View source for Category:Tryptamine psychedelics

The tryptamine psychedelics are a family of psychoactive substances that produce profound changes in perception, thought, and mood, and that share a chemical kinship with serotonin, one of the body's own signalling molecules. The family includes some of the oldest substances known to have been used by human beings — the psilocybin mushrooms and the seeds of the morning glory, both used ceremonially in Mesoamerica for many centuries — and some of the most famous discoveries of twentieth-century chemistry, above all [[LSD]]. Their history is unusually entangled with religion, with anthropology, and with the politics of prohibition, and it is best told as a history of people.

== The sacred plants of Mesoamerica ==
Long before any chemist isolated a tryptamine, several of these substances were sacred plants. The psilocybin mushrooms were, in the language of the Aztecs, ''teonanácatl'' — "flesh of the gods" — eaten in night-long healing ceremonies. The seeds of the morning glory were a second sacred preparation, known by the Nahuatl name ''ololiuhqui'', used by Aztec priests and diviners; their effects, it would later emerge, come from ergot-type tryptamine alkaloids related to [[LSD]]. Both practices survived the Spanish conquest by retreating into the remote mountains of what is now southern Mexico — and both survived against determined opposition. The Spanish Church persecuted these plant ceremonies with particular vehemence, and in 1620 the Holy Office of the Inquisition in Mexico City formally declared the ingestion of such plants to be heresy.

{{PendellsCorner
| quote  = In 1620 the Holy Office of the Inquisition in Mexico City formally decreed that ingestion of inebriating plants was heresy. The War on Drugs is still a religious war.
| volume = Gnosis
| page   = 31
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The mushroom tradition was carried into the twentieth century by Mazatec healers, among whom the most famous was '''María Sabina''' (c. 1894–1985), a ''curandera'' of Huautla de Jiménez in Oaxaca. She had used the mushrooms — which she called "the children" — in healing ''veladas'' for decades. In 1955 she allowed an American visitor, the banker and amateur mycologist '''R. Gordon Wasson''', to take part in a velada; in May 1957 Wasson published an account of it, "Seeking the Magic Mushroom," in ''Life'' magazine.<ref name="wasson1957">Wasson RG. Seeking the Magic Mushroom. ''Life,'' May 13, 1957.</ref> The article reached millions of readers and is often said to have introduced the [[psilocybin]] mushroom to the Western world.

For María Sabina and her community the consequences were grievous. The flood of outsiders who followed Wasson's article disrupted the village; Sabina was blamed by many of her neighbours for giving away a sacred thing, her house was burned, and she was harassed by the authorities. She died poor. Her story is now often told as a cautionary one — about what is lost when a living tradition is treated as a curiosity.

{{PendellsCorner
| quote  = The experts, the people who kept the ally alive for four hundred years while the rest of the world pursued more destructive visions, say that matters relating to the mushroom allies are muy delicado.
| volume = Gnosis
| page   = 29
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== Hofmann, LSD, and the laboratory ==
The laboratory history of the tryptamine psychedelics begins with the Swiss chemist '''Albert Hofmann''', working at the Sandoz pharmaceutical company in Basel. In 1938, while investigating compounds derived from ergot — a fungus that grows on rye — Hofmann first synthesized [[LSD]] (lysergic acid diethylamide). Its remarkable properties went unnoticed for five years, until, in April 1943, Hofmann absorbed a trace of the substance and experienced its effects; days later he deliberately took a measured dose and rode home from the laboratory, an episode since mythologized as "Bicycle Day." [[LSD]]'s effects were unlike anything in the pharmacology of the time, and it was studied intensively through the 1950s and 1960s as a possible tool in psychiatry.<ref name="hofmann">Nichols DE. Dark classics in chemical neuroscience: Lysergic acid diethylamide (LSD). ''ACS Chem Neurosci.'' 2018;9(10):2331–2343. PMID 29461039.</ref>

It was Hofmann, too, who connected the laboratory to the sacred plants. Prompted by Wasson's ''Life'' article, Hofmann obtained mushroom samples and in 1958 isolated and identified their active constituents, naming them '''[[psilocybin]]''' and '''[[psilocin]]'''. Two years later, in 1960, he turned to another ancient Mesoamerican sacred plant — the morning glory, whose seeds had been used ceremonially under the Nahuatl name ''ololiuhqui'' — and found, to general surprise, that their psychoactive constituent was lysergic acid amide, an ergot-type alkaloid closely related to [[LSD]] itself. A sacred mushroom, a sacred seed, and a synthetic substance had all been shown to belong to the same chemical family.<ref name="hofmann"/>

The third great member of the family, '''[[DMT]]''' (dimethyltryptamine), had a quieter early history. It was first synthesized in 1931 by the Canadian chemist Richard Manske, but its psychoactivity in humans was not demonstrated until 1956, when the Hungarian psychiatrist Stephen Szara — unable to obtain [[LSD]], which its maker would not supply him — synthesized [[DMT]] himself and established its effects through self-experiment. [[DMT]] was later found to occur very widely in nature: in many plants, and in trace amounts in the human body itself.

{{PendellsCorner
| quote  = In the old days, for pot-smokers and acid heads, there was pot, there was acid, and then, beyond them all, there was DMT.
| volume = Gnosis
| page   = 227
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== Prohibition and revival ==
The intense scientific and cultural interest of the 1950s and 1960s did not last. As psychedelics moved out of the laboratory and into the counterculture, a political reaction followed: by the early 1970s [[LSD]], [[psilocybin]], and [[DMT]] had been placed under the strictest category of legal control in the United States and, through international treaty, across much of the world. Research very largely stopped for a generation.

Since roughly the year 2000, a careful revival of medical research has been under way. [[Psilocybin]] in particular has been studied in clinical trials as a treatment for depression — especially depression that has not responded to standard treatments — and the United States Food and Drug Administration granted [[psilocybin]] therapy a "breakthrough therapy" designation in 2018 (Compass Pathways, for treatment-resistant depression) and again in 2019 (Usona Institute, for major depressive disorder), a status meant to speed the study of promising treatments for serious conditions.<ref name="breakthrough">US Food and Drug Administration breakthrough therapy designations for psilocybin: Compass Pathways for treatment-resistant depression, October 2018; Usona Institute for major depressive disorder, November 2019.</ref> A widely cited phase 2 trial published in 2021 compared psilocybin-assisted therapy with the antidepressant escitalopram in moderate-to-severe depression, with the two showing broadly comparable efficacy on the primary endpoint.<ref name="carhart2021">Carhart-Harris R, Giribaldi B, Watts R, et al. Trial of psilocybin versus escitalopram for depression. ''N Engl J Med.'' 2021;384(15):1402–1411. PMID 33852780.</ref> [[DMT]], and the [[DMT]]-containing Amazonian brew ayahuasca, have been studied in earlier trials for depression as well. Alongside the medical research, several jurisdictions have moved to decriminalize [[psilocybin]] or to permit its supervised therapeutic use; the state of Colorado, for example, voted to decriminalize it in 2022. This research is genuinely promising but still developing, and the medicines remain investigational rather than approved general treatments.

== Members ==
The tryptamine psychedelics fall into a few groups. The classical members are '''[[psilocybin]]''' (with its active form [[psilocin]]), the substance of the psilocybin or "magic" mushrooms; '''[[DMT]]''', which occurs in many plants and is the active principle of ayahuasca; and '''[[LSD]]''', a semi-synthetic substance derived from ergot. Closely related naturally occurring tryptamines include [[5-MeO-DMT]], found in certain plants and in the secretion of a toad, [[bufotenin]], and the ergoline alkaloids of morning glory seeds (''ololiuhqui''). A large number of synthetic tryptamines have also been made, several of them first prepared and described by the chemist Dr. Alexander "Sasha" Shulgin. The list is not exhaustive, and the boundaries of the family are drawn differently by different authorities.

== Mechanisms ==
The classical tryptamine psychedelics are understood to produce their effects chiefly by acting at a particular serotonin receptor, known as the 5-HT2A receptor, where they behave as agonists — that is, they bind to the receptor and activate it, in the manner of serotonin itself. This shared action is thought to be the common thread that links substances as chemically varied as [[psilocin]], [[DMT]], and [[LSD]], and it is consistent with their close structural resemblance to serotonin. That these substances act as 5-HT2A agonists is well established; how that receptor activity gives rise to the actual psychedelic experience — the changes in perception, emotion, and the sense of self — is far less well understood and remains a subject of active research.

A separate and much-debated question concerns the [[DMT]] that occurs naturally in the mammalian body. That [[DMT]] is present in trace amounts is not in dispute; what its function is — whether it has a meaningful physiological or psychological role, or is merely an incidental by-product of other chemistry — is genuinely contested. Studies comparing [[DMT]] levels between people with psychotic illness and others have not found a clear difference, and the chemist Alexander Shulgin, surveying the question of whether endogenous [[DMT]] is a natural psychotogen or a neurotransmitter, concluded simply that "the jury is still out on this one."<ref name="shulgin">Shulgin A, Shulgin A. ''TiHKAL: The Continuation.'' Transform Press; 1997.</ref> The proposal that endogenous [[DMT]] is a "spirit molecule" mediating extraordinary states of consciousness, associated especially with the psychiatrist Rick Strassman, is regarded by much of the scientific community as unproven and speculative.

<vote slug="tryptamine-endogenous-dmt">Does endogenous DMT play a meaningful role in human consciousness?</vote>

{{PendellsCorner
| quote  = Deep psychonauts of DMT space usually agree that it is very difficult to bring anything back from the space, or to talk about it in any way with someone who hasn't been there.
| volume = Gnosis
| page   = 227
}}

== Effects ==
The experience produced by the tryptamine psychedelics is notoriously difficult to describe, and the words commonly used for it each capture only a part.

{{PendellsCorner
| quote  = Entheogenic, manifesting god within. And yet that doesn't say it. Psychedelic, revealing the soul. And yet that doesn't say it. Hallucinogenic, generating visions. And yet that doesn't say it, either.
| volume = Gnosis
| page   = 28
}}

Reported effects include changes in visual perception, an altered sense of time, shifts in mood that may be euphoric or fearful, a feeling of insight or of contact with something greater than the self, and — at higher doses — a profound dissolution of the ordinary boundaries of the self. The character of the experience depends heavily on the dose, the substance, and on what are traditionally called "set and setting" — the person's state of mind and the surroundings. The substances differ markedly in how they are taken and how long they last: [[psilocybin]]'s effects last some hours, [[LSD]]'s considerably longer, and smoked or injected [[DMT]] produces an extremely intense experience lasting only minutes.

== Safety ==
The classical tryptamine psychedelics have a low potential for the kind of physical dependence associated with substances such as opioids, and their direct physiological toxicity is low — fatal overdose from [[psilocybin]] or [[LSD]] alone is, on the available evidence, very rare. This relatively favourable physiological profile, however, should not be mistaken for an absence of risk.

The most important risks are psychological. A psychedelic experience can be acutely frightening or distressing — a "bad trip" — and such an experience can be more likely, and more dangerous, for people who are predisposed to or living with a psychotic illness, in whom these substances may precipitate or worsen symptoms; a personal or family history of psychosis is generally treated as a strong reason for caution. A minority of people experience lasting perceptual disturbances afterward, a condition known as hallucinogen persisting perception disorder. Because [[DMT]] and ayahuasca act on the serotonin system, combining them with other serotonergic drugs — including some antidepressants — carries a risk of serotonin toxicity, a potentially serious reaction. There are also real physical cautions: the substances typically raise heart rate and blood pressure, which matters for people with cardiovascular disease, and ayahuasca in particular commonly causes nausea and vomiting. Figures for all these risks are population estimates that vary between studies, and individual response varies considerably between people.

== References ==

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