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D. Nichols

The History of Psychedelics in Psychiatry

January 21, 2022 / Papers / Leave a Comment / By / ,

Abstract

Initial interest in the value of psychedelic drugs (“psychotomimetics”) in psychiatry began in the early 20th century, with explorations of the possibility that mescaline or peyote could produce psychosis-like effects. Over time, interest was focused on whether the effects of psychedelics could inform as to the underlying basis for psychiatric disorders. As research continued, and especially after the discovery of LSD in 1943, increasing interest in a role for psychedelics as adjuncts to psychotherapy began to evolve and became the major focus of work with psychedelics up to the present day.

Nichols, D. E., & Walter, H. (2021). The History of Psychedelics in Psychiatry. Pharmacopsychiatry, 54(4), 151–166. https://doi.org/10.1055/a-1310-3990

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Structure of a Hallucinogen-Activated Gq-Coupled 5-HT 2A Serotonin Receptor

November 18, 2021 / LSD, Neuroscience, Papers, Pharmacology & Chemistry / Leave a Comment / By / , , , , , , , , , , , ,

Abstract

Hallucinogens like lysergic acid diethylamide (LSD), psilocybin, and substituted N-benzyl phenylalkylamines are widely used recreationally with psilocybin being considered as a therapeutic for many neuropsychiatric disorders including depression, anxiety, and substance abuse. How psychedelics mediate their actions-both therapeutic and hallucinogenic-are not understood, although activation of the 5-HT2A serotonin receptor (HTR2A) is key. To gain molecular insights into psychedelic actions, we determined the active-state structure of HTR2A bound to 25-CN-NBOH-a prototypical hallucinogen-in complex with an engineered Gαq heterotrimer by cryoelectron microscopy (cryo-EM). We also obtained the X-ray crystal structures of HTR2A complexed with the arrestin-biased ligand LSD or the inverse agonist methiothepin. Comparisons of these structures reveal determinants responsible for HTR2A-Gαq protein interactions as well as the conformational rearrangements involved in active-state transitions. Given the potential therapeutic actions of hallucinogens, these findings could accelerate the discovery of more selective drugs for the treatment of a variety of neuropsychiatric disorders.

Kim, K., Che, T., Panova, O., DiBerto, J. F., Lyu, J., Krumm, B. E., Wacker, D., Robertson, M. J., Seven, A. B., Nichols, D. E., Shoichet, B. K., Skiniotis, G., & Roth, B. L. (2020). Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor. Cell, 182(6), 1574–1588.e19. https://doi.org/10.1016/j.cell.2020.08.024

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Psilocybin: from ancient magic to modern medicine

February 6, 2022 / Humanities & Art, Mushrooms / Psilocybin, Papers / Leave a Comment / By /

Abstract

Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is an indole-based secondary metabolite produced by numerous species of mushrooms. South American Aztec Indians referred to them as teonanacatl, meaning “god’s flesh,” and they were used in religious and healing rituals. Spanish missionaries in the 1500s attempted to destroy all records and evidence of the use of these mushrooms. Nevertheless, a 16th century Spanish Franciscan friar and historian mentioned teonanacatl in his extensive writings, intriguing 20th century ethnopharmacologists and leading to a decades-long search for the identity of teonanacatl. Their search ultimately led to a 1957 photo-essay in a popular magazine, describing for the Western world the use of these mushrooms. Specimens were ultimately obtained, and their active principle identified and chemically synthesized. In the past 10-15 years several FDA-approved clinical studies have indicated potential medical value for psilocybin-assisted psychotherapy in treating depression, anxiety, and certain addictions. At present, assuming that the early clinical studies can be validated by larger studies, psilocybin is poised to make a significant impact on treatments available to psychiatric medicine.

Nichols D. E. (2020). Psilocybin: from ancient magic to modern medicine. The Journal of antibiotics, 73(10), 679–686. https://doi.org/10.1038/s41429-020-0311-8

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Psilocybin: from ancient magic to modern medicine

May 12, 2020 / Anthropology & Sociology, Anxiety Disorders / PTSD, Biology & Ethnobotany, Depressive Disorders, Humanities & Art, Mushrooms / Psilocybin, Papers, Psychology, Publications / By /

Abstract

Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is an indole-based secondary metabolite produced by numerous species of mushrooms. South American Aztec Indians referred to them as teonanacatl, meaning “god’s flesh,” and they were used in religious and healing rituals. Spanish missionaries in the 1500s attempted to destroy all records and evidence of the use of these mushrooms. Nevertheless, a 16th century Spanish Franciscan friar and historian mentioned teonanacatl in his extensive writings, intriguing 20th century ethnopharmacologists and leading to a decades-long search for the identity of teonanacatl. Their search ultimately led to a 1957 photo-essay in a popular magazine, describing for the Western world the use of these mushrooms. Specimens were ultimately obtained, and their active principle identified and chemically synthesized. In the past 10–15 years several FDA-approved clinical studies have indicated potential medical value for psilocybin-assisted psychotherapy in treating depression, anxiety, and certain addictions. At present, assuming that the early clinical studies can be validated by larger studies, psilocybin is poised to make a significant impact on treatments available to psychiatric medicine.

Nichols, D. E. (2020). Psilocybin: from ancient magic to modern medicine. The Journal of Antibiotics, 1-8., doi.org/10.1038/s41429-020-0311-8
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Microdosing psychedelics: More questions than answers? An overview and suggestions for future research.

July 14, 2019 / LSD, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , , , , ,

Abstract

BACKGROUND:
In the past few years, the issue of ‘microdosing’ psychedelics has been openly discussed in the public arena where claims have been made about their positive effect on mood state and cognitive processes such as concentration. However, there are very few scientific studies that have specifically addressed this issue, and there is no agreed scientific consensus on what microdosing is.
AIM:
This critique paper is designed to address questions that need to be answered by future scientific studies and to offer guidelines for these studies.
APPROACH:
Owing to its proximity for a possible approval in clinical use and short-lasting pharmacokinetics, our focus is predominantly on psilocybin. Psilocybin is allegedly, next to lysergic acid diethylamide (LSD), one of the two most frequently used psychedelics to microdose. Where relevant and available, data for other psychedelic drugs are also mentioned.
CONCLUSION:
It is concluded that while most anecdotal reports focus on the positive experiences with microdosing, future research should also focus on potential risks of (multiple) administrations of a psychedelic in low doses. To that end, (pre)clinical studies including biological (e.g. heart rate, receptor turnover and occupancy) as well as cognitive (e.g. memory, attention) parameters have to be conducted and will shed light on the potential negative consequences microdosing could have.
Kuypers, K. P., Ng, L., Erritzoe, D., Knudsen, G. M., Nichols, C. D., Nichols, D. E., … & Nutt, D. (2019). Microdosing psychedelics: More questions than answers? An overview and suggestions for future research. Journal of Psychopharmacology, 0269881119857204., https://doi.org/10.1177/0269881119857204
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Dark Classics in Chemical Neuroscience: Lysergic Acid Diethylamide (LSD)

March 1, 2018 / Humanities & Art, LSD, Papers, Psychology, Publications / By /

Abstract

Lysergic acid diethylamide (LSD) is one of the most potent psychoactive agents known, producing dramatic alterations of consciousness after submilligram (≥20 μg) oral doses. Following the accidental discovery of its potent psychoactive effects in 1943, it was supplied by Sandoz Laboratories as an experimental drug that might be useful as an adjunct for psychotherapy, or to give psychiatrists insight into the mental processes in their patients. The finding of serotonin in the mammalian brain in 1953, and its structural resemblance to LSD, quickly led to ideas that serotonin in the brain might be involved in mental disorders, initiating rapid research interest in the neurochemistry of serotonin. LSD proved to be physiologically very safe and nonaddictive, with a very low incidence of adverse events when used in controlled experiments. Widely hailed by psychiatry as a breakthrough in the 1950s and early 1960s, clinical research with LSD ended by about 1970, when it was formally placed into Schedule 1 of the Controlled Substances Act of 1970 following its growing popularity as a recreational drug. Within the past 5 years, clinical research with LSD has begun in Europe, but there has been none in the United States. LSD is proving to be a powerful tool to help understand brain dynamics when combined with modern brain imaging methods. It remains to be seen whether therapeutic value for LSD can be confirmed in controlled clinical trials, but promising results have been obtained in small pilot trials of depression, anxiety, and addictions using psilocybin, a related psychedelic molecule.
Nichols, D. E. (2018). Dark Classics in Chemical Neuroscience: Lysergic Acid Diethylamide (LSD). ACS chemical neuroscience. 10.1021/acschemneuro.8b00043
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Is LSD toxic?

February 2, 2018 / LSD, Papers, Psychology, Publications / By / ,

Abstract

LSD (lysergic acid diethylamide) was discovered almost 75 years ago, and has been the object of episodic controversy since then. While initially explored as an adjunctive psychiatric treatment, its recreational use by the general public has persisted and on occasion has been associated with adverse outcomes, particularly when the drug is taken under suboptimal conditions. LSD’s potential to cause psychological disturbance (bad trips) has been long understood, and has rarely been associated with accidental deaths and suicide. From a physiological perspective, however, LSD is known to be non-toxic and medically safe when taken at standard dosages (50–200 μg). The scientific literature, along with recent media reports, have unfortunately implicated “LSD toxicity” in five cases of sudden death. On close examination, however, two of these fatalities were associated with ingestion of massive overdoses, two were evidently in individuals with psychological agitation after taking standard doses of LSD who were then placed in maximal physical restraint positions (hogtied) by police, following which they suffered fatal cardiovascularcollapse, and one case of extreme hyperthermia leading to death that was likely caused by a drug substituted for LSD with strong effects on central nervous system temperature regulation (e.g. 25i-NBOMe). Given the renewed interest in the therapeutic potential of LSD and other psychedelic drugs, it is important that an accurate understanding be established of the true causes of such fatalities that had been erroneously attributed to LSD toxicity, including massive overdoses, excessive physical restraints, and psychoactive drugs other than LSD.

Nichols, D. E., & Grob, C. S. (2018). Is LSD toxic?. Forensic science international, 284, 141-145. 10.1016/j.forsciint.2018.01.006
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N,N-dimethyltryptamine and the pineal gland: Separating fact from myth

October 1, 2017 / DMT, Neuroscience, Papers, Psychology, Publications / By /

Abstract

The pineal gland has a romantic history, from pharaonic Egypt, where it was equated with the eye of Horus, through various religious traditions, where it was considered the seat of the soul, the third eye, etc. Recent incarnations of these notions have suggested that N,N-dimethyltryptamine is secreted by the pineal gland at birth, during dreaming, and at near death to produce out of body experiences. Scientific evidence, however, is not consistent with these ideas. The adult pineal gland weighs less than 0.2 g, and its principal function is to produce about 30 µg per day of melatonin, a hormone that regulates circadian rhythm through very high affinity interactions with melatonin receptors. It is clear that very minute concentrations of N,N-dimethyltryptamine have been detected in the brain, but they are not sufficient to produce psychoactive effects. Alternative explanations are presented to explain how stress and near death can produce altered states of consciousness without invoking the intermediacy of N,N-dimethyltryptamine.
Nichols, D. E. (2017). N, N-dimethyltryptamine and the pineal gland: Separating fact from myth. Journal of Psychopharmacology, 0269881117736919.
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Psychedelic Drugs in Biomedicine

September 22, 2017 / Anxiety Disorders / PTSD, Depressive Disorders, LSD, Mescaline / Cacti, Mushrooms / Psilocybin, Neuroscience, Papers, Psychiatry & Medicine, Psychology, Substance Use Disorder / By / , , , ,

Abstract

Psychedelic drugs, such as lysergic acid diethylamide (LSD), mescaline, and psilocybin, exert profound effects on brain and behavior. After decades of difficulties in studying these compounds, psychedelics are again being tested as potential treatments for intractable biomedical disorders. Preclinical research of psychedelics complements human neuroimaging studies and pilot clinical trials, suggesting these compounds as promising treatments for addiction, depression, anxiety, and other conditions. However, many questions regarding the mechanisms of action, safety, and efficacy of psychedelics remain. Here, we summarize recent preclinical and clinical data in this field, discuss their pharmacological mechanisms of action, and outline critical areas for future studies of psychedelic drugs, with the goal of maximizing the potential benefits of translational psychedelic biomedicine to patients.
Kyzar, E. J., Nichols, C. D., Gainetdinov, R. R., Nichols, D. E., & Kalueff, A. V. (2017). Psychedelic Drugs in Biomedicine. Trends in Pharmacological Sciences. 10.1016/j.tips.2017.08.003
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Chemistry and Structure-Activity Relationships of Psychedelics

March 26, 2017 / LSD, Mescaline / Cacti, Mushrooms / Psilocybin, Neuroscience, Papers, Publications / By /

Abstract

This chapter will summarize structure-activity relationships (SAR) that are known for the classic serotonergic hallucinogens (aka psychedelics), focusing on the three chemical types: tryptamines, ergolines, and phenethylamines. In the brain, the serotonin 5-HT2Areceptor plays a key role in regulation of cortical function and cognition, and also appears to be the principal target for hallucinogenic/psychedelic drugs such as LSD. It is one of the most extensively studied of the 14 known types of serotonin receptors. Important structural features will be identified for activity and, where possible, those that the psychedelics have in common will be discussed. Because activation of the 5-HT2A receptor is the principal mechanism of action for psychedelics, compounds with 5-HT2A agonist activity generally are quickly discarded by the pharmaceutical industry. Thus, most of the research on psychedelics can be related to activation of 5-HT2A receptors. Therefore, much of the discussion will include not only clinical or anecdotal studies, but also will consider data from animal models as well as a certain amount of molecular pharmacology where it is known.
Nichols, D. E. (2017). Chemistry and Structure–Activity Relationships of Psychedelics. 10.1007/7854_2017_475
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