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Distinct acute effects of LSD, MDMA, and D-amphetamine in healthy subjects.

November 16, 2019 / Anxiety disorders / PTSD, Consciousness, LSD, MDMA, Mystical experiences, Papers, Psychology, Psychopharmacology, Psychotherapy, Publications, Safety / By / , , , , ,

Abstract

Lysergic acid diethylamide (LSD) is a classic psychedelic, 3,4-methylenedioxymethamphetamine (MDMA) is an empathogen, and D-amphetamine is a classic stimulant. All three substances are used recreationally. LSD and MDMA are being investigated as medications to assist psychotherapy, and D-amphetamine is used for the treatment of attention-deficit/hyperactivity disorder. All three substances induce distinct acute subjective effects. However, differences in acute responses to these prototypical psychoactive substances have not been characterized in a controlled study. We investigated the acute autonomic, subjective, and endocrine effects of single doses of LSD (0.1 mg), MDMA (125 mg), D-amphetamine (40 mg), and placebo in a randomized, double-blind, cross-over study in 28 healthy subjects. All of the substances produced comparable increases in hemodynamic effects, body temperature, and pupil size, indicating equivalent autonomic responses at the doses used. LSD and MDMA increased heart rate more than D-amphetamine, and D-amphetamine increased blood pressure more than LSD and MDMA. LSD induced significantly higher ratings on the 5 Dimensions of Altered States of Consciousness scale and Mystical Experience Questionnaire than MDMA and D-amphetamine. LSD also produced greater subjective drug effects, ego dissolution, introversion, emotional excitation, anxiety, and inactivity than MDMA and D-amphetamine. LSD also induced greater impairments in subjective ratings of concentration, sense of time, and speed of thinking compared with MDMA and D-amphetamine. MDMA produced greater ratings of good drug effects, liking, high, and ego dissolution compared with D-amphetamine. D-Amphetamine increased ratings of activity and concentration compared with LSD. MDMA but not LSD or D-amphetamine increased plasma concentrations of oxytocin. None of the substances altered plasma concentrations of brain-derived neurotrophic factor. These results indicate clearly distinct acute effects of LSD, MDMA, and D-amphetamine and may assist the dose-finding in substance-assisted psychotherapy research.
Holze, F., Vizeli, P., Müller, F., Ley, L., Duerig, R., Varghese, N., … & Liechti, M. E. (2019). Distinct acute effects of LSD, MDMA, and d-amphetamine in healthy subjects. Neuropsychopharmacology, 1-11., https://doi.org/10.1038/s41386-019-0569-3
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Locomotor effects of 3,4-methylenedioxymethamphetamine (MDMA) and its deuterated form in mice: psychostimulant effects, stereotypy, and sensitization

November 15, 2019 / MDMA, Neuroscience, New substances, Other subjects, Papers, Psychopharmacology, Psychotherapy, Publications, Safety, Toxicology / By / , , ,

Abstract

Rationale

There is a renewed interest in the use of 3,4-methylenedioxymethamphetamine (MDMA) for treating psychiatric conditions. Although MDMA has entered phase II clinical trials and shows promise as an adjunct treatment, there is an extensive literature detailing the potential neurotoxicity and adverse neurobehavioral effects associated with MDMA use. Previous research indicates that the adverse effects of MDMA may be due to its metabolism into reactive catechols that can enter the brain and serve directly as neurotoxicants. One approach to mitigate MDMA’s potential for adverse effects is to reduce O-demethylation by deuterating the methylenedioxy ring of MDMA. There are no studies that have evaluated the effects of deuterating MDMA on behavioral outcomes.

Objectives

The purpose of the present study was to assess the motor-stimulant effects of deuterated MDMA (d2-MDMA) and compare them to MDMA in male mice.

Methods

Two experiments were performed to quantify mouse locomotor activity and to vary the drug administration regimen (single bolus administration or cumulative administration).

Results

The results of Experiments 1 and 2 indicate that d2-MDMA is less effective at eliciting horizontal locomotion than MDMA; however, the differences between the compounds diminish as the number of cumulative administrations increase. Both d2-MDMA and MDMA can elicit sensitized responses, and these effects cross-sensitize to the prototypical drug of abuse methamphetamine. Thus, d2-MDMA functions as a locomotor stimulant similar to MDMA, but, depending on the dosing regimen, may be less susceptible to inducing sensitization to stereotyped movements.

Conclusions

These findings indicate that d2-MDMA is behaviorally active and produces locomotor effects that are similar to MDMA, which warrant additional assessments of d2-MDMA’s behavioral and physiological effects to determine the conditions under which this compound may serve as a relatively safer alternative to MDMA for clinical use.
Berquist, M. D., Leth-Petersen, S., Kristensen, J. L., & Fantegrossi, W. E. (2020). Locomotor effects of 3, 4-methylenedioxymethamphetamine (MDMA) and its deuterated form in mice: psychostimulant effects, stereotypy, and sensitization. Psychopharmacology, 237(2), 431-442; https://doi.org/10.1007/s00213-019-05380-3

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Classical psychedelics for the treatment of depression and anxiety: A systematic review.

July 30, 2019 / Anxiety disorders / PTSD, Ayahuasca, Depression, LSD, Mushrooms / Psilocybin, Papers, Psychiatry, Psychology, Psychopharmacology, Psychotherapy, Publications, Safety / By / , ,

Abstract

BACKGROUND:
Depression and anxiety are prevalent psychiatric disorders that carry significant morbidity. Pharmacological and psychosocial interventions are used to manage these conditions, but their efficacy is limited. Recent interest into the use of psychedelic-assisted therapy using ayahuasca, psilocybin or lysergic acid diethylamide (LSD) may be a promising alternative for patients unresponsive to traditional treatments. This review aims to determine the efficacy and tolerability of psychedelics in the management of resistant depression.
METHODS:
Clinical trials investigating psychedelics in patients with depression and/or anxiety were searched via MEDLINE, EMBASE and PsychINFO. Efficacy was assessed by measuring symptom improvement from baseline, and tolerability was evaluated by noting the incidence and type of adverse effects reported. Risk of bias was assessed.
RESULTS:
Seven studies, with 130 patients, were analysed in this review. Three were conducted in patients with depression, two in patients with anxiety and two in patients with both. In a supportive setting, ayahuasca, psilocybin, and LSD consistently produced immediate and significant anti-depressant and anxiolytic effects that were endured for several months. Psychedelics were well-tolerated. The most common adverse effects were transient anxiety, short-lived headaches, nausea and mild increases in heart rate and blood pressure.
LIMITATIONS:
At present, the number of studies on this subject is very limited; and the number of participating patients within these is also limited as the treatment under investigations is a relatively novel concept.
CONCLUSIONS:
Though further evidence is required, psychedelics appear to be effective in significantly reducing symptoms of depression and anxiety and are well-tolerated.

Muttoni, S., Ardissino, M., & John, C. (2019). Classical psychedelics for the treatment of depression and anxiety: a systematic review. Journal of affective disorders., https://doi.org/10.1016/j.jad.2019.07.076
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Metabolism of lysergic acid diethylamide (LSD): an update.

July 16, 2019 / LSD, Other subjects, Papers, Psychology, Psychopharmacology, Publications, Safety, Toxicology / By /

Abstract

Lysergic acid diethylamide (LSD) is the most potent hallucinogen known and its pharmacological effect results from stimulation of central serotonin receptors (5-HT2). Since LSD is seen as physiologically safe compound with low toxicity, its use in therapeutics has been renewed during the last few years. This review aims to discuss LSD metabolism, by presenting all metabolites as well as clinical and toxicological relevance. LSD is rapidly and extensively metabolized into inactive metabolites; whose detection window is higher than parent compound. The metabolite 2-oxo-3-hydroxy LSD is the major human metabolite, which detection and quantification is important for clinical and forensic toxicology. Indeed, information about LSD pharmacokinetics in humans is limited and for this reason, more research studies are needed.
Libânio Osório Marta, R. F. (2019). Metabolism of lysergic acid diethylamide (LSD): an update. Drug metabolism reviews, 51(3), 378-387. https://doi.org/10.1080/03602532.2019.1638931
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First study of safety and tolerability of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in patients with alcohol use disorder: preliminary data on the first four participants

July 15, 2019 / Papers, Psychiatry, Psychology, Psychopharmacology, Psychotherapy, Publications, Safety, Substance Use Disorder / By / , , ,

Abstract

We present the preliminary data in an ongoing open-label safety and tolerability proof of concept study exploring the potential role for 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in treating patients with alcohol use disorder. At this stage, seven participants have completed the full 8-week MDMA-assisted psychotherapy course, including two therapy sessions each with MDMA. This paper focuses on the safety and tolerability of the therapeutic course for the first four participants to complete treatment. Longer-term outcomes of drinking behaviour will be presented later when the full project data are published. Results show all four participants have successfully tolerated the treatment. There have been no serious adverse events related to MDMA, no unexpected physiological responses to the MDMA sessions or changes to blood results or electrocardiograms, measured before and after the 8-week course. We conclude that the treatment is well- tolerated and are making plans to expand the project into a randomised placebo-controlled study.

Sessa, B., Sakal, C., O’Brien, S., & Nutt, D. (2019). First study of safety and tolerability of 3, 4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in patients with alcohol use disorder: preliminary data on the first four participants. BMJ Case Reports CP, 12(7), e230109, http://dx.doi.org/10.1136/bcr-2019-230109
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Microdosing psychedelics: More questions than answers? An overview and suggestions for future research.

July 14, 2019 / LSD, Mushrooms / Psilocybin, Other subjects, Papers, Personal development, Psychology, Psychopharmacology, Publications, Safety / 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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Psychedelic microdosing benefits and challenges: an empirical codebook.

July 10, 2019 / Anxiety disorders / PTSD, Depression, LSD, Mushrooms / Psilocybin, Papers, Personal development, Psychiatry, Psychology, Psychopharmacology, Psychotherapy, Publications, Safety / By / , , , , , ,

Abstract

BACKGROUND:
Microdosing psychedelics is the practice of consuming very low, sub-hallucinogenic doses of a psychedelic substance, such as lysergic acid diethylamide (LSD) or psilocybin-containing mushrooms. According to media reports, microdosing has grown in popularity, yet the scientific literature contains minimal research on this practice. There has been limited reporting on adverse events associated with microdosing, and the experiences of microdosers in community samples have not been categorized.
METHODS:
In the present study, we develop a codebook of microdosing benefits and challenges (MDBC) based on the qualitative reports of a real-world sample of 278 microdosers.
RESULTS:
We describe novel findings, both in terms of beneficial outcomes, such as improved mood (26.6%) and focus (14.8%), and in terms of challenging outcomes, such as physiological discomfort (18.0%) and increased anxiety (6.7%). We also show parallels between benefits and drawbacks and discuss the implications of these results. We probe for substance-dependent differences, finding that psilocybin-only users report the benefits of microdosing were more important than other users report.
CONCLUSIONS:
These mixed-methods results help summarize and frame the experiences reported by an active microdosing community as high-potential avenues for future scientific research. The MDBC taxonomy reported here informs future research, leveraging participant reports to distil the highest-potential intervention targets so research funding can be efficiently allocated. Microdosing research complements the full-dose literature as clinical treatments are developed and neuropharmacological mechanisms are sought. This framework aims to inform researchers and clinicians as experimental microdosing research begins in earnest in the years to come.
Anderson, T., Petranker, R., Christopher, A., Rosenbaum, D., Weissman, C., Dinh-Williams, L. A., … & Hapke, E. (2019). Psychedelic microdosing benefits and challenges: an empirical codebook. Harm reduction journal, 16(1), 43., https://doi.org/10.1186/s12954-019-0308-4
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Acute subjective and behavioral effects of microdoses of LSD in healthy human volunteers

June 3, 2019 / LSD, Other subjects, Papers, Psychology, Psychopharmacology, Publications, Safety / By / , , , ,

Abstract

Background
Numerous anecdotal reports suggest that repeated use of very low doses of lysergic acid diethylamide (LSD), known as “microdosing,” improves mood and cognitive function. These effects are consistent both with the known actions of LSD on serotonin receptors, and with limited evidence that higher doses of LSD (100-200 μg) positively bias emotion processing. Yet, the effects of such sub-threshold doses of LSD have not been tested in a controlled laboratory setting. As a first step, we examined the effects of single very low doses of LSD (0 – 26μg) on mood and behavior in healthy volunteers under double-blind conditions.
Methods
Healthy young adults (N=20) attended four laboratory sessions during which they received placebo, 6.5μg, 13μg, or 26μg LSD in randomized order at one-week intervals. During expected peak drug effect, they completed mood questionnaires and behavioral tasks assessing emotion processing and cognition. Cardiovascular measures and body temperature were also assessed.
Results
LSD produced dose-related subjective effects across the three doses (6.5μg, 13μg, or 26μg). At the highest dose the drug also increased ratings of “vigor” and slightly decreased positivity ratings of images with positive emotional content. Other mood measures, cognition, and physiological measures were unaffected.
Conclusions
Single “microdoses” of LSD produced orderly dose-related subjective effects in healthy volunteers. These findings indicate that a threshold dose of 13μg of LSD might be used safely in an investigation of repeated administrations. It remains to be determined whether the drug improves mood or cognition in individuals with symptoms of depression.
Bershad, A. K., Schepers, S. T., Bremmer, M. P., Lee, R., & de Wit, H. (2019). Acute subjective and behavioral effects of microdoses of LSD in healthy human volunteers. Biological Psychiatry., https://doi.org/10.1016/j.biopsych.2019.05.019
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Psychedelic-assisted therapies: The past, and the need to move forward responsibly.

May 25, 2019 / LSD, Mushrooms / Psilocybin, Papers, Psychiatry, Psychology, Psychopharmacology, Psychotherapy, Publications, Safety / By / , , ,

Abstract

Recent clinical studies illustrate that psychedelics such as LSD and psilocybin may represent much-needed new treatment options for mood disorders and alcohol and other drug use disorders. More clinical studies are required to confirm the safety and efficacy of psychedelic-assisted therapies, but the cultural stigma that has surrounded psychedelics since the 1960s has hindered research. This problem is amplified in Australia. There has been a complete absence of research into psychedelic therapies, and Australian-based research advocates claim to have encountered a number of barriers. In this commentary, we provide a brief account of the historical stigma associated with psychedelics, and an overview of the contemporary context of research into psychedelic-assisted therapies, including the purported barriers to research in Australia. In light of the complex history of psychedelics, we identify a number of pressing questions relating to the social and legal context that need to be addressed so that clinical studies can proceed. Research is needed to address such questions so that the nature and extent of purported barriers to clinical studies with psychedelics can be properly elucidated, and strategies developed – with practitioners, patients, families and other stakeholders – to responsibly address these barriers. This is important because it will enable Australian researchers to contribute robust evidence about the possible efficacy and safety of psychedelic therapies, and to facilitate local expertise needed to implement psychedelic-assisted therapies, should they prove efficacious.
Gardner, J., Carter, A., O’Brien, K., & Seear, K. (2019). Psychedelic-assisted therapies: The past, and the need to move forward responsibly. International Journal of Drug Policy, 70, 94-98., https://doi.org/10.1016/j.drugpo.2019.05.019
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Dimethyltryptamine: Endogenous Role and Therapeutic Potential.

April 25, 2019 / Anxiety disorders / PTSD, Depression, DMT, Papers, Psychiatry, Psychology, Psychopharmacology, Psychotherapy, Publications, Safety, Substance Use Disorder / By / , ,

Abstract

N, N-dimethyltryptamine (DMT) is an indole alkaloid produced by a number of plants and animals, including humans. Its psychoactive effects were first described in 1956 by Stephen Szára, but have been exploited for centuries by South American indigenous populations in the form of ayahuasca. In the present review, we assess the state of the art regarding a putative role for endogenous DMT and potential clinical applications of ayahuasca and DMT. A review assessing the pharmacological profile of DMT and its clinical effects in humans was performed using the PubMed data base until 5 August 2018 with the words: ayahuasca and N,N-dimethyltryptamine. While the role of endogenous DMT remains unclear, ayahuasca has promising results in anxiety, depression and substance dependence. Since ayahuasca has a good safety profile, it is crucial to conduct further research aimed at developing new treatments for psychiatric disorders.
Rodrigues, A. V., Almeida, F. J., & Vieira-Coelho, M. A. (2019). Dimethyltryptamine: endogenous role and therapeutic potential. Journal of psychoactive drugs, 1-12., https://doi.org/10.1080/02791072.2019.1602291
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