Category:Phenethylamines: Difference between revisions

The phenethylamines are one of the largest and most varied families in all of pharmacology, a family defined by a simple shared chemical skeleton, the phenethylamine structure, from which an enormous range of substances is built. The breadth is striking: the body's own signalling molecules: dopamine, noradrenaline, and adrenaline are phenethylamines; so are the stimulants amphetamine and methamphetamine; so is the empathogen MDMA; so are the psychostimulant cathinones; and so are a number of ordinary medicines, among them some decongestants and bronchodilators. This page concerns one particular branch of that family: the psychedelic phenethylamines, the serotonergic, vision-producing members, of which the oldest and most famous is mescaline.^[1] Their history, like that of the tryptamine psychedelics, is best told as a history of people, and it begins with a cactus.

Mescaline is the active principle of peyote (Lophophora williamsii), a small, spineless cactus of the deserts of northern Mexico and the southern United States, and of related cacti including the San Pedro. Peyote is among the most anciently used psychoactive plants known: dried peyote buttons recovered from caves in Texas and Mexico have been dated to several thousand years before the present, and it has been used ceremonially and medicinally by the indigenous peoples of the region for a very long time.

That long tradition was met, after the Spanish conquest, with sustained persecution. The Catholic Church treated the divinatory use of peyote as evidence of a pact with the devil, and the Inquisition condemned it; peyote ceremonies survived chiefly among peoples such as the Huichol, the Cora, and the Tarahumara, who could retreat into terrain remote enough to escape the authorities.

Not every voice of the period was condemnatory. As early as 1591 the physician Juan de Cárdenas argued that peyote's effects were a matter of its natural properties, not of the supernatural, a strikingly early statement of what would now be called a pharmacological view.

Pendell, writing in our own time, draws the line from that history straight to the present.

In the nineteenth century peyote drew the attention of Western science. The German toxicologist Louis Lewin examined the cactus in the 1880s, and in 1897 the chemist Arthur Heffter, working in Leipzig, isolated its principal active alkaloid and, by a series of self-experiments, identified it as the substance responsible for peyote's visions. He named it mescaline. In 1919 the Viennese chemist Ernst Späth achieved the first complete synthesis of mescaline, making it the first psychedelic substance both identified and made in the laboratory.^[2] Mescaline became, for the first half of the twentieth century, the standard tool for the scientific study of visionary states, and its literary fame was secured when Aldous Huxley described his own mescaline experience in The Doors of Perception in 1954.^[3]

The modern history of the psychedelic phenethylamines is, to an unusual degree, the work of one person: the chemist Dr. Alexander "Sasha" Shulgin. Beginning in the 1960s, Shulgin took the mescaline molecule as a template and systematically varied it, synthesizing and then personally evaluating, first on himself, then with his wife Ann and a small circle of friends, a great number of new substances. This work produced whole families of psychedelic phenethylamines, among them the 2C-x series and the DOx series, and established much of what is understood about how small changes in chemical structure change psychedelic effect.

In 1991 Alexander and Ann Shulgin published PiHKAL, the title an acronym for Phenethylamines i Have Known And Loved, which combined an autobiographical account with detailed descriptions of some two hundred substances.^[4] The book made the chemistry public in a way nothing before it had, and several of the substances first described in it, 2C-B among them, went on to wide use. In 1994, two years after publication, Shulgin's laboratory was raided by the United States Drug Enforcement Administration. The 2C-x series, the best known of these families, is covered in detail on its own page; this page treats the psychedelic phenethylamines as a whole.

As with the other classical psychedelics, the psychedelic phenethylamines were brought under strict legal control: mescaline was placed in the most restrictive category of control in the United States by the early 1970s, with a narrow exemption for the religious use of peyote by the Native American Church, and the later synthetic phenethylamines were controlled as they appeared. Research nonetheless continued at a low level and has revived in recent years, with renewed scientific and commercial interest in mescaline and related substances as possible treatments in psychiatry;^[1] as of the mid-2020s this work is at an early stage and these remain investigational rather than approved medicines.

The psychedelic phenethylamines fall into several groups. At the head of the family stands mescaline, the naturally occurring member. The largest synthetic groups are the 2C-x series, covered as a class on its own page, and the DOx series, the latter being the amphetamine-type relatives, longer-acting and more potent. A further group, the NBOMe series, consists of N-benzyl derivatives of the 2C compounds; these are far more potent than their parents and, as noted below, considerably more dangerous. The list is not exhaustive, and the boundaries of the family are drawn differently by different authorities. The broader, non-psychedelic phenethylamines, the amphetamine-type stimulants, MDMA and the other empathogens, the cathinones, are treated under their own categories.

The psychedelic phenethylamines are understood to produce their effects, like the tryptamine psychedelics, chiefly by acting as agonists at a particular serotonin receptor, the 5-HT2A receptor, that is, by binding to that receptor and activating it. This shared action is thought to be the common thread linking the psychedelic phenethylamines to the chemically quite different tryptamine psychedelics, and it is why the two families are grouped together as the "classical" or serotonergic psychedelics. That these substances act at the 5-HT2A receptor is well established; how that receptor activity gives rise to the actual psychedelic experience is far less well understood and remains a subject of active research. The amphetamine-type members, such as the DOx compounds, also carry the structural features of a stimulant, which contributes to their long duration and their effects on the cardiovascular system.

The psychedelic phenethylamines do not all carry the same risks, and the differences between them matter a great deal. Mescaline itself, used in the forms in which it has the longest record, has a low potential for the kind of physical dependence associated with substances such as opioids; its characteristic acute effects include nausea and vomiting, a marked rise in heart rate and blood pressure, and the psychological risks common to all psychedelics: acute fear or distress, and the possibility of precipitating or worsening a psychotic illness in those who are predisposed to one.

The NBOMe series is a different and more serious matter, and the distinction is important. These substances are extremely potent, active in amounts measured in micrograms, and they have been associated with severe poisonings and with deaths, through effects including seizures, dangerously high body temperature, breakdown of muscle tissue, and kidney failure.^[5] Because they can resemble other psychedelics in their effects but are vastly more potent, NBOMe substances have been sold deceptively as other drugs, sometimes as 2C-B, sometimes on blotter resembling LSD, with dangerous consequences for people who did not know what they had taken. Figures for all these risks are population estimates that vary between studies, and individual response varies considerably between people.