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Psychedelics as anti-inflammatory agents

/ Mushrooms / Psilocybin, Papers, Psychiatry & Medicine, Publications / / ,

Abstract

Serotonin (5-hydroxytryptamine, 5-HT)2A receptor agonists have recently emerged as promising new treatment options for a variety of disorders. The recent success of these agonists, also known as psychedelics, like psilocybin for the treatment of anxiety, depression, obsessive-compulsive disorder (OCD), and addiction, has ushered in a renaissance in the way these compounds are perceived in the medical community and populace at large. One emerging therapeutic area that holds significant promise is their use as anti-inflammatory agents. Activation of 5-HT2A receptors produces potent anti-inflammatory effects in animal models of human inflammatory disorders at sub-behavioural levels. This review discusses the role of the 5-HT2A receptor in the inflammatory response, as well as highlight studies using the 5-HT2A agonist (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] to treat inflammation in cellular and animal models. It also examines potential mechanisms by which 5-HT2A agonists produce their therapeutic effects. Overall, psychedelics regulate inflammatory pathways via novel mechanisms, and may represent a new and exciting treatment strategy for several inflammatory disorders.

Flanagan, T. W., & Nichols, C. D. (2018). Psychedelics as anti-inflammatory agents. International Review of Psychiatry, 30(4), 363-375., 10.1080/09540261.2018.1481827

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Iterative l-Tryptophan Methylation in Psilocybe Evolved by Subdomain Duplication

/ Biology & Ethnobotany, Mushrooms / Psilocybin, Neuroscience, Papers, Pharmacology & Chemistry, Publications / / , , , ,

Abstract

Psilocybe mushrooms are best known for their l-tryptophan-derived psychotropic alkaloid psilocybin. Dimethylation of norbaeocystin, the precursor of psilocybin, by the enzyme PsiM is a critical step during the biosynthesis of psilocybin. However, the “magic” mushroom Psilocybe serbica also mono- and dimethylates l-tryptophan, which is incompatible with the specificity of PsiM. Here, a second methyltransferase, TrpM, was identified and functionally characterized. Mono- and dimethylation activity on l-tryptophan was reconstituted in vitro, whereas tryptamine was rejected as a substrate. Therefore, we describe a second l-tryptophan-dependent pathway in Psilocybe that is not part of the biosynthesis of psilocybin. TrpM is unrelated to PsiM but originates from a retained ancient duplication event of a portion of the egtDB gene that encodes an ergothioneine biosynthesis enzyme. During mushroom evolution, this duplicated gene was widely lost but re-evolved sporadically and independently in various genera. We propose a new secondary metabolism evolvability mechanism, in which weakly selected genes are retained through preservation in a widely distributed, conserved pathway.

Blei, F., Fricke, J., Wick, J., Slot, J. C., & Hoffmeister, D. (2018). Iterative l‐Tryptophan Methylation in Psilocybe Evolved by Subdomain Duplication. ChemBioChem, 19(20), 2160-2166., 10.1002/cbic.201800336.
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N, N-Dimethyltryptamine (DMT), an Endogenous Hallucinogen: Past, Present, and Future Research to Determine Its Role and Function

/ DMT, Neuroscience, Papers, Publications / /

Abstract

This report provides a historical overview of research concerning the endogenous hallucinogen N, N-dimethyltryptamine (DMT), focusing on data regarding its biosynthesis and metabolism in the brain and peripheral tissues, methods and results for DMT detection in body fluids and brain, new sites of action for DMT, and new data regarding its possible physiological and therapeutic roles. Research that further elaborates its consideration as a putative neurotransmitter is also addressed. Taking these studies together, the report proposes several new directions and experiments to ascertain the role of DMT in the brain, including brain mapping of enzymes responsible for the biosynthesis of DMT, further studies to elaborate its presence and role in the pineal gland, a reconsideration of binding site data, and new administration and imaging studies. The need to resolve the “natural” role of an endogenous hallucinogen from the effects observed from peripheral administration are also emphasized.

Barker, S. A. (2018). N, N-Dimethyltryptamine (DMT), an Endogenous Hallucinogen: Past, Present and Future Research to Determine Its Role and Function. Frontiers in neuroscience, 12, 536., 10.3389/fnins.2018.00536
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Psychedelics and psychotherapy in Canada: Humphry Osmond and Aldous Huxley.

/ Papers, Psychology, Publications / / ,

Abstract

The decade of the 1950s is well known among historians of psychiatry for the unprecedented shift toward psychopharmacological solutions to mental health problems. More psychiatric medications were introduced than ever before or since (Healy, 2002). While psychiatric researchers later credited these drugs, in part, for controlling psychotic, depressive, and anxious symptoms-and subsequently for emptying decaying psychiatric institutions throughout the Western world-psychiatrists also produced a number of other theories that relied on a more delicate and nuanced blending of psychotherapy and psychopharmacology. Canadian-based researchers were at the forefront of experiments combining mescaline, LSD, and psychoactive substances later described as “psychedelics.” From a relatively isolated setting on the Canadian prairies, in one of the most notorious mental hospitals in North America, this blending of traditions generated a unique approach. A close look at the correspondence between the psychiatrist Humphry Osmond and his friend, the writer Aldous Huxley, who shared interests in psychoactive substances and their effects on perception, and the stimulation of empathy, gives us an opportunity to explore how they developed their psychedelic approach to therapy in the 1950s. The combination of working in an isolated hospital, far from the main research powers in North America, produced a sense of regional incubation and required Osmond to look for collaborators well beyond his own field of psychiatry. (PsycINFO Database Record
Dyck, E., & Farrell, P. (2018). Psychedelics and psychotherapy in Canada: Humphry Osmond and Aldous Huxley. History of psychology, 21(3), 240., 10.1037/hop0000088.
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Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: effects on cognition

/ Mushrooms / Psilocybin, Neuroscience, Papers, Psychiatry & Medicine, Publications / / , , , ,

Abstract

Objectives

Classic psychedelics (serotonin 2A receptor agonists) and dissociative hallucinogens (NMDA receptor antagonists), though differing in pharmacology, may share neuropsychological effects. These drugs, however, have undergone limited direct comparison. This report presents data from a double-blind, placebo-controlled within-subjects study comparing the neuropsychological effects of multiple doses of the classic psychedelic psilocybin with the effects of a single high dose of the dissociative hallucinogen dextromethorphan (DXM).

Methods

Twenty hallucinogen users (11 females) completed neurocognitive assessments during five blinded drug administration sessions (10, 20, and 30 mg/70 kg psilocybin; 400 mg/70 kg DXM; and placebo) in which participants and study staff were informed that a large range of possible drug conditions may have been administered.

Results

Global cognitive impairment, assessed using the Mini-Mental State Examination during peak drug effects, was not observed with psilocybin or DXM. Orderly and dose-dependent effects of psilocybin were observed on psychomotor performance, working memory, episodic memory, associative learning, and visual perception. Effects of DXM on psychomotor performance, visual perception, and associative learning were in the range of effects of a moderate to high dose (20 to 30 mg/70 kg) of psilocybin.

Conclusions

This was the first study of the dose effects of psilocybin on a large battery of neurocognitive assessments. Evidence of delirium or global cognitive impairment was not observed with either psilocybin or DXM. Psilocybin had greater effects than DXM on working memory. DXM had greater effects than all psilocybin doses on balance, episodic memory, response inhibition, and executive control.

Barrett, F. S., Carbonaro, T. M., Hurwitz, E., Johnson, M. W., & Griffiths, R. R. (2018). Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: effects on cognition. Psychopharmacology, 235(10), 2915-2927., 10.1007/s00213-018-4981-x
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A Gratuitous Grace: The Influence of Religious Set and Intent on the Psychedelic Experience

/ Papers, Psychology, Publications / / ,

ABSTRACT

Psychedelic drugs, or entheogens, have been used for religious purposes among various cultures for thousands of years. Recently, these substances have caught the attention of Westerners for many reasons, including their propensity to induce mystical experiences. This study examined the relationship between religion and having mystical experiences. A total of 119 participants were drawn from psychedelic-related websites and asked to complete an anonymous online questionnaire containing items regarding history of psychedelic use, set and setting for psychedelic use, and a measure for mystical experiences. A majority of respondents were White males who displayed at least some level of post-secondary education. The findings indicated that respondents who used psychedelics for specifically religious purposes, as well as those who identified with a religion, were more likely to score higher on the Mysticism Scale than those who did not.
Neitzke-Spruill, L., & Glasser, C. (2018). A Gratuitous Grace: The Influence of Religious Set and Intent on the Psychedelic Experience. Journal of psychoactive drugs, 50(4), 314-321., 10.1080/02791072.2018.1494869
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Efficacy of Ketamine in the Treatment of Substance Use Disorders: A Systematic Review

/ Anxiety Disorders / PTSD, Depressive Disorders, Ketamine, Neuroscience, Papers, Psychiatry & Medicine, Publications / / , , , ,

Abstract

Background: Despite advances in behavioral and pharmacotherapy interventions, substance use disorders (SUDs) are frequently refractory to treatment. Glutamatergic dysregulation has received increasing attention as one common neuropathology across multiple substances of abuse. Ketamine is a potent N-methyl-D-aspartate (NMDA) glutamatergic receptor antagonist which has been found to be effective in the treatment of severe depression. Here we review the literature on the efficacy of ketamine in the treatment of SUDs.

Methods: A systematic review of the PubMed, Scopus, and ClinicalTrials.gov databases was undertaken to identify completed and ongoing human studies of the effectiveness of ketamine in the treatment of SUDs between January 1997 and January 2018.

Results and conclusion: Seven completed studies were identified. Two studies focused on alcohol use disorder, two focused on cocaine use disorder, and three focused on opioid use disorder. Both cocaine studies found improvements in craving, motivation, and decreased cocaine use rates, although studies were limited by small sample sizes, a homogeneous population and short follow-up. Studies of alcohol and opioid use disorders found improvement in abstinence rates in the ketamine group, with significant between-group effects noted for up to two years following a single infusion, although these were not placebo-controlled trials. These results suggest that ketamine may facilitate abstinence across multiple substances of abuse and warrants broader investigation in addiction treatment. We conclude with an overview of the six ongoing studies of ketamine in the treatment of alcohol, cocaine, cannabis, and opioid use disorders and discuss future directions in this emerging area of research.

Jones, J. L., Mateus, C. F., Malcolm, R. J., Brady, K. T., & Back, S. E. (2018). Efficacy of ketamine in the treatment of substance use disorders: a systematic review. Frontiers in Psychiatry, 9., 10.3389/fpsyt.2018.00277
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Dark Classics in Chemical Neuroscience: N, N-Dimethyltryptamine (DMT).

/ DMT, Papers, Psychology, Publications / / ,

Abstract

Though relatively obscure, N, N-dimethyltryptamine (DMT) is an important molecule in psychopharmacology as it is the archetype for all indole-containing serotonergic psychedelics. Its structure can be found embedded within those of better-known molecules such as lysergic acid diethylamide (LSD) and psilocybin. Unlike the latter two compounds, DMT is ubiquitous, being produced by a wide variety of plant and animal species. It is one of the principal psychoactive components of ayahuasca, a tisane made from various plant sources that has been used for centuries. Furthermore, DMT is one of the few psychedelic compounds produced endogenously by mammals, and its biological function in human physiology remains a mystery. In this review, we cover the synthesis of DMT as well as its pharmacology, metabolism, adverse effects, and potential use in medicine. Finally, we discuss the history of DMT in chemical neuroscience and why this underappreciated molecule is so important to the field of psychedelic science.
Cameron, L. P., & Olson, D. E. (2018). Dark classics in chemical neuroscience: N, N-Dimethyltryptamine (DMT). ACS chemical neuroscience, 9(10), 2344-2357., 10.1021/acschemneuro.8b00101
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Blood pressure safety of subanesthetic ketamine for depression: A report on 684 infusions

/ Depressive Disorders, Ketamine, Papers, Psychology, Publications / / , , , , , ,

Abstract

BACKGROUND:
The dissociative anesthetic agent ketamine is increasingly being utilized to treat depression, despite not having FDA (Food and Drug Administration) approval for this indication. There are many questions about the potential risks of this treatment and hence the proper setting and degree of monitoring required to ensure patient safety. There is limited data about the cardiovascular safety of ketamine when administered at subanesthetic doses to treat depression.
METHODS:
66 patients in the Department of Psychiatry at Emory University received a total of 684 ketamine infusions between 2014 and 2016. Ketamine was dosed at 0.5 mg/kg body weight and infused over 40 min. Blood pressure was measured every 10 min during the infusions and every 15 min thereafter.
RESULTS:
Mean age of the patients was 56.7 years, 87.9% had unipolar depression and 36.1% had essential hypertension. No infusions were discontinued due to instability of vital signs, adverse physiological consequences or acute psychotomimetic effects. The biggest increases in blood pressure were measured at 30 min (systolic 3.28 mmHg, diastolic 3.17 mmHg). Hypertensive patients had higher blood pressure peaks during the infusions. Blood pressures returned to baseline during post-infusion monitoring. There was no development of tolerance to the blood pressure elevating effects of ketamine between the first and sixth infusions.
LIMITATIONS:
This is a single site, retrospective analysis, of patients who were spontaneously seeking clinical care.
CONCLUSIONS:
The blood pressure changes observed when ketamine is administered over 40 min at 0.5 mg/kg for the treatment of depression are small, well tolerated and clinically insignificant.
Riva-Posse, P., Reiff, C. M., Edwards, J. A., Job, G. P., Galendez, G. C., Garlow, S. J., … & McDonald, W. M. (2018). Blood pressure safety of subanesthetic ketamine for depression: A report on 684 infusions. Journal of affective disorders, 236, 291-297. 10.1016/j.jad.2018.02.025
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A Mixed-Method Analysis of Persisting Effects Associated with Positive Outcomes Following Ibogaine Detoxification

/ Iboga / Ibogaine, Neuroscience, Papers, Psychology, Publications, Substance Use Disorder / / , , , ,

Abstract

We examined persisting effects, self-perceived challenges, and potential benefits associated with positive outcomes following ibogaine detoxification using data collected as part of a larger online retrospective study of 73 patients who received treatment for chronic opioid use in Mexico between 2012 and 2015. A mixed-methods design was used comparing treatment responders versus non-responders, as well as content coding of themes from open-ended questions. Most participants reported positive persisting effects of ibogaine detoxification (e.g., enhanced personal sense of gratitude and authenticity, and meaning and appreciation for life). Compared to non-responders, treatment responders endorsed greater persisting changes in their ability to tolerate difficult/painful feelings, capacity for coping with stress, and reduced unhealthy anger. Treatment responders reported greater change in subjective levels of inner peace, joy, feelings of love/openheartedness, and experiences of sacredness in life. Qualitative analyses revealed that treatment responders reported a heightened sense of spiritual awareness and greater connection to their intra-/interpersonal relationships after ibogaine detoxification. Notable challenges of ibogaine detoxification included psychological and health-related difficulties during treatment and challenges with post-treatment integration. Findings highlight the persisting effects associated with positive response to ibogaine detoxification and possible post-treatment needs (i.e., more integration/aftercare resources). Future research using rigorous experimental designs is needed.

Davis, A. K., Renn, E., Windham-Herman, A. M., Polanco, M., & Barsuglia, J. P. (2018). A mixed-method analysis of persisting effects associated with positive outcomes following ibogaine detoxification. Journal of psychoactive drugs, 50(4), 287-297., 10.1080/02791072.2018.1487607.
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