However, potent brains are not strengthened by milk, but by alkaloids. An organ of such small size and great vulnerability, which not only approached the pyramids and gamma-rays, lions and icebergs, but created and invented them, cannot be watered like a forget-me-not, it will discover its own supplies. […] The brain is the mutative, revolutionary organ par excellence. Its nature was always form, not content; its means expansion, its needs -- stimuli.
Gottfried Benn, Provoziertes Leben [1941]

Physiology, medicine and pharmacology in the classical world, especially at the zenith of the Roman Empire, but indeed throughout the Dark Ages, until the advent of a science of medicine, were informed by the concept of the bodily humours, or cardinal humours; principally four, each with its corresponding element or fundamental physical substance, underlying all matter. Although generally attributed to Hippocrates of Cos, like the famous Hippocratic Oath, the philosophy and life of this great pioneer, who lived in the fifth century B.C., is known indirectly, through the writings of his intellectual progeny, especially Galen of Pergamum, who codified the cardinal humours, and their corresponding elements, as: sanguis/blood [air]; phlegm [water]; choler [fire] and melancholy [earth]; the last two sometimes known as yellow bile and black bile. According to this system, which was to dominate western medicine for two millennia, health entailed the maintenance of a balance between these contrasting elementary principles; disease consisted in some pathological imbalance, and healing plants were characterized according to their predominance of one or another of these elements/humours, which they might reinforce or supplement in the patient. The humours and elements were dichotomized as hot-cold and moist-dry, as follows: blood/air was hot and moist; phlegm/water, cold and moist; choler/fire, hot and dry; melancholy/earth, cold and dry. This system is generally known as Galenism or as Galenic[al], although based on the four so-called Hippocratic Humours.81

Of particular interest in this scheme is its subdivision of human beings into four basic physical subtypes, again according to purported constitutional predominance of one or another cardinal humour. These four types, and their attendant humours, are: sanguine [sanguis]; phlegmatic [phlegm]; choleric [choler] and melancholic [melancholy]. The sanguine person, of ruddy complexion, was said to be courageous, hopeful, amorous; the phlegmatic, of watery complexion, indolent, apathetic, calm; the choleric being of bilious aspect, irascible, passionate, volatile; and the melancholic of dark countenance, sullen, gloomy and depressed. Our word complexion, which for us has purely a physically descriptive, superficial meaning, in fact refers to temperament, to the combination or 'complexing' of the four humours within a given body to yield a certain characteristic bodily type and corresponding personality. We still conserve this original sense when we speak of someone as being 'good-humored' or 'ill-humored,' that is, as of dulcent or iracundious temperament; and people might still commonly be characterized as being melancholic, or much less commonly called sanguine; while describing a phlegmatic or choleric person is today to hazard incomprehension.82

This Galenical system of cardinal humours, coupled with Pedanius Dioscorides' [circa 1st century A.D.] famous Materia Medica listing some 700 herbs, reigned supreme throughout Europe and the Arab world, where it was championed by Avicenna or Abu 'Ali al-Husayn ibn-Sina [980-1037], until Paracelsus [vide supra, Note 4] publicly immolated hallowed medical treatises by both Galen and Avicenna in Basel in 1527. Although ostracized by Basel's orthodox medical authorities for this iconoclastic conflagration, Paracelsus effectively publicized his credo, that medicine ought to be founded on scientific experimentation, not unverified ancient dogmas, handed down like sacred scriptures and every bit as sacrosanct. This was the era of the Reformation, and Paracelsus was every inch the herald of the dawning Renaissance. Two years after his death at age 48 in 1541, arrived the point of no return for the scientific revolution he had presaged -- 1543, the year of the first translation of Archimedes' [circa B.C. 287-211] mathematical and physical treatises; and publication of Andreas Vesalius' [1514-1564] anatomical drawings, De Humani Corporis Fabrica; plus Nicolaus Copernicus' [1473-1543] 'revolutionary' De Revolutionibus Orbium Cœlestium. Although reviled by some as the prototypical charlatan and medical mountebank, Paracelsus is rightly revered as a father of scientific medicine; a heroic heresiarch who dared challenge hidebound hewing to a hagiarchy of healing!83

Nevertheless, Paracelsus foisted his own dogma onto the healing arts, promoting the 'Doctrine of Signatures,' which held that "the outward shapes and qualities of things" -- of healing herbs-betrayed "their inward virtues, which God hath put in them for the use of man." This therapeutic teleology, predicated on the assumption that humankind was the crown of creation, the remainder of which existed for its benefit, was further elaborated by Giovanni Battista Della Porta [1538-1615], taken from the ridiculous to the sublime in combinations with astrology, and continues to dog phytomedicine in our own day. So now the superficial anatomy of plants, as opposed to their supposititious endowments of cardinal humours, was of crucial importance! Like the theory of the Hippocratic Humours, the Doctrine of Signatures revolved around a superficial fixation on gross anatomy, whether of the patient or the putative panacea, and there have been repeated iterations of such in the long history of healing, which yet remains as much art as science. The rather grandiosely-named 'mental science' of phrenology, invented early in the 19th century, was based on minute examinations and measurements of the human cranium, and in the 20th century the classical somatology or anatomy of Vesalius gave way to 'somatotyping,' classification of human bodies [and temperaments] into a system having three primary 'somatotypes,' according to a presumed predominance of fetal tissue types -- the 'ectomorphic,' 'endomorphic' and 'mesomorphic' somatotypes.

Our modern universe is considerably more complex than that of the classical philosophers, built of merely four elements. We now recognize 90 natural elements in the universe: the philosophers' air being composed of several [chiefly nitrogen and oxygen]; water of two [oxygen and hydrogen]; earth of the bulk of the elements; whereas for us fire is not an element or substance per se, but the radiant energy of oxidation of gases. Living bodies like ours, and kindred bodies of plants, are made up of approximately 25 elements -- mainly carbon, oxygen, nitrogen and hydrogen -- which participate in the metabolic reactions of biochemistry, and they may sequester other elements such as lead, mercury and cadmium, that play no active roles in the chemistry of life. While the 'natural philosophy' of the ancients seems naïve and simplistic in the light of our contemporary science, as this illuminates a far more detailed view of our brains and nervous systems, it increasingly lends verisimilitude to archaic conceptions of innate temperament and constitution, albeit divulging infinitely greater intricacies than allowed by the 'complexions' of but four cardinal humours. We can be certain, moreover, that there exist many more than four fundamental human 'behavioral phenotypes.'

At risk of stepping into the hornets' nest of the 'nature versus nurture' controversy, and repudiating from the outset any racial generalizations or eugenic conceptions extrapolable from this, I wish to examine the genetic aspects of human biochemical individuality, particularly neurochemical individuality, as such pertain to the pharmacology of inebriants. This will shed considerable light on broad diversity in tastes for inebriants, and show that our specious classifications of drugs as being 'good' or 'bad,' 'hard' or 'soft,' is quite as simplistic as that archaic universe built of four elements, or its classical pharmacology based on four cardinal humours. Indeed, we will discover that any inebriant, licit or illicit, orthodox or heterodox, 'hard' or 'soft,' could in fact be a 'smart drug' for somebody; while the converse also obtains.

It is evident to any sighted person that there are an infinitude of superficial anatomical variations in human faces and physiques, and surgeons are well aware that such external anatomical diversity has its counterparts in internal anatomy. Even medical science, however, is just beginning to appreciate human biochemical individuality and its manifestation as idiosyncrasy in pharmacological responses. Investigations of human idiosyncrasies with regard to nutritional requirements for eight essential amino acids show a 2-7-fold range, from minimal to maximal needs for any particular amino acid, when examining merely two to five dozen individuals. In a study involving only 19 human subjects, nearly a 5-fold range in calcium requirements was found! Animal experiments show similar broad variability in the requirements of individual animals for various vitamins. It is well-known that some people have 'lactase deficiency,' or some diminished ability to digest lactose or milk sugar, and the 'normal' human range of lactase, as well as of sucrase and maltase enzymes in intestinal mucosa, varied over a 10-20-fold range. In studies involving the pepsin [digestive enzyme] and hydrochloric acid levels in the stomachs of thousands of 'normal' individuals, a 100-200-fold range of variance was found!84

Not surprisingly, individual human beings also vary with regard to metabolism of drugs. In a simple study of 10 human volunteers, each of whom inhaled the vapor of a standard amount of cocaine freebase [thereby mimicking the 'smoking' of so-called 'crack' cocaine], there was a 5-fold variation in the peak plasma-concentrations of cocaine each person attained [that is, the maximum amount that could be detected in periodic analyses of the subjects' blood]. In parallel studies involving the smoking of marijuana, commensurate variation was found in peak plasma-levels of the active principle, thc. The famed opiate analgesic codeine [morphine methyl-ether; vide supra, Note 37], is metabolized by our bodies to morphine, which is what effects analgesia -- but in the United States, 5-10% of the Caucasian population is deficient in an hepatic enzyme which catalyzes this transformation, and for such individuals, codeine has only placebo analgesic properties.85 By the action of the enzyme ethanol dehydrogenase, our bodies metabolize ethanol or ethyl alcohol to acetaldehyde, and it is known that 50% of Asians and Native Americans have substantially lower levels of this enzyme than typical individuals of African or European descent, and so are more susceptible to the effects of alcohol. Of course, within any given racial group, there is likewise considerable variability in this trait, or alcohol [ethanol] sensitivity.86

There has even been speculation that there is a specific 'alcoholism gene,' or heritable genetic defect, which predisposes people to so-called 'alcoholism.' Although there appears to be a genetic component to susceptibility to alcohol habituation, it is unlikely a single-gene defect will account for this. Genetic linkage to drug effects and habituation is generally related to three phenomena: acute sensitivity to psychotropic properties; adaptation responses to chronic administration [tolerance and withdrawal syndrome]; and reward or pleasure attending psychotropic effects [or, conversely, aversion/dysphoria of such].87 Present understanding of neuropharmacology [vide supra, pages 22-25 and Notes 17-21 and 27] has led to conjecture that genetically-based variations in drug responses could derive singly or severally from perturbations in the following neurochemical factors: 1) levels of enzymes involved in the synthesis and breakdown of neurotransmitter compounds [hence, the levels of these neurotransmitters]; 2) the neurotransmitter receptor-proteins themselves [vide supra, Note 19]; 3) the transporters or 'reuptake pumps' for various neurotransmitters [vide supra, Note 29]; and 4) the ion-channels in the membranes of neurons which are directly or indirectly influenced by these neurotransmitters.88

There exist animal models for most of these neuropharmacological mechanisms. Observation of divergent drug responses in distinct inbred strains of laboratory animals led to selective breeding for these traits. In the case of drug sensitivity, here to ethanol, so-called long-sleep [ls] and short-sleep [ss] mice vary markedly in sensitivity to ethanol, as well as to other CNS depressants, such as benzodiazepines and general anæsthetics. Studies showed these strains differed in effect of ethanol on the GABA-A inhibitory receptor, owing to gene-based variation in one part of the protein structure of this receptor/ion-channel [vide supra, Note 88]. In ls mice, ethanol activated the ion-channel, but didn't in ss mice, mediating the greater sensitivity to the depressant properties of ethanol in the former. An inbred strain of mice, cxbk, is genetically deficient in m endopioid receptors in the brain, but not d receptors [vide supra, Note 19]. These mice were found to be insensitive to analgesic, locomotor- and respiratory-depressive effects of morphine [also to the analgesic effects of acupuncture, facilitated by endopioids], whose primary binding site is that m receptor. Nicotine sensitivity was shown to be a function of brain nicotine-binding-site density in 19 inbred strains of mice displaying broadly varying responses to that drug.89

With regard to neuroadaptation to chronic drug administration, in this case of ethanol, there are so-called withdrawal-seizure-prone [wsp] and -resistant [wsr] mice; the former an order of magnitude more sensitive to ethanol withdrawal syndrome [although bred for this trait, the wsp mice showed a parallel sensitivity with benzodiazepines and general anesthetics, even to the point of displaying withdrawal symptoms after a single dose!]. While this effect is poorly understood, one notable difference in brain adaptation to chronic ethanol administration consisted in the relatively much greater increase [so-called 'up-regulation'] of calcium ion-channels in the brains of wsp, as opposed to wsr mice; in which ethanol-habituated animals showed less of an increase in such channels compared to non-habituated peers.90

Less is known of those mechanisms behind genetic aspects of drug reward/aversion. Varying human tastes in inebriants are self-evident, as illustrated by a famous experiment in which some naïve human subjects found injection of heroin to be highly pleasurable [rewarding], while others found it to be quite nauseating [aversive]. Tests exposing animals to a choice between two drugs, or to the possibility of receiving a drug in response to some action, divulge considerable differences in preferences for the full gamut of human pleasure-drugs in genetically-distinct strains of laboratory mice and rats.91 While nobody would dispute the manifestly diverse and eclectic variation in human tastes for pleasure-drugs, and we have seen there exist animal models for a variety of subtle neurophysiological traits influencing the psychopharmacology of inebriants, what is the evidence for any human parallels?

Human pharmacogenetics per se remains little investigated, beyond premature attempts to attribute alcoholism to a single-gene defect, allegedly involving a dopamine receptor [drd2], or observations of racial variations with regard to enzymes crucial to metabolism of inebriants, like ethanol dehydrogenase and cytochrome p450iid6. However, there exist at least three well-documented examples of human genetic variations [so-called 'polymorphisms'] of neuropharmacological significance. It was recently reported that neuroticism and anxiety-related personality characteristics were associated with one of two variants in a human gene encoding the serotonine transporter [this is a membrane protein which serves to reabsorb the neurotransmitter serotonine from a synapse, in which it mediates transmission from one neuron to another, thus 'resetting' the signaling mechanism; vide supra, Note 29]. In a sample of 505 individuals, 57% had the 'long allele' [l] of the gene for the serotonine transporter; 43% a corresponding 'short allele' [s]. In the former case, these subjects had higher 'expression' [that is, more production of the protein product of the gene, the serotonine transporter], hence more serotonine transporters in their neurons, leading to roughly twice as much reuptake of serotonine from synapses as counterparts having the s-type gene. In comparison to their s-type cohorts, these individuals displayed significantly lower levels of neuroticism and anxiety, at least in part attributable to their more efficient clearance of serotonine from synapses. While this is not a pharmacogenetic effect in itself, this serotonine transporter is an important target of psychotropic 'anti-depression' and 'anti-anxiety' medications, like the famous Prozac® or fluoxetine [Merck Index 12: 4222], which is an SRI or 'serotonine reuptake inhibitor' -- that is, an inhibitor of this serotonine transporter.92

Our second human example involves the enzyme monoamine oxidase [MAO]. Unlike the serotonine transporter, MAO metabolizes neurotransmitters like serotonine within nerve endings [in this case degrading them], also helping to maintain the signaling 'switch.' A human behavioral phenotype was recently described, related to a defective gene for monoamine oxidase a [MAOA], in which a single mutation led to a structural change in the MAOA enzyme, completely destroying its activity, viz. in degrading serotonine and norepinephrine. Males in families carrying this gene had "complete MAOA deficiency" -- although their bodies could make this vital enzyme, the mutation rendered it non-functional. Moreover, this genetic defect was associated with "a recognizable behavioral phenotype," with "borderline mental retardation and abnormal behavior" including "aggression, arson, attempted rape, and exhibitionism." Subsequently, a line of transgenic mice was bred for a parallel MAOA deficiency, and the animals showed a ninefold increase in brain serotonine levels, while adults manifested "a distinct behavioral syndrome, including enhanced aggression in males." Once again, this is not directly a pharmacogenetic phenomenon, but MAO-inhibitors [MAOI] are an important category of psychotropic drugs used in treatment of depression and other mental disorders, and natural MAOI figure in psychopharmacology of the Amazonian amrta, ayahuasca [vide supra, Note 52].93

Our third human example involves a recently-reported, and as yet poorly-characterized, genetic polymorphism related to a heritable neurological defect associated with schizophrenia. In this case, a neurological disorder involving impaired ability to discriminate responses to auditory stimuli was mapped to human chromosome 15, and appears to involve the gene for a so-called 'cholinergic' [for the neurotransmitter acetylcholine (Merck Index 12: 88)] nicotine or 'nicotinic' neuroreceptor in human brains. Evidently nicotine from tobacco affords temporary compensation for the sequelae of this receptor defect, which is thought to account for the extremes of tobacco habituation commonly observed in schizophrenics.94

There are other genetic candidates for human behavioral phenotypes, involving neuroreceptors both for serotonine and dopamine. Variants encompassing also the enzymes for synthesis of neurotransmitters and other membrane proteins like ion-channels will doubtless be identified. In the case of peptide neurochemicals, like the endopioids [vide supra, Note 17], there is the possibility of genetic mutations affecting the amino-acid sequence of the neurotransmitters themselves, and hence their activity. Attempts genetically to map those traits in rodent strains, which result in differential responses to inebriants, have implicated the full gamut of genes for the various receptor sites, ion-channels, peptide neurotransmitters, neurotransmitter transporters, and enzymes -- both for neurotransmitter synthesis and degradation.95

I have been at such pains to elucidate thus fully neurochemical minutiae, courting grave risk, moreover, of exhausting the patience of my long-suffering readers, so to underscore the devilish complexity of neurophysiology, and the near-limitless possibilities for subtle constitutional differences -- idiosyncrasies -- impinging upon psychopharmacology. Forsooth, should one [wo]man's meat be another [wo]man's poison; verily, this [wo]man's kick must surely be some other [wo]man's katzenjammer… that sedulously smart drug for Sally, perforce some dilatorily dumb drug for Dan… pharmacologically robbing Peter of productivity… to pay Paul in prodigality!

Perhaps it is germane to note that, pursuant to our classical theory of the cardinal humours, at least one humour -- phlegm -- was believed to originate in the brain, and neurotransmitters were at one time denominated neurohumours. The manifest oversimplification of merely four humours and four corresponding temperaments [although as many as a dozen humours were postulated by Praxagoras of Cos a century after Hippocrates], obscures the fact that the ancients were fundamentally correct in their perceptions of innate human temperaments. We may no longer speak of persons as being phlegmatic [excepting in the sense of emunctory excrescence or efluvium!], but there may soon come a time when we recognize a 'hypoendopioid' temperament, or the 'hyperserotenoid' character; mayhap even a 'dysdopaminic-depressive disorder'!

Indeed, we can be certain that human beings will show at least as much genetic variability with regard to responses to inebriants, as do their rodent relatives. We've already seen that there exist human behavioral phenotypes associated with genetic 'polymorphisms' and mutations in genes for proteins key to basic neurochemistry. It is to be expected that in human beings, as in rodents, genetic variations affecting enzymes for synthesis and degradation of neurotransmitters and their receptor sites will also be found, along with genetic variations in allied neuronal membrane ion-channels and other cogs in the complex neurochemical machinery of thought and consciousness. Identifying and elucidating human genetic polymorphisms which lead to idiosyncratic responses to inebriants requires no scientific breakthroughs or new technology, simply continuing ongoing research into behavioral and molecular genetics of inbred rodent strains, with extrapolation to the human genome. Indeed, this task becomes progressively simpler, in proportion as the level of detail of human and laboratory-animal genetic maps inexorably increases as a result of the Human Genome Project and allied genomic research. Once genetic variations corresponding to specific drug- or drug-withdrawal-sensitivity traits are mapped to human chromosomes, their mutations characterized, it would likewise be a matter of application of existing technology, to design simple biomedical assays to identify these in routine medical screening procedures. Blood or other biomedical tests could easily be developed to detect these genetic polymorphisms directly, or in some cases indirectly, by quantifying appropriate enzymes or other peptide or non-peptide biochemicals.

To be sure, genetics is but one piece of the complex puzzle of human and other animal behavior. While I suspect genetic and other biomedical testing will prove to be the most fruitful approach to a phenotypology of inebriant idiosyncrasy, it is likely that straightforward psychological testing with extant psychometric tools will demonstrate its value as adjunct or complement to this. It has long been known that persons readily differentiated psychometrically as introverts or extroverts have predictably characteristic, varying responses to inebriants. Whereas extroverts are generally far more sensitive to the effects of sedatives like alcohol than are introverts; the converse obtains for stimulants like cocaine or the amphetamines -- introverts being as a rule more susceptible than extroverts to their inebriating caresses. It is even possible to use simple 'psychometric' [that is, behavioral] tests to predict the vulnerability of individual laboratory animals to particular inebriants, and psychometric tests in human beings have likewise been able to detect indirectly genetic variations affecting the metabolism of inebriants.96

There is mounting scientific evidence, which some regard to be conclusive, for a 'common reward pathway' or 'reward circuit' in our brains, which constitutes a fundamental substrate of drug dependence, irrespective of gross pharmacological differences between drugs [sedative, stimulating, etc.]. Since it was demonstrated in 1984 that the rewarding aspects of opiate inebriation were separable from physical-dependence phenomena, the artificial distinction between so-called 'physical' and 'psychological' addiction has disappeared, and current research focuses ever more on reward or 'positive reinforcement' as engine of drug habituation; as opposed to the 'negative reinforcement' model which previously held sway, and postulated that aversion -- avoidance of pain/dysphoria attendant on withdrawal of a drug causing physical dependence -- was the driving force. This 'paradigm shift' derived in part from the demonstration of 'pleasure centers' in the brain amenable to direct electrical stimulation, and to the recognition that stimulants like cocaine and nicotine -- classic positive reinforcers showing virtually no physical dependence/withdrawal phenomena -- were among the most 'addictive' or habituating of all drugs. As this new model came to the fore, and science provided much greater neuroanatomical, neurophysiological and neuropharmacological detail, research into the neurobiology of addiction concentrated ever more on the reward circuitry of the neurotransmitter dopamine, recently baptized "the master molecule of addiction."97

Dopamine [vide supra, Notes 29 and 87] is an important neurotransmitter in the 'mesolimbic system' of the brain, which is now thought to be a primary locus of the reward pathway. Dopaminergic neurons originating in the 'ventral tegmental' area of the midbrain, especially those connecting to the 'nucleus accumbens' in the basal forebrain area, are now believed to constitute a major substrate of this reward circuitry common to habituations to disparate drugs. We have seen that cocaine and amphetamines act by blocking the dopamine transporter, causing accumulation of dopamine in synapses [vide supra, Note 29]; opioids provoke an increased dopamine release in the nucleus accumbens by inhibiting gabaergic neurons which ordinarily inhibit connected dopaminergic neurons [vide supra, Note 88]; both ethanol and the cannabinoids can provoke increased dopamine levels in the nucleus accumbens; and nicotinic receptors on dopaminergic cells in the nucleus accumbens allow nicotine directly to stimulate these cells. In every case, dopamine figures in a 'common final pathway' of reward, and it is accordingly supposed that drug withdrawal is attended by the 'rebound depression' of this dopaminic reward system, whether such be accompanied by a physical withdrawal syndrome or not.98

We have also seen that a dopamine-receptor [the so-called drd2] gene polymorphism has been related to alcoholism, alleged to be an 'alcoholism gene' [vide supra, Note 87]. Similarly, this drd2 gene polymorphism has shown a "modest, significant association" with 'polysubstance abuse,' or the use of multiple inebriant drugs in addition to alcohol. In an analysis of three genetic variants of the drd2 receptor protein expressed in mammalian cells, it was found that two of these abnormal receptor proteins had a two-fold lower affinity for binding dopamine than did the 'wild type' receptor protein. By the same token, gene-based variations in the dopamine transporter protein [vide supra, Note 29] were shown to be related to a predisposition to drug-induced paranoia among white, but not black, cocaine users. To be sure, these studies remain preliminary and any conclusions are highly speculative, but given the importance of dopaminic neurons in the pharmacology of pleasure and in the substrate neural reward pathways, it stands to reason that genetic variations affecting dopamine receptors and the dopamine transporter itself could prove to be of significance in idiosyncrasy with regard to inebriant sensitivity and susceptibility.99

It is generally thought that the brain reward pathway is an archaic evolutionary feature of animals, subservient to basic survival-oriented behaviors such as seeking after food and sex. In contrast to gustatory or sexual pleasure/reward, however:

Drugs of abuse [sic] may actually be preferred over other natural reinforcers such as food and water in a free-choice situation, because drugs provide a more robust and long-lasting activation of this reward system. [M.T. Bardo et alii, 1996, page 24; italics mine]100

This astute observation is consistent with the fact that inebriation, as we saw in the first chapter, is embedded in our natural animal matrix of feeding and reproduction and must be taken into account in any comprehensive evolutionary theory. Inebriants provide a more robust reward even than food or perchance also sex; so it follows that drug-seeking behavior is potentially more rewarding than food- or mate-seeking behaviors; robust… yes, indeed -- before reading the above-quoted article, I had likewise characterized the natural pharmacoparadises as robust [vide supra, page 26]. Not only is there but a vague line demarcating foods from drugs -- which boundary blurs and fades the more closely we approach it -- but it happens their respective rewards and pleasures are one and the same; emanate, ebullient, from every epicurean ego; ecstatic efflux of Eros' efflorescent essence; are sybaritic cerebral siblings; that vibrant and vital, voluptuary vinculum between dreamy desire, destiny and deed; rugged requisite reaching for ravenous realization; robust, rubicund.

That being the case, what is pharmacophilia, the much-maligned 'drug-seeking behavior,' but basic biological business writ large, pursuit of the purest pleasure per se, a dancing dalliance with the distillate of desire, a courtship of crystalline craving? Pursuit of pleasure is as prominent a part of our biological heritage, as the pursuit of happiness is, of our political. Far from being pathological, it is natural and healthy that animals gravitate toward exogenous activators of hard-wired cerebral reward pathways -- whether such activators be other organisms eaten as food, eroticized as mates, or ingested as inebriants. After all, these reward circuits are the millenary matrix of motivation, existential engines of evolution, every animal's archaic animus.

Whereas the prevailing paradigm among neuroscientists is shifting, tending ever more to view inebriation as basic biological imperative, lending ever less verisimilitude to the police approach to drug dissidence as criminal behavior; that disastrous and decadent model of drug deviance is being replaced by an equally-flawed theory of pharmacological pathology. Leading authorities on habituation are given to such bald statements as… "addiction can be viewed as a mental disease," and "addiction is a disorder of the brain no different from other forms of mental illness." Never mind the semiotic confusion in this latter statement -- that a 'brain disorder' be not characterized in neurological terms but metaphorically, as 'mental' illness -- this is pharmacological Puritanism par excellence, and amounts to diagnosing virtually every human being as 'mentally ill'; adding the pathology of pleasure to the toxicomania of theism! For pharmacophilia transcends boundaries of race, religion, culture, historical era, even of species; is as close to universal as 'most any aspect of human behavior. Pleasure piously posited as sin is perverted enough… but pleasure as pathology -- the debilitating disease of desire itself -- boggles the mind! Indeed, in the United States, 9 of 10 adults are habitués of caffeine, more than half seek surcease from care in ethanolic ebriety; near one in three needs nicotine to nurse her through the day. While exaggerated attention is focused on illicit inebriants, only Cannabis can claim more than 1 in 20 Usan adults as votaries, with the remaining illicit inebriants being decidedly bit-players. At least the hypocrisy of artificially separating licit inebriants from their illicit counterparts is finally being overcome, and a recent article in Time [vide supra, Note 97] gave pride of place to alcohol, tobacco, Cannabis and heroin as emblematic of drug addictions, thus highlighting three of the four top drugs, in terms of numbers of habitués. Conspicuous by their absence were caffeine and cocaine, but the article made plain the close kinship among nicotine and other stimulants; even acknowledged the commonality between habituation to these infamous inebriants and to "gambling, chocolate and even sex."101

To be sure, much muddled thinking continues to cloud this controversial subject. A prominent medical expert on addictions estimated there were 30-40 million "chemically dependent individuals" in the United States, citing by name in the next paragraph "cocaine, heroin, tobacco and other drugs," and stressed that tobacco was added "to counter the perception that… addiction medicine only deals with illicit drugs" -- but Time's above-cited article estimated 61 million Usan nicotine habitués alone! Something so common, yea, all-but-universal as the pursuit of pleasure, basic to biology, can't be dismissed as dysfunction, nor can it be argued that drug-seeking behavior involves the 'abuse' of reward pathways designed for other pursuits, given our knowledge of zoöpharmacognosy. Our innate impetus to inebriation is part and parcel of survival-oriented biological drives -- feeding and reproduction -- and best viewed, as I have said, as another type of alimentation. On the other hand, I would not be understood as contending there cannot exist pathological expressions of intrinsic drives, whether violent and hurtful sexual perversions of the mating instinct, addictions to fasting and extreme and unhealthful feeding habits, or, of course, unhealthy fixations on inebriation. But the drive underlying such pathological manifestations is not itself pathological; we scarcely could exist absent food and sex, and pleasurable and healthful indulgence in inebriants no more betrays some medical problem than do drives to succeed in business or prevail at sport. As for me, I am an inveterate pharmacophile, but would have to acknowledge that the habituation which most rules my life, is my lifelong addiction to books -- reading them, writing them, even handling and smelling them! Some might rebel at this notion of 'book addiction,' but in fact one of the earliest uses of this word in English [in 1675], was "His own proper Industry and Addiction to Books," and a century passed before addiction was used in reference to drugs -- to tobacco, at first [vide: Oxford English Dictionary, page 26]. As I wrote 12 years ago, in a book about my chocolate addiction [vide supra, Note 21], which treated our provincial and prejudiced attitudes toward drug habituations with ludibrious levity:

We are all addict to one or another pursuit, the vast majority of us to one or another drug. [The Cacahuatl Eater, Chapter one, page 7]

In 1985 a Usan psychiatrist shook up the 'drug abuse' field, when he advanced what he called the 'self-medication hypothesis of addictive disorders,' proposing that heroin and cocaine addicts suffered "severe and significant psychopathology":

Rather than simply seeking escape, euphoria, or self-destruction, addicts are attempting to medicate themselves for a range of psychiatric problems and painful emotional states. [E.J. Khantzian, page 1263]102

Of course, this may be true in some cases, for instance among the 11 million problem habitués of alcohol in the United States. The great majority of inebriant users, however, like the 95 million controlled and moderate Usan ethanol imbibers, are better viewed as seeking euphoria or pleasure in inebriation, as they do via a vast range of other rewarding behaviors. Furthermore, for the roughly 10% who fall into the so-called 'abuser' or 'addict' or 'alcoholic' category, it will surely prove far more fruitful to examine their 'addictive disorders' in the context of biochemical individuality -- inebriant idiosyncrasy -- than disease. We accept unquestioningly variegated tastes in foods, even as we acknowledge some viands to be unhealthy in excess; even as we recognize that some people cannot control their alimentation, and come to grief as a result. Why should it be any different with inebriants, why should we look askant at others' tastes in inebriants? Just as our taste buds vary, so too our neuroreceptors. Beauty is in the eye of the beholder, and pleasure lies on the reward pathway of each individual -- pursuing pleasures in a manner particular, perchance even peculiar.

Neuroscientists would do well to abandon any notions of inebriation as pathology, to concentrate instead on identifying the full range of human genetic variations which impinge on basic neurophysiology and the metabolism of the various classes of inebriants. As mentioned above, it is within our capabilities to identify and map these 'polymorphisms,' and to develop routine biomedical tests to identify such in individual human beings. Although we are undeniably the product of our genes interfacing with their environment, and genotype is not absolute destiny, we already have hard evidence that gene-based biochemical individuality may to a considerable extent determine sensitivity to particular inebriants, as well as susceptibility to compulsive or uncontrolled use or habituation to these. Understanding the neurochemical bases for inebriant idiosyncrasy will at once lead to therapies for those problem users who need and wish them, and facilitate the prevention of destructive, unhealthful use. Awareness of constitutional debilities with respect to a given type of inebriant -- whether derived from some defective enzyme or receptor-site, transporter-protein or ion-channel-might deter one individual from pursuing pleasure where lies the pathway to pathologies; enable another to distinguish a potential palliative from a possible poison. The adventurous among us might assay the diverse inebriants on our bodies and nervous systems, and with diligence identify those which do not agree with us; 'though running betimes the risk of discovering a susceptibility to compulsive use of some given drug, when finding ourselves uncomfortably in its thrall!

It may be so, that some drug habitués become enthralled by a certain drug in an attempt to medicate painful emotional states; surely others hunger after a particular drug, pharmacologically to assuage some inborn metabolic deficiency, like hard use of nicotine by some schizophrenics. We have seen that absence of an enzyme involved in biosynthesis of morphine and metabolism of many drugs, a congenital defect which afflicts 5-10% of Caucasian North Americans, makes sufferers more sensitive to pain [vide supra, Note 85]. Like those heirs to many other conjectured congenital deficiencies in the endopioid system of endogenous analgesia, such individuals will likely prove to be more interested in ingesting opioids than less pain-sensitive peers. If there be individuals bearing constitutional overproduction of the anxiety-causing ligands of the benzodiazepine receptor [vide supra, Note 27], they could probably acquire a taste for the anxiolytic drugs like Valium,® and so on, for the various classes of inebriants we have examined. A 'reward deficiency syndrome' has even been hypothesized as correlate to drug habituations, some deficiency in the very dopaminic reward pathway! Perhaps the more drug-specific genetic polymorphisms ordain tastes for various types of inebriants, and only when combined with some defect in the reward pathway itself, might predispose to compulsive use of such compounds.

In all events, it certainly behooves us to hold fast to the baby while we discard her bath water, for it makes no more sense to conclude that impetus to inebriation implies infirmity, inasmuch as some people cannot control its expressions; than to regard alimentary appetite as a priori aberrant, insofar as some diners succumb to obesity or anorexia nervosa! Indulgence in inebriants, both ludible and sacred, is common to all human races and cultures and ages; and should we wish to speak of abnormal or aberrant behavior respecting pleasure-drugs, the rare abstemious teetotalers among us come first to mind, rather than any raucous revelers! Indeed, in the classical world, those who categorically rejected inebriation were dismissed as dysfunctional and antisocial, for refusing to 'relax the soul,' let down their masks, to reveal their true, inner selves. As Baudelaire put it bluntly [vide supra, page 17]:

A man who drinks nought but water guards some secret from his fellows. ["Du Vin et du Hachish," Part ii]

Here in México, there are social situations in which to refuse a proffered drink is to give grave offense, even invite violence. We must accept our impulses to inebriation as a given, and would do well to cultivate open-minded tolerance with regard to the tastes and habits of others. Although sufferers from uncontrolled drug habituations deserve our compassion rather than our scorn, our gratuitous condescension is unwarranted and unbecoming. If some cancer patient who must take opioids daily to bear excruciating pain merits our pity, why should we despise another person who perhaps takes opioids to overcome habitual hypersensitivity to pain? If the unduly anxious businesswoman or househusband finds sanctioned relief in Valium,® is it so difficult to understand alcohol or Cannabis dispelling another's discomfiture?

The coffee-break is an inseparable feature of our western workdays; daily use of caffeine in some form all but universal among Usan adults. It bothers us not if one co-worker chooses tea in lieu of coffee, or some caffeinated 'soft-drink.' Why should it upset us that cocaine-rich coca serves as the workday stimulant in Perú and Bolivia; or cathinone-rich qat in Yemen and Somalia? Alcoholic drinks constitute one principal, legal inebriant in the United States; why should it matter if some other culture or counterculture might prefer opium's morphean mansuetude to the bibulous beatitudes of Bacchus? After all, alcoholic inebriation is scarcely without its problems, and something like one in ten Usan users succumbs to so-called 'abuse,' 'addiction,' to alcoholism. Alcohol brings premature death to 0.1% of us population yearly, besides being the preëminent drug of violence, accidents, absenteeism and crime.103

There is mounting evidence, moreover, that those individual animals who seek inebriation most avidly, may be those most inquisitive, daring, intelligent; anything but the 'deadbeats' and the 'down-and-out.' We saw in Note 96 that rats most likely actively to explore a novel environment were also most likely to use amphetamines, and it has been suggested that animals "more generally susceptible to learning of any kind" -- that is, more intelligent -- are likewise more apt to self-administer inebriants. A recent article [vide supra, Note 100] explored the manifold parallels between drug-seeking behavior and 'novelty-seeking,' which is also thought to activate the reward pathway of the limbic system. In experimental animals, drugs which antagonize the effects of dopamine inhibit both drug-seeking and novelty-seeking behavior. In test animals and human beings, 'high novelty responders' are at once more sensitive to, and show more interest in inebriants, and many biochemical indices are associated with this, such as lower levels of platelet MAO [vide supra, Notes 52 and 93], which is thought to correlate with elevated levels of dopamine in cerebral reward circuits. What is this high novelty-seeking behavior, if not intelligence -- an inquiring, open attitude to the novel, the unknown? That novelty-seeking should activate archaic reward pathways bears witness to its evolutionary importance, and it is not difficult to imagine how, within a given species adapting to the constraints of its niche in an ecosystem, high novelty-seeking behavior -- or a courageous, inquisitive, outgoing, forward-looking attitude -- should be rewarding, even confer adaptive advantages. While curiosity perchance sometimes kills the cat, it has undeniably served our species well; a unique species emblematic of the premium evolution put on intelligence. It was even conjectured by R.G. Wasson in 1957 [vide supra, pages 39-41; Notes 62-64] that the amritous alkaloids of entheogenic plants functioned as kairomones [vide supra, Note 34] for our protohuman ancestors millennia ago, having "unlimbered the imagination of those first men who ate them, stirred their curiosity and speculative faculties," serving indeed as:

[A] veritable detonator to his soul, arousing in him sentiments of awe and reverence, and gentleness and love, to the highest pitch of which mankind is capable, all those sentiments and virtues that mankind has ever since regarded as the highest attribute of his kind. It made him see what this perishing mortal eye cannot see. [1961, page 157]

Assuming Wasson's astonishing vision acute, we owe not just our religions and other attributes of culture, but the very hypertrophy of our cerebral cortex which begot them, to kairomonal kykeons kaleidoscopic; to drug- and novelty-seeking behavior; which has also been hypothesized to account for the earliest human migrations into Neogaea, that barbarous and beckoning, brave New World!104

Be that as it may, pharmacophilia is nothing new, nor uniquely human, nor nugatory -- neither a nuisance, nor necessarily negative, whatever troubles it may cause for some. It is incumbent on neuroscientists, not to try to cure the incurable -- "how better to exasperate one sick with joy, than to wish to cure him?"105 as Baudelaire asked -- but to engineer euphoria, optimize the pharmacology of pleasure; yea, create better and safer inebriants! Anti-inebriants may be the 'magic bullets' indicated for some people's addictions, but the great majority rather yearn for more exquisite ecstasies; the prodigious, paradisian promise of psychopharmacological engineering.