They are promptly pacified by the riot police with soma-gas, and the rioters end up hugging each other:
"Two minutes later the Voice and the soma vapour had produced their effect. In tears, the Deltas were kissing and hugging one another - half a dozen twins at a time in a comprehensive embrace. Even Helmholtz and the Savage were almost crying. A fresh supply of pill-boxes was brought in from the Bursary; a new distribution was hastily made and, to the sound of the Voice's richly affectionate, baritone valedictions, the twins dispersed, blubbering as though their hearts would break. "Good-bye, my dearest, dearest friends, Ford keep you! Good-bye, my dearest, dearest friends, Ford keep you. Good-bye my dearest, dearest..."Too far-fetched? In 1998, a former South African government scientist told a hearing of the Truth Commission that the minority Apartheid government had planned to use MDMA on rioters. Desperate to retain their faltering grip on power, the embattled regime apparently ordered its chemists to make one tonne of Ecstasy for riot-control. Thus the Calgary Herald (10 June 1998) reports:
"Dr. John Koekemoer, former head of chemical and biological weapons research, at the secret Delta G facility, said he disapproved, "I did not believe Ecstasy was a good incapacitant and I told my superiors that", he told the commission, which is investigating human rights abuses during the apartheid era. "Ecstasy enhances interpersonal relationships. I told them I did not want to kiss my enemy."The scary notion of kissing one's enemies, perhaps half-recalled cameos from Huxley's satirical fiction - and the reality of strangers of either sex at raves hugging each other on E and telling each other how wonderful they are - contribute to the perception that E-like states of blissful empathy are inauthentic, shallow or false. How can the MDMA experience have true emotional depth if the cosmic hug-bunny of the dance-floor reverts back at the office next week to his old Darwinian mindset - and the (anti-)social vices it spawns? A corrosive cynicism easily sets in. For that's the nature of social reality, an emotionally frazzled post-Ecstatic may reflect, not the magical interlude of Peace, Love and Understanding and Respect.
Sadly, in today's world, this may be so. The depressive realism of the serotonin-depleted and jaded cynicism of the chronically world-weary are often justified. Yet our descendants may recognize that we are the sociopathic emotional primitives in the grip of an affective psychosis. Jealousy, envy, resentment, ridicule, hate, anger, disgust, spite, contempt, schadenfreude and a whole gamut of nameless but mean-spirited states we undergo each day are a toxic legacy of our Darwinian past. More commonly, perhaps, our genetic make-up ensures we simply feel indifference to the plight of all but a handful of significant others in our lives. Right now, for instance, one knows dimly at some level that there is frightful and preventable suffering in the world. Yet most of us feel no overpowering moral urgency to do anything about it. Idealists might vaguely entertain the second-order desire to care more deeply and give, say, a larger proportion of one's money to Third World charities dedicated to those who need the resources more urgently than we do. Yet the biological roots to sustain "saintly" self-sacrifice just aren't there in most of us. In contrast, taking MDMA can give rise to a prodigious sense of compassion in even the otherwise morally inert. Regrettably, such compassion is usually ineffectual; it's too short-lived to do much good. If and when we understand the neurochemical basis of empathy, however, then sustaining the molecular substrates of empathetic love can turn boundless compassion into an automatic reaction to distress, not a sign of drug-induced psychiatric disorder. Intervention can go further. If we decode and opt to amplify the molecular machinery of volition too, then such heightened compassion can be translated into effective action.
Fortunately, compassion if not empathy for others may ultimately be redundant. In the long run, if biotechnology can be used to eradicate suffering from the living world, then a shared celebration of life, not sympathy for the misfortunes of others, may come to seem as natural as breathing. Yet right now too many people walk the Earth who have no cause to celebrate anything. Therapeutic agents designed to deepen empathy and sustainably awaken our compassion are a priority. The functional prototype of what's needed exists today in the form of a fast-acting hugdrug; but MDMA itself is not the recipe for perpetual sainthood.
The design of richer functional analogues of MDMA entails more than finding medicines to make us sweeter-natured. Improving human nature is perhaps ethically all-important, but MDMA is also an entactogen - a more elusive concept than that of an empathogen. MDMA offers "insight without fear" (Dr Shulgin). The nature of entactogenesis is far harder to fathom, let alone communicate, than the nature of empathy. The word for such states comes close to being a primitive term, its sense semantically inaccessible to the MDMA-naïve. The clarity of MDMA-mediated self-insight is perhaps a form of what Dr Charles Tart calls "state-specific knowledge". E-less cynics may be sceptical. Just what's the propositional content of this so-called "insight"? Couldn't it be delusive? ["It's not hard to hear voices. It's knowing whether they tell you the truth."] But on pure MDMA, the subject can inwardly access the kind of person s/he wants to be; "the ideal me". Whether this idealised self-identity is created or discovered may be philosophically debatable. But the deeply-felt sense of authenticity and emotional self-honesty of the MDMA experience is an unexpected delight. One just won't ever get to read about its nature in the peer-reviewed Journal of Introspective Studies.
In Western culture, a capacity for reflective self-insight is not highly prized. Introspective genius and a talent for meditation aren't respected in either academia or business. Nothing in our education system is geared toward making young people feel that introspective self-analysis, enhanced self-awareness or personal growth matters in the slightest. How can they be tested, graded and quantified? What's their market value? Anyone in Western society with a tendency to quiet contemplation is likely to be stigmatised as lazy, feckless and unenterprising - unlike the sound and fury of the lionised Man Of Action, and his larger-than-life ego on whose life-energies lesser mortals may feed. In similar manner, our (limited) vision of future civilisations tends to focus on their technological marvels - and the supposed Darwinian dominance-battles of their science-fictional inhabitants - rather than on odysseys into the inner depths of their souls. Yet the design of long-acting entactogens - and their neurological analogues - should allow introspective depth and a capacity for higher-order self-reflection to be fabulously enriched as well. Tomorrow's counterparts of today's bunch of furtive adolescent introspectionists won't have to shuffle around faint little tickles of thought. Drugs to enrich self-insight and heighten self-reflection may eventually become commonplace. They may be distributed as freely as aspirin if not smarties; and prove safer in excess than either.
This prospect is some way off. Full-blooded pharmacological and genetic emancipation is still decades away. Even so, we are poised to acquire a literally life-transforming technology - a toolkit for enlightenment powerful enough to implement Heaven-On-Earth and beyond - yet we balk at the sorts of public health policy decision needed to accelerate the transition. An enriched conception of mental health is blocked by entrenched elites who've never sampled what they outlaw - whether designer genes or utopian pharmacology. In the jaundiced eyes of (most of) the older generation, Ecstasy and rave-culture are an aberration, not a portent. "Peace, Love, Understanding and Respect" sounds like a hollow slogan. Today, in the wider world, the words can't be anything else. Ecstasy itself is too short-acting, unsustainable and neurotoxic at high doses to form part of anyone's global health plan. But a permanent distillation of the MDMA magic, if feasible, offers an extraordinary if unorthodox vision of one post-Darwinian paradise to come.
Beyond MDMA : mental superhealth?
Moore's Law in computing is named after semiconductor engineer and Intel co-founder Gordon Moore. It states that processing power in computers doubles every eighteen months or so. Moore's Law has roughly held good since 1965 when it was first propounded. It's a rule-of-thumb about how many transistors we can cram onto successive generations of chip rather than a fundamental truth about Nature. Yet the trend it captures seems set to continue, at least until chip designers run up against the physical constraints of the nanoscale later next decade, or perhaps until quantum computers allow calculations orders of magnitude more powerful than today's toys.Unfortunately, the dizzying rate of technical progress that Moore's law quantifies hasn't been matched by an analogous law of progress for generations of human mental health. On average, we are probably no happier than our malaise-ridden hominid ancestors. We aren't noticeably fonder of each other. By way of consolation, we can take refuge in the pre-scientific notion that happiness is unquantifiable. Yet if such quasi-objective indices of mental health as suicide rates are anything to go by, then we would probably be psychologically better off as hunter-gatherers. Over 800,000 people in the world took their own lives last year. The World Health Organisation (WHO) estimated that this figure will rise to around 1.5 million by the year 2020. Here in the UK, suicide is the most common cause of death for men under 35 years old. Globally, several hundred million people are clinically or "sub-clinically" depressed; and a spectrum of chronic anxiety disorders afflicts further hundreds of millions more. Even as we progressively conquer physical disease as conventionally defined, the toll of psychological distress is still rising. Admittedly, "mental illness" and "mental health" are value-laden, ideologically contested terms. Even the new scientific discipline of biological psychiatry is inescapably culture-bound. Yet "Progress" that doesn't leave us emotionally better off would seem something of a misnomer.
Not merely has there been no discernible growth in average mental health to match the tempo of scientific advance, technophobes claim there never will be such a mental health revolution. As long as we rely on the same legacy wetware to animate our lives, the neo-Luddites and religious fundamentalists may even be right. Our levels of well-being - and ill-being - compute fitness functions that served the inclusive fitness of our DNA in our ancestral environment in Africa. Our genes didn't design us with the emotional welfare of their throwaway vehicles in mind. So the genetically adaptive hedonic treadmill - for many of us better named the dolorous treadmill - ensures that average levels of well-being/ill-being of Darwinian life remain stagnant. Six months after winning the national lottery or becoming quadriplegic in a catastrophic accident, the winner/victim statistically reverts to his or her average level of ill-being/well-being before the win/trauma. Hence such affirmations as Rajinder Johar's "The Joy of Quadriplegia". Illustrating the hedonic treadmill at its most extreme, "locked-in syndrome" leaves its victims paralysed. The subject is fully conscious but unable to move any extremities, talk, or make horizontal eye movements. Yet in the words of James Hall, longest surviving (2002) American victim of a midbrain pontine stroke: "In some ways, my stroke was a blessing....Since my stroke, I've published books, articles, poems. I'm busier and happier than I've ever been." Completely paralysed, Mr Hall communicates by focusing on particular letters that his computer picks up from his limited eye-motions.
Such triumph-of-the-human-spirit stories are comforting, up to a point. The downside of the emotional homeostasis they reflect is that millions of temperamentally depressive and dysthymic people would feel gloomy in the Garden of Eden. Again, this hypothesis isn't easy to test rigorously. The more dramatic manifestations of emotional homeostasis at work are hard to investigate ethically in well-controlled prospective studies. Anecdotes and impressions aren't science. Yet the cumulative evidence for a genetically constrained "set-point" in our pleasure-pain axis is compelling. The dismally low dial-setting doesn't bode well for any utopian project based around mere social reform.
Fortunately there is no reason, in principle, why an analogue of Moore's law can't be implemented in successive generations of the reward circuitry of organic life-forms. The affective, aesthetic, intellectual, interpersonal (and spiritual?) well-being of neurochemical robots like us can be genetically pre-coded. If rationally redesigned, our enlightened successors may view today's "natural" rewards as poor surrogates for genetically underwritten happiness. When the mechanisms underlying bliss and its gradients are understood, the molecular machinery of the sublime can be modulated - and amplified indefinitely. Within a few decades at most, we will be scientifically enlightened enough to redesign the neurochemical pathways of emotion. Meanwhile our pleasure centres are too small for us to flourish; and their functional architecture is inefficient. They needn't be either: our normal homeostatic "set-point" of well-being can be genetically ratcheted up to a far higher plane; and archaic Darwinian notions of mental "illness" and "wellness" consigned to oblivion. Gradients of indescribable happiness can potentially animate our lives no less powerfully than gradients of ill-being. Until this fabulous era dawns, then - to borrow the words of Oscar Wilde - "we are all in the gutter, but some of us are looking at the stars".
Critically, such gradients of celestial bliss can also be lucid, serene, entactogenic and empathetic - i.e. MDMA-like and better, not manic or vulgarly hedonistic. The godlike powers of tomorrow's biotechnologists will allow the neurological substrates of empathy and self-insight to be permanently up-regulated. Aesthetically, the mundane ugliness of life in the present epoch can be replaced by gradations of hitherto unimaginable beauty. Potentially again, an E-like magic can imbue the texture of normal waking consciousness. If we so wish, our emotional palette can be genetically enriched, mixed and then pharmacologically refined in ways that transcend the crude primary colours of our Darwinian past.
Counter-intuitively, yet indispensably for the long-term evolutionary stability of a ecstatic society of redesigned post-humans, allelic combinations that promote blissful empathy can also potentially be fitness-enhancing - in the technical Darwinian as well as in the popular sense of "fitness". The dawning reproductive era of "designer-babies" promises to be empowering because the capacity for parental love and nurture can be genetically and pharmacologically enhanced, not just levels of personal happiness, health and superintelligence. The age-old scourge of child-neglect (and worse) can be relegated to evolutionary history. Very speculatively, our future offspring may not merely be more loved by their caregivers, but much more "loveable" too. For if given the [genetic] freedom to choose, then parents-to-be may understandably want their offspring to be loving as well as smart and happy.
The prospect of unleashing such parental freedom is disturbing to most of us. Why not leave babymaking, as before, either to the mysterious workings of Providence or the blind shufflings of selfish DNA? Yet now we're imminently free to choose, there is nothing self-evidently morally admirable about playing genetic Russian-roulette with the lifeforms we create. Many of the nastier behaviours and modes of consciousness that so often proved fitness-enhancing in the ancestral environment will cease to be adaptive if the alleles that promote them tend to be shunned by prospective parents intent on creating the children of their dreams. The "nastier" alleles may well get out-competed. Selection pressure will tend to favour a very different range of heritable adaptive traits once evolution is no longer "blind" i.e. when genotypes are parentally chosen or designed in anticipation of their likely effects on a child's behavioural phenotype. If we want to, we can systematically redesign ourselves and choose the traits of our offspring. The details, for sure, are sketchy. Reproductive science and genetic engineering are in their infancy. But Homo sapiens is poised to bootstrap its way out of the cruel Darwinian abyss.
Inevitably, talk of treating humans like organic robots, and then mooting a baseline of mental health orders of magnitude richer than the Darwinian mind can contemplate, sounds fantastical today. In the context of our traditional conceptual framework, the idea of an analogue of Moore's law for successive generations of human mental health evokes thoughts of cloud-cuckoo-land, not a global health-plan. Set against the daily messiness of our ecstasy-impoverished lives, the prospect of using biotechnology to abolish suffering, and a post-Darwinian transition to paradise-engineering, strikes most of us as fanciful, its liberatory potential just a mirage. At best, such heady words fall lifelessly off the page or screen. Yet a major discontinuity - a momentous evolutionary transition in the development of life on earth - is imminent as the biotechnology revolution unfolds. The advent of genomic medicine is set to challenge the old Darwinian regime of natural selection and the emotionally crippled minds it spawned.
In the long run, genomic medicine can underwrite mental and physical superhealth for everyone. For in principle, lifelong well-being can be genetically hardwired from conception. In the short run, better-designed research tools and therapeutic agents can probe, and then repair, our damaged minds. As chemical stopgaps go, MDMA is a magical revelation. It's perhaps the best aid to insight-oriented psychotherapy ever synthesized. Tragically, when MDMA is used to excess the outcome can be harmful, not healing. So as a weekend club drug, MDMA is seriously flawed. Today, of course, empathogens and entactogens are outlawed for any purpose. The altered states of consciousness they induce are criminalised. People who take such agents are stigmatised as "drug abusers". Yet some MDMA users feel, rightly or wrongly, they've been granted a tantalising glimpse of what true mental health may be like in centuries to come; and an insight into what the rest of us are missing.
David Pearce
(last updated 2024)
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2023 Update.
Safe, sustainable analogues of MDMA do not yet exist. The prospect of gene therapy to enable existing human and nonhuman animals to enjoy perpetual MDMA-like consciousness is still decades away. Likewise, routine access of all prospective parents to preimplantation genetic screening, counselling and gene-editing to enable innate MDMA-like mental health as a default condition of everyday life can seem like science-fiction in the wake of the He Jiankui affair and the public backlash against "designer babies". Reflex invocation of the "e" word still retards progress towards genome reform and a reproductive revolution.
However, three encouraging developments are worth noting.
First, MAPS' Phase 3 clinical trial of MDMA-assisted therapy for PTSD, published on May 10, 2021, in Nature Medicine, showed statistically significant improvement. In 2017, the FDA granted Breakthrough Therapy designation for MDMA-Assisted therapy for PTSD (cf. MDMA-assisted Psychotherapy (Wikipedia)). The positive MAPS trial augurs well for FDA approval of MDMA-assisted therapy in 2024. The media routinely describe MDMA as a "psychedelic"; but the distinction between psychedelics and entactogen-empathogens is worth preserving. Putative "psychedelic therapy" for dark, Darwinian minds may be too dangerous and unpredictable. MDMA is different.
Second, PharmAla Biotech's MDXX drug discovery program of MDMA analogues delivered its lead drug candidate,
Third, a revolution in AI heralds a passable imitation of artificial general intelligence. GPT-4 is a gamechanger. Digital zombies can now write more intelligently about consciousness and MDMA than the vast majority of humans. For example, see ChatGPT-4 on MDMA. In collaboration with human investigators, GPT-4 and its cousins can play a role in psychoactive drug discovery and novel MDMA-analogues in a recursive cycle of improvement. To be clear, classical Turing machines and connectionist systems are idiots savants whose insentience is architecturally hardwired. "Digital mind" is an oxymoron. Phenomenal binding into mind is classically impossible. So classical computers are not going to "wake up" and become psychonauts - i.e. phenomenally-bound subjects of experience like humans who explore myriad state-spaces of consciousness. In consequence, full-spectrum superintelligence - supersentience, so to speak - will most likely retain a neuronal core. But AI plus psychonautic research promise an awesome future for sentience in the cosmos.
2024 Update.
In June 2024, a study published in the Journal of Neurochemistry identifies three new variants of MDMA as promising candidates for safer use: ODMA, TDMA and SeDMA. The three drugs have been developed with a view to retaining the extraordinary positive effects of taking MDMA while reducing adverse after-effects. The authors write: “Our findings suggest that these new MDMA bioisosteres might constitute appealing therapeutic alternatives to MDMA, sparing the primary pharmacological activity at hSERT, hDAT, and hNET, but displaying a reduced activity at 5-HT2A/2B/2C receptors and alternative hepatic metabolism. Whether these MDMA bioisosteres may pose lower risk alternatives to the clinically re-emerging MDMA warrants further studies."
Also in June 2024, a U.S. Food and Drug Administration advisory committee voted that evidence is lacking that MDMA-assisted therapy is effective for treating post-traumatic stress disorder (PTSD). The advisory committee reported that the benefits of MDMA-assisted therapy don’t outweigh the risks to patients. Panellists voiced various concerns with the data. Issues ranged from study design; uncertainty whether MDMA-assisted therapy offers long-lasting benefits; and the potential risk of heart problems and abuse. The sponsor of the MDMA treatment, Lykos Therapeutics, formerly MAPS, conducted two clinical trials showing that patients treated with MDMA experienced a significant improvement in their PTSD symptoms relative to subjects who received only a placebo. Unfortunately, the consciousness-altering properties of MDMA also vastly complicate the double-blind, placebo-controlled gold-standard for clinical trials. An FDA official, Tiffany R. Farchione, told the panel that although the agency had asked Lykos to report impacts associated with abuse, Lykos did not note effects such as “euphoria” or “elated mood.”
On August 9th, the FDA accepted the advisory committee's recommendation and declined to approve MDMA-assisted therapy for PTSD. In its letter of rejection, the FDA asked the drugmaker Lykos Therapeutics further to study the safety and efficacy of the proposed treatment. The decision was widely reckoned a setback for the nascent field of psychedelic medicine. But classifying MDMA as a psychedelic in the first instance is problematic. Not least, psychedelics don't tend to promote a heightened sense of authenticity: this-is-the-real-me. MDMA is in a class of its own.
Research on safe and sustainable MDMA analogues continues. See ODMA, TDMA, SeDMA (Wikipedia). But the vision of loved-up life and civilization sketched in Utopian Pharmacology (2002, 2024) is currently a distant dream.