Psychedelics Research Recap August 2020

Research slowed down a bit during this August, but still enough interesting things were found. The effect of 20 µg LSD on increasing pain tolerance was widely reported. This dosage is not psychedelic and not much above the ‘normal’ microdose range. More research on the pain-relieving (analgesic) effects of LSD in specific patient populations is the next logical step.

Where much of the research on psychedelics is focused on the quantitative aspects, one review looked at the qualitative reports of 15 studies (n=178). Between the different psychedelics, participants reported similar themes and in the article you can find quotes and links to the original studies.

A large survey study (n=358) found that people reported several benefits in the 2 and 4 weeks after using psychedelics. There was less avoidance of feelings (experiential avoidance), fewer depressive symptoms and suicidal ideation. The researchers concluded that therapy that targets experiential avoidance such as ACT therapy may be a good match with psychedelics.

Ketamine improves short-term plasticity in depression by enhancing sensitivity to prediction errors

Authors: Rachael L. Sumner, Rebecca McMillan, Meg J. Spriggs, Doug Campbell, Gemma Malpas, Elizabeth Maxwell, Carolyn Deng, John Hay, Rhys Ponton, Frederick Sundram, Suresh D. Muthukumaraswamy

Published: 3 August 2020

One-sentence summary: Prediction error sensitivity, a possible proxy for brain plasticity that is lacking for patients with depression, is improved by ketamine for that population.

“Major depressive disorder negatively impacts the sensitivity and adaptability of the brain’s predictive coding framework. The current electroencephalography study into the antidepressant properties of ketamine investigated the downstream effects of ketamine on predictive coding and short-term plasticity in thirty patients with depression using the auditory roving mismatch negativity (rMMN). The rMMN paradigm was run 3-4 h after a single 0.44 mg/kg intravenous dose of ketamine or active placebo (remifentanil infused to a target plasma concentration of 1.7 ng/mL) in order to measure the neural effects of ketamine in the period when an improvement in depressive symptoms emerges. Depression symptomatology was measured using the Montgomery-Asberg Depression Rating Scale (MADRS); 70% of patients demonstrated at least a 50% reduction their MADRS global score. Ketamine significantly increased the MMN and P3a event related potentials, directly contrasting literature demonstrating ketamine’s acute attenuation of the MMN. This effect was only reliable when all repetitions of the post-deviant tone were used. Dynamic causal modelling showed greater modulation of forward connectivity in response to a deviant tone between right primary auditory cortex and right inferior temporal cortex, which significantly correlated with antidepressant response to ketamine at 24 h. This is consistent with the hypothesis that ketamine increases sensitivity to unexpected sensory input and restores deficits in sensitivity to prediction error that are hypothesised to underlie depression. However, the lack of repetition suppression evident in the MMN evoked data compared to studies of healthy adults suggests that, at least within the short term, ketamine does not improve deficits in adaptive internal model calibration.”

Post-Psychedelic Reductions in Experiential Avoidance Are Associated With Decreases in Depression Severity and Suicidal Ideation

Authors: Richard J. Zeifman, Anne C. Wagner, Ros Watts, Hannes Kettner, Lea J. Mertens & Robin L. Carhart-Harris

Published: 7 August 2020

One-sentence summary: A prospective survey study (n=358) found that psychedelics may lead to significant decreases in experiential avoidance, depression severity, and suicidal ideation.

“Psychedelic therapy shows promise as a novel intervention for a wide range of mental health concerns but its therapeutic action is incompletely understood. In line with acceptance and commitment therapy’s (ACT’s) transdiagnostic model, qualitative research has suggested that reductions in experiential avoidance are an important component of therapeutic outcomes associated with psychedelics. However, limited research has quantitatively explored the association between decreases in experiential avoidance and therapeutic outcomes associated with psychedelics. Therefore, in two prospective studies, using convenience samples of individuals with plans to use a psychedelic, we explored the impact of psychedelic use on experiential avoidance, depression severity, and suicidal ideation, as well as relationships between changes in these outcomes. Participants (Study 1, N=104; Study 2, N=254) completed self-report questionnaires of depression severity, suicidal ideation, and experiential avoidance: 1) before using a psychedelic (in ceremonial and non-ceremonial contexts), as well as 2) 2-weeks and 3) 4-weeks after psychedelic use. Across both studies, repeated measures ANOVAs indicated significant decreases in experiential avoidance, depression severity, and suicidal ideation after psychedelic use. Furthermore, decreases in experiential avoidance were significantly associated with decreases in depression severity and suicidal ideation. These results suggest that psychedelics may lead to significant decreases in experiential avoidance, depression severity, and suicidal ideation. Additionally, these findings imply that reduced experiential avoidance may be a transdiagnostic mechanism mediating treatment success within psychedelic therapy. We conclude that integrating psychedelics with psychotherapeutic interventions that target experiential avoidance (e.g. ACT) may enhance therapeutic outcomes.”

Also reported in Interesting Engineering and PsyPost.

Psychedelic Treatments for Psychiatric Disorders: A Systematic Review and Thematic Synthesis of Patient Experiences in Qualitative Studies

Authors: Joost J. Breeksema, Alistair R. Niemeijer, Erwin Krediet, Eric Vermetten & Robert A. Schoevers

Published: 17 August 2020

One-sentence summary: This review identified 15 studies (n=178) that used a variety of psychedelics to have overlapping therapeutic processes, were compared favorably over conventional treatments and often elicited other positive changes beyond the specific diagnosis.

“Introduction Interest in the use of psychedelic substances for the treatment of mental disorders is increasing. Processes that may affect therapeutic change are not yet fully understood. Qualitative research methods are increasingly used to examine patient accounts; however, currently, no systematic review exists that synthesizes these findings in relation to the use of psychedelics for the treatment of mental disorders. Objective To provide an overview of salient themes in patient experiences of psychedelic treatments for mental disorders, presenting both common and diverging elements in patients’ accounts, and elucidating how these affect the treatment process. Methods We systematically searched the PubMed, MEDLINE, PsycINFO, and Embase databases for English-language qualitative literature without time limitations. Inclusion criteria were qualitative research design; peer-reviewed studies; based on verbalized patient utterances; and a level of abstraction or analysis of the results. Thematic synthesis was used to analyze and synthesize results across studies. A critical appraisal of study quality and methodological rigor was conducted using the Critical Appraisal Skills Programme (CASP). Results Fifteen research articles, comprising 178 patient experiences, were included. Studies exhibited a broad heterogeneity in terms of substance, mental disorder, treatment context, and qualitative methodology. Substances included psilocybin, lysergic acid diethylamide (LSD), ibogaine, ayahuasca, ketamine and 3,4-methylenedioxymethamphetamine (MDMA). Disorders included anxiety, depression, eating disorders, post-traumatic stress disorder, and substance use disorders. While the included compounds were heterogeneous in pharmacology and treatment contexts, patients reported largely comparable experiences across disorders, which included phenomenological analogous effects, perspectives on the intervention, therapeutic processes and treatment outcomes. Comparable therapeutic processes included insights, altered self-perception, increased connectedness, transcendental experiences, and an expanded emotional spectrum, which patients reported contributed to clinically and personally relevant responses. Conclusions This review demonstrates how qualitative research of psychedelic treatments can contribute to distinguishing specific features of specific substances, and carry otherwise undiscovered implications for the treatment of specific psychiatric disorders.”

P300-mediated modulations in self-other processing under psychedelic psilocybin are related to connectedness and changed meaning: A window into the self-other overlap

Authors: Lukasz Smigielski, Michael Kometer, Milan Scheidegger, Cornelia Stress, Katrin H. Preller, Thomas Koenig & Franz X. Vollenweider

Published: 21 August 2020

One-sentence summary: This brain-mapping study (n=17) sheds more light on the relationship between self and other with a macro dose of psilocybin (16mg/70kg).

“The concept of self and self-referential processing has a growing explanatory value in psychiatry and neuroscience, referring to the cognitive organization and perceptual differentiation of self-stimuli in health and disease. Conditions in which selfhood loses its natural coherence offer a unique opportunity for elucidating the mechanisms underlying self-disturbances. We assessed the psychoactive effects of psilocybin (230 μg/kg p.o.), a preferential 5-HT1A/2A agonist known to induce shifts in self-perception. Our placebo-controlled, double-blind, within-subject crossover experiment (n = 17) implemented a verbal self-monitoring task involving vocalizations and participant identification of real-time auditory source- (self/other) and pitch-modulating feedback. Subjective experience and task performance were analyzed, with time-point-by-time-point assumption-free multivariate randomization statistics applied to the spatiotemporal dynamics of event-related potentials. Psilocybin-modulated self-experience, interacted with source to affect task accuracy, and altered the late phase of self-stimuli encoding by abolishing the distinctiveness of self- and other-related electric field configurations during the P300 timeframe. This last effect was driven by current source density changes within the supragenual anterior cingulate and right insular cortex. The extent of the P300 effect was associated with the intensity of psilocybin-induced feelings of unity and changed meaning of percepts. Modulations of late encoding and their underlying neural generators in self-referential processing networks via 5-HT signaling may be key for understanding self-disorders. This mechanism may reflect a neural instantiation of altered self-other and relational meaning processing in a stimulus-locked time domain. The study elucidates the neuropharmacological foundation of subjectivity, with implications for therapy, underscoring the concept of connectedness.”

A low dose of lysergic acid diethylamide decreases pain perception in healthy volunteers

Authors: Johannes G. Ramaekers, Nadia Hutten, Natasha L. Mason, Patrick Dolder, Eef L. Theunissen, Friederike Holze, Matthias E. Liechti, Amanda Feilding & Kim P. C. Kuypers

Published: 25 August 2020

One-sentence summary: A low/micro (20 µg) dose of LSD increased the pain tolerance (n=24).

“Background: Lysergic acid diethylamide (LSD) is an ergot alkaloid derivative with psychedelic properties that has been implicated in the management of persistent pain. Clinical studies in the 1960s and 1970s have demonstrated profound analgesic effects of full doses of LSD in terminally ill patients, but this line of research evaporated after LSD was scheduled worldwide. Aim: The present clinical study is the first to revisit the potential of LSD as an analgesic, and at dose levels which are not expected to produce profound mind-altering effects. Methods: Twenty-four healthy volunteers received single doses of 5, 10 and 20 µg LSD as well as placebo on separate occasions. A Cold Pressor Test was administered at 1.5 and 5 h after treatment administration to assess pain tolerance to experimentally evoked pain. Ratings of dissociation and psychiatric symptoms as well as assessments of vital signs were included to monitor mental status as well as safety during treatments. Results: LSD 20 µg significantly increased the time that participants were able to tolerate exposure to cold (3°C) water and decreased their subjective levels of experienced pain and unpleasantness. LSD elevated mean blood pressure within the normal range and slightly increased ratings of dissociation, anxiety and somatization. Conclusion: The present study provides evidence of a protracted analgesic effect of LSD at a dose that is low enough to avoid a psychedelic experience. The present data warrant further research into the analgesic effects of low doses of LSD in patient populations.”

Low Doses of LSD Acutely Increase BDNF Blood Plasma Levels in Healthy Volunteers

Authors: Nadia R. P. W. Hutten, Natasha L. Mason, Patrick C. Dolder, Eef L. Theunissen, Friederike Holze, Matthias E. Liechti, Nimmy Varghese, Anne Eckert, Amanda Feilding, Johannes G. Ramaekers & Kim P. C. Kuypers

Published: 31 August 2020

One-sentence summary: A low/micro (20 µg) dose of LSD increased neuroplasticity as measured by brain-derived neurotrophic factor (BDNF) levels at 6 hours (but not at all dosages!).

“Despite preclinical evidence for psychedelic-induced neuroplasticity, confirmation in humans is grossly lacking. Given the increased interest in using low doses of psychedelics for psychiatric indications and the importance of neuroplasticity in the therapeutic response, this placebo-controlled within-subject study investigated the effect of single low doses of LSD (5, 10, and 20 μg) on circulating BDNF levels in healthy volunteers. Blood samples were collected every 2 h over 6 h, and BDNF levels were determined afterward in blood plasma using ELISA. The findings demonstrated an increase in BDNF blood plasma levels at 4 h (5 μg) and 6 h (5 and 20 μg) compared to that for the placebo. The finding that LSD acutely increases BDNF levels warrants studies in patient populations.”

Related papers

Use CTRL/CMD+F to quickly search if anything relevant for you has been published this month.

• The Agency of Ibogaine: Emic Understandings of a Grassroots Psychiatry in Mexico (thesis)

• At the Intersection of Palliative Care, Psychedelic Medicine, and Healthcare Reform: A Call for a New Hospice and Palliative Care Movement (commentary article)

• Increased use of ketamine for the treatment of depression: Benefits and concerns (review on the current state of ketamine for (treatment-resistant) depression (TRD), and suggestions for the future development of glutamatergic drugs without the ‘psychomimetic’ effects)

• Patterns of ecstasy use amongst live music event attendees and their opinions on pill testing: a cross-sectional study (a survey study finds that visitors of a live music event claim they would change their (MDMA) drug-taking behavior if more pill testing was done)

• Safety pharmacology and pharmacogenetics of 3,4-methylenedioxymethamphetamine (MDMA) (thesis, analysis of data from 166 phase I MDMA studies. “In summary, apart from variations within CYPs, genetic polymorphisms seem to play a subordinate role in the acute MDMA effects and are unlikely to sum up all interindividual variations.“)

• Connectome Harmonic Decomposition of Human Brain Dynamics Reveals a Landscape of Consciousness (pre-print, could be very interesting neuroscience paper on consciousness)

• Hallucinogens and Psychedelics (chapter in ‘Principles of Forensic Toxicology’, does however start with describing psychedelics as psychomimetic and as hallucinogens, phrasing that is out of style)

• Better living through chemistry: MDMA’s prosocial mechanism as a starting point for improved therapeutics (short article, a ‘hot topic’, about MDMA)

• What Psilocybin Taught Me, One Year Later (personal experience one year after psilocybin experience)

• The Yale Manual for Psilocybin-Assisted Therapy of Depression (using Acceptance and Commitment Therapy as a Therapeutic Frame)

• Psychedelics and virtual reality: parallels and applications (finding parallels between psychedelics and VR)

• Structure–Activity Relationship Analysis of Psychedelics in a Rat Model of Asthma Reveals the Anti-Inflammatory Pharmacophore (2C-H was found to be the most anti-inflammatory and least-psychedelic combo, in a rat model) (also reported on in Massive Science)

• Reflections on the Role of Language in Psychedelic Research (article on language from MIND Foundation)

• Psychedelic Science in Post-Covid Psychiatry (commentary on how psychedelic/psilocybin-assisted psychotherapy (PAP) can help a post-covid world)

• Reframing Bummer Trips: Scientific and Cultural Explanations to Adverse Reactions to Psychedelic Drug Use (reflection on how ‘bad’ trips were used politically)

• Plasma psilocin critically determines behavioral and neurobiological effects of psilocybin (preprint)

• The Evolution of Posttraumatic Stress Disorder Treatment: Lessons Learned from MDMA-Assisted Psychotherapy (thesis)

• Pharmacological treatment of eating disorders, comorbid mental health problems, malnutrition and physical health consequences (Review of pharmacological treatments of eating disorders that mentions psychedelics (as promising))

• MDMA-Assisted Psychotherapy for Posttraumatic Stress Disorder: Examining Ethnoracial Differences in Efficacy and Safety, and a Mixed-Methods Case Study of a Participant of Color (thesis, but positive signal that effects hold beyond the WEIRD population)

• Can ‘floating’ predict treatment response to ketamine? Data from three randomized trials of individuals with treatment-resistant depression (no, “the findings do not support the hypothesis that ketamine’s antidepressant effects are mediated by the dissociative depersonalization subtype SE of floating”)

• Addressing fear of death and dying: traditional and innovative interventions

• Phytochemical, Cytotoxicity, Antioxidant and Anti-Inflammatory Effects of Psilocybe Natalensis Magic Mushroom (finding anti-inflammatory effects)

• Psilocybin as an Effective Treatment for Patients with Life-Threatening Cancer and Psychological Distress: A Critically Appraised Topic (thesis, review)

• Who takes the trip? Personality and hallucinogen use among college students and adolescents (“…facets of sensation seeking, impulsivity, and emotion dysregulation positively predicted ever having used hallucinogens, earlier initiation of use, and lifetime use among college students“)

• Psychedelics as a Treatment for Alzheimer’s Disease Dementia (mini-review)