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Hallucinogens in Mental Health: Preclinical and Clinical Studies on LSD, Psilocybin, MDMA, and Ketamine

January 7, 2022 / Ketamine, LSD, MDMA, Mushrooms / Psilocybin, Papers / Leave a Comment / By / , , , , , ,

Abstract

A revamped interest in the study of hallucinogens has recently emerged, especially with regard to their potential application in the treatment of psychiatric disorders. In the last decade, a plethora of preclinical and clinical studies have confirmed the efficacy of ketamine in the treatment of depression. More recently, emerging evidence has pointed out the potential therapeutic properties of psilocybin and LSD, as well as their ability to modulate functional brain connectivity. Moreover, MDMA, a compound belonging to the family of entactogens, has been demonstrated to be useful to treat post-traumatic stress disorders. In this review, the pharmacology of hallucinogenic compounds is summarized by underscoring the differences between psychedelic and nonpsychedelic hallucinogens as well as entactogens, and their behavioral effects in both animals and humans are described. Together, these data substantiate the potentials of these compounds in treating mental diseases.

De Gregorio, D., Aguilar-Valles, A., Preller, K. H., Heifets, B. D., Hibicke, M., Mitchell, J., & Gobbi, G. (2021). Hallucinogens in Mental Health: Preclinical and Clinical Studies on LSD, Psilocybin, MDMA, and Ketamine. The Journal of neuroscience : the official journal of the Society for Neuroscience, 41(5), 891–900. https://doi.org/10.1523/JNEUROSCI.1659-20.2020

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Post-acute psychological effects of classical serotonergic psychedelics: a systematic review and meta-analysis

January 3, 2022 / Ayahuasca, LSD, Mushrooms / Psilocybin, Papers, Psychology / Leave a Comment / By / , , , , , ,

Abstract

Background: Scientific interest in the therapeutic effects of classical psychedelics has increased in the past two decades. The psychological effects of these substances outside the period of acute intoxication have not been fully characterized. This study aimed to: (1) quantify the effects of psilocybin, ayahuasca, and lysergic acid diethylamide (LSD) on psychological outcomes in the post-acute period; (2) test moderators of these effects; and (3) evaluate adverse effects and risk of bias.

Methods: We conducted a systematic review and meta-analysis of experimental studies (single-group pre-post or randomized controlled trials) that involved administration of psilocybin, ayahuasca, or LSD to clinical or non-clinical samples and assessed psychological outcomes ⩾24 h post-administration. Effects were summarized by study design, timepoint, and outcome domain.

Results: A total of 34 studies (24 unique samples, n = 549, mean longest follow-up = 55.34 weeks) were included. Classical psychedelics showed significant within-group pre-post and between-group placebo-controlled effects on a range of outcomes including targeted symptoms within psychiatric samples, negative and positive affect-related measures, social outcomes, and existential/spiritual outcomes, with large between-group effect in these domains (Hedges’ gs = 0.84 to 1.08). Moderator tests suggest some effects may be larger in clinical samples. Evidence of effects on big five personality traits and mindfulness was weak. There was no evidence of post-acute adverse effects.

Conclusions: High risk of bias in several domains, heterogeneity across studies, and indications of publication bias for some models highlight the need for careful, large-scale, placebo-controlled randomized trials.

Goldberg, S. B., Shechet, B., Nicholas, C. R., Ng, C. W., Deole, G., Chen, Z., & Raison, C. L. (2020). Post-acute psychological effects of classical serotonergic psychedelics: a systematic review and meta-analysis. Psychological medicine, 50(16), 2655–2666. https://doi.org/10.1017/S003329172000389X

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Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide Microdoses in Healthy Participants

November 26, 2021 / LSD, Microdosing, Papers / Leave a Comment / By / , , , , , , , , ,

Abstract

“Microdoses” of lysergic acid diethylamide (LSD) are used recreationally to enhance mood and cognition. Increasing interest has also been seen in developing LSD into a medication. Therefore, we performed a pharmacokinetic-pharmacodynamic study using very low doses of LSD. Single doses of LSD base (5, 10, and 20 µg) and placebo were administered in a double-blind, randomized, placebo-controlled crossover study in 23 healthy participants. Test days were separated by at least 5 days. Plasma levels of LSD and subjective effects were assessed up to 6 hours after administration. Pharmacokinetic parameters were determined using compartmental modeling. Concentration-subjective effect relationships were described using pharmacokinetic-pharmacodynamic modeling. Mean (95% confidence interval) maximal LSD concentrations were 151 pg/mL (127-181), 279 pg/mL (243-320), and 500 pg/mL (413-607) after 5, 10, and 20 µg LSD administration, respectively. Maximal concentrations were reached after 1.1 hours. The mean elimination half-life was 2.7 hours (1.5-6.2). The 5 µg dose of LSD elicited no significant acute subjective effects. The 10 µg dose of LSD significantly increased ratings of “under the influence” and “good drug effect” compared with placebo. These effects began an average of 1.1 hours after 10 µg LSD administration, peaked at 2.5 hours, and ended at 5.1 hours. The 20 µg dose of LSD significantly increased ratings of “under the influence,” “good drug effects,” and “bad drug effects.” LSD concentrations dose-proportionally increased at doses as low as 5-20 µg and decreased with a half-life of 3 hours. The threshold dose of LSD base for psychotropic effects was 10 µg.

Holze, F., Liechti, M. E., Hutten, N., Mason, N. L., Dolder, P. C., Theunissen, E. L., Duthaler, U., Feilding, A., Ramaekers, J. G., & Kuypers, K. (2021). Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide Microdoses in Healthy Participants. Clinical pharmacology and therapeutics, 109(3), 658–666. https://doi.org/10.1002/cpt.2057

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Mood and cognition after administration of low LSD doses in healthy volunteers: A placebo controlled dose-effect finding study

November 26, 2021 / LSD, Microdosing, Papers, Psychology / Leave a Comment / By / , , , , , , , ,

Abstract

There is a popular interest in microdosing with psychedelics such as LSD. This practice of using one-tenth of a full psychedelic dose according to a specific dosing schedule, anecdotally enhances mood and performance. Nonetheless, controlled research on the efficacy of microdosing is scarce. The main objective of the present dose-finding study was to determine the minimal dose of LSD needed to affect mood and cognition. A placebo-controlled within-subject study including 24 healthy participants, was conducted to assess the acute effects of three LSD doses (5, 10, and 20 mcg) on measures of cognition, mood, and subjective experience, up until 6 h after administration. Cognition and subjective experience were assessed using the Psychomotor Vigilance Task, Digit Symbol Substitution Test, Cognitive Control Task, Profile of Mood States, and 5-Dimensional Altered States of Consciousness rating scale. LSD showed positive effects in the majority of observations by increasing positive mood (20 mcg), friendliness (5, 20 mcg), arousal (5 mcg), and decreasing attentional lapses (5, 20 mcg). Negative effects manifested as an increase in confusion (20 mcg) and anxiety (5, 20 mcg). Psychedelic-induced changes in waking consciousness were also present (10, 20 mcg). Overall, the present study demonstrated selective, beneficial effects of low doses of LSD on mood and cognition in the majority of observations. The minimal LSD dose at which subjective and performance effects are notable is 5 mcg and the most apparent effects were visible after 20 mcg.

Hutten, N., Mason, N. L., Dolder, P. C., Theunissen, E. L., Holze, F., Liechti, M. E., Feilding, A., Ramaekers, J. G., & Kuypers, K. (2020). Mood and cognition after administration of low LSD doses in healthy volunteers: A placebo controlled dose-effect finding study. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 41, 81–91. https://doi.org/10.1016/j.euroneuro.2020.10.002

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Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects

November 26, 2021 / LSD, Papers / Leave a Comment / By / , , , , , , , , , ,

Abstract

Growing interest has been seen in using lysergic acid diethylamide (LSD) in psychiatric research and therapy. However, no modern studies have evaluated subjective and autonomic effects of different and pharmaceutically well-defined doses of LSD. We used a double-blind, randomized, placebo-controlled, crossover design in 16 healthy subjects (eight women, eight men) who underwent six 25 h sessions and received placebo, LSD (25, 50, 100, and 200 µg), and 200 µg LSD 1 h after administration of the serotonin 5-hydroxytryptamine-2A (5-HT2A) receptor antagonist ketanserin (40 mg). Test days were separated by at least 10 days. Outcome measures included self-rating scales that evaluated subjective effects, autonomic effects, adverse effects, plasma brain-derived neurotrophic factor levels, and pharmacokinetics up to 24 h. The pharmacokinetic-subjective response relationship was evaluated. LSD showed dose-proportional pharmacokinetics and first-order elimination and dose-dependently induced subjective responses starting at the 25 µg dose. A ceiling effect was observed for good drug effects at 100 µg. The 200 µg dose of LSD induced greater ego dissolution than the 100 µg dose and induced significant anxiety. The average duration of subjective effects increased from 6.7 to 11 h with increasing doses of 25-200 µg. LSD moderately increased blood pressure and heart rate. Ketanserin effectively prevented the response to 200 µg LSD. The LSD dose-response curve showed a ceiling effect for subjective good effects, and ego dissolution and anxiety increased further at a dose above 100 µg. These results may assist with dose finding for future LSD research. The full psychedelic effects of LSD are primarily mediated by serotonin 5-HT2A receptor activation.

Holze, F., Vizeli, P., Ley, L., Müller, F., Dolder, P., Stocker, M., Duthaler, U., Varghese, N., Eckert, A., Borgwardt, S., & Liechti, M. E. (2021). Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 46(3), 537–544. https://doi.org/10.1038/s41386-020-00883-6

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Acute subjective effects in LSD- and MDMA-assisted psychotherapy

March 16, 2022 / LSD, MDMA, Papers / Leave a Comment / By / , , ,

Abstract

Background: Lysergic acid diethylamide (LSD) and 3,4-methylenedioxymethamphetamine (MDMA) were used in psychotherapy in the 1960s-1980s, and are currently being re-investigated as treatments for several psychiatric disorders. In Switzerland, limited medical use of these substances is possible in patients not responding to other treatments (compassionate use).

Methods: This study aimed to describe patient characteristics, treatment indications and acute alterations of mind in patients receiving LSD (100-200 µg) and/or MDMA (100-175 mg) within the Swiss compassionate use programme from 2014-2018. Acute effects were assessed using the 5 Dimensions of Altered States of Consciousness scale and the Mystical Experience Questionnaire, and compared with those in healthy volunteers administered with LSD or MDMA and patients treated alone with LSD in clinical trials.

Results: Eighteen patients (including 12 women and six men, aged 29-77 years) were treated in group settings. Indications mostly included posttraumatic stress disorder and major depression. Generally, a drug-assisted session was conducted every 3.5 months after 3-10 psychotherapy sessions. LSD induced pronounced alterations of consciousness on the 5 Dimensions of Altered States of Consciousness scale, and mystical-type experiences with increases in all scales on the Mystical Experience Questionnaire. Effects were largely comparable between patients in the compassionate use programme and patients or healthy subjects treated alone in a research setting.

Conclusion: LSD and MDMA are currently used medically in Switzerland mainly in patients with posttraumatic stress disorder and depression in group settings, producing similar acute responses as in research subjects. The data may serve as a basis for further controlled studies of substance-assisted psychotherapy.

Schmid, Y., Gasser, P., Oehen, P., & Liechti, M. E. (2021). Acute subjective effects in LSD- and MDMA-assisted psychotherapy. Journal of psychopharmacology (Oxford, England), 35(4), 362–374. https://doi.org/10.1177/0269881120959604

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Potential safety, benefits, and influence of the placebo effect in microdosing psychedelic drugs: A systematic review

November 26, 2021 / LSD, Microdosing, Mushrooms / Psilocybin, Papers, Psychology / Leave a Comment / By / ,

Abstract

Microdosing psychedelic drugs-that is, taking sub-behavioral doses of lysergic acid diethylamide (LSD) or psilocybin-is a growing practice in Western societies. Taken mainly for creative or mood-enhancing purposes, thousands of users are increasingly being exposed to (micro)doses of psychedelic drugs. In this systematic review, we searched the available evidence from human studies, focusing our results in terms of three main axes: efficacy, safety, and the influence of the placebo effect in microdosing practices. While the available evidence has some strengths (e.g. large sample sizes, robust methodologies) there are also remarkable limitations (e.g. gender bias, heterogeneity of dosing schedules and drugs used). Highly contradictory results have been found, showing both the benefits and detriments of microdosing in terms of mood, creative processes, and energy, among other regards. This review provides a general overview of the methods and approaches used, which could be useful for improving future studies.

Ona, G., & Bouso, J. C. (2020). Potential safety, benefits, and influence of the placebo effect in microdosing psychedelic drugs: A systematic review. Neuroscience and biobehavioral reviews, 119, 194–203. https://doi.org/10.1016/j.neubiorev.2020.09.035

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Biosynthesis, total synthesis, and biological profiles of Ergot alkaloids

February 21, 2022 / LSD, Papers, Pharmacology & Chemistry / Leave a Comment / By / ,

Abstract

While the use of ergot alkaloids in folk medicine has been practiced for millennia, systematic investigations on their therapeutic potential began about 100 years ago. Subsequently, Albert Hofmann’s discovery of lysergic acid diethylamide (LSD) and its intense psychedelic properties garnered worldwide attention and prompted further studies of this compound class. As a result, several natural ergot alkaloids were discovered and unnatural analogs were synthesized, and some were used to treat an array of maladies, including Alzheimer’s and Parkinson’s disease. While LSD was never commercially approved, recent clinical studies have found it can be an innovative and effective treatment option for several psychiatric disorders. Ongoing biosynthetic and total synthetic investigations aim to understand the natural origins of ergot alkaloids, help develop facile means to produce these natural products and enable their continued use as medicinal chemistry lead structures. This review recounts major developments over the past 20 years in biosynthetic, total synthetic, and pharmaceutical studies. Many ergot alkaloid biosynthetic pathways have been elucidated, with some of them subsequently applied toward “green” syntheses. New chemical methodologies have fostered a fast and efficient access to the ergoline scaffold, prompting some groups to investigate biological properties of natural product-like ergot alkaloids. Limited pharmaceutical applications have yet to completely bypass the undesirable side effects of ergotism, suggesting further studies of this drug class are likely needed and will potentially harness major therapeutic significance.

Tasker, N. R., & Wipf, P. (2021). Biosynthesis, total synthesis, and biological profiles of Ergot alkaloids. The Alkaloids. Chemistry and biology, 85, 1–112. https://doi.org/10.1016/bs.alkal.2020.08.001

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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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Efficacy of Psychoactive Drugs for the Treatment of Posttraumatic Stress Disorder: A Systematic Review of MDMA, Ketamine, LSD and Psilocybin

November 18, 2021 / Anxiety Disorders / PTSD, Ketamine, LSD, MDMA, Mushrooms / Psilocybin, Papers, Psychology / Leave a Comment / By / , , , ,

Abstract

The aim of this systematic review was to examine the efficacy of MDMA, ketamine, LSD, and psilocybin for the treatment of posttraumatic stress disorder (PTSD). A search of four databases for English language, peer-reviewed literature published from inception to 18th October 2019 yielded 2,959 records, 34 of which were screened on full-text. Observational studies and RCTs which tested the efficacy of MDMA, ketamine, LSD, or psilocybin for reducing PTSD symptoms in adults, and reported changes to PTSD diagnosis or symptomatology, were included. Nine trials (five ketamine and four MDMA) met inclusion criteria. Trials were rated on a quality and bias checklist and GRADE was used to rank the evidence. The evidence for ketamine as a stand-alone treatment for comorbid PTSD and depression was ranked “very low”, and the evidence for ketamine in combination with psychotherapy as a PTSD treatment was ranked “low”. The evidence for MDMA in combination with psychotherapy as a PTSD treatment was ranked “moderate”.

Varker, T., Watson, L., Gibson, K., Forbes, D., & O’Donnell, M. L. (2021). Efficacy of Psychoactive Drugs for the Treatment of Posttraumatic Stress Disorder: A Systematic Review of MDMA, Ketamine, LSD and Psilocybin. Journal of psychoactive drugs, 53(1), 85–95. https://doi.org/10.1080/02791072.2020.1817639

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