Psychedelics are being studied for use with many mental health disorders. This ranges from end-of-life anxiety and depression, to eating disorders, to demoralization in AIDS survivors. What underlies this work is the increased neuronal growth (flexibility in the brain) that psychedelics elicit. This needs to be done in conjunction with therapy though, and that is what most articles this month are about.

To dive deeper into the neuroscience, go read Kim et al. (2020) who worked on a huge project to better understand what happens at the serotonin 5-HT2a receptor. This work may help us better understand the currently available psychedelics, and develop novel ones in the future.

We finish the month with a report on microdosing and their pharmacokinetics/dynamics. The study finds that only at 10µg (vs 5µg) the effects (both good and bad) were noticeable by the participants.

Psilocybin as a New Approach to Treat Depression and Anxiety in the Context of Life-Threatening Diseases-A Systematic Review and Meta-Analysis of Clinical Trials

Authors: Ana Sofia Vargas, Ângelo Luís, Mário Barroso, Eugenia Gallardo & Luísa Pereira

Published: 5 September 2020

One-sentence summary: This meta-analysis (n=92) highlights the large, and positive effects of psilocybin-assisted psychotherapy for depression and anxiety related to life-threatening diseases (end-of-life anxiety), it also recommends using it in the first-line (considering the safety profile).

“Psilocybin is a naturally occurring tryptamine known for its psychedelic properties. Recent research indicates that psilocybin may constitute a valid approach to treat depression and anxiety associated with life-threatening diseases. The aim of this work was to perform a systematic review with meta-analysis of clinical trials to assess the therapeutic effects and safety of psilocybin on those medical conditions. The Beck Depression Inventory (BDI) was used to measure the effects in depression and the State-Trait Anxiety Inventory (STAI) was used to measure the effects in anxiety. For BDI, 11 effect sizes were considered (92 patients) and the intervention group was significantly favored (WMD = -4.589; 95% CI = -4.207 to -0.971; p-value = 0.002). For STAI-Trait, 11 effect sizes were considered (92 patients), being the intervention group significantly favored when compared to the control group (WMD = -5.906; 95% CI = -7.852 to -3.960; p-value ˂ 0.001). For STAI-State, 9 effect sizes were considered (41 patients) and the intervention group was significantly favored (WMD = -6.032; 95% CI = -8.900 to -3.164; p-value ˂ 0.001). The obtained results are promising and emphasize the importance of psilocybin translational research in the management of symptoms of depression and anxiety, since the compound may be effective in reducing symptoms of depression and anxiety in conditions that are either resistant to conventional pharmacotherapy or for which pharmacologic treatment is not yet approved. Moreover, it may be also relevant for first-line treatment, given its safety.”

Positive effects of psychedelics on depression and wellbeing scores in individuals reporting an eating disorder

Authors: Meg J. Spriggs, Hannes Kettner & Robin L. Carhart-Harris

Published: 8 September 2020

One-sentence summary: This prospective survey study (n=28) found significant improvements in depression and well-being scores after psychedelics use for those with eating disorders (EDs). (a clinical trial is planned for 2021)

“Purpose Psychedelic therapy is showing promise for a broad range of mental health conditions, indicative of a transdiagnostic action. While the efficacy of symptom-focused treatments for eating disorders (EDs) is limited, improved mental health and psychological wellbeing are thought to contribute to greater treatment outcomes. This study provides the first quantitative exploration of the psychological effects of psychedelics in those reporting an ED diagnosis. Methods Prospective, online data were collected from individuals planning to take a psychedelic drug. Twenty-eight participants reporting a lifetime ED diagnosis completed measures of depressive symptomology (Quick Inventory of Depressive Symptomology; QIDS-SR16) and psychological wellbeing (Warwick–Edinburgh Mental Wellbeing Scale; WEMWBS) 1–2 weeks before, and 2 weeks after a psychedelic experience. Twenty-seven of these participants also completed a measure of emotional breakthrough [Emotional Breakthrough Inventory (EBI)] in relation to the acute psychedelic experience. Results Bayesian t tests demonstrated overwhelming evidence for improvements in depression and wellbeing scores following the psychedelic experience. Marginal evidence was also found for a correlation between emotional breakthrough and the relevant mental health improvements. Conclusion These findings provide supportive evidence for positive psychological aftereffects of a psychedelic experience that are relevant to the treatment of EDs. It is hoped that this will encourage further research and will bolster initiatives to directly examine the safety and efficacy of psychedelic assisted therapy as a treatment of EDs in future clinical trials.”

Further analysis.

Transient Stimulation with Psychoplastogens Is Sufficient to Initiate Neuronal Growth

Authors: Calvin Ly , Alexandra C. Greb, Maxemiliano V. Vargas, Whitney C. Duim, Ana Cristina G. Grodzki, Pamela J. Lein & David E. Olson

Published: 11 September 2020

One-sentence summary: Psychedelics (psychoplastogens) promote cortical neuron growth (increased plasticity), this study (in-vitro/cell cultures) shows that ketamine and LSD promote plasticity via TrkB (initial) and mTOR and AMPA receptor activation (sustained).

“Cortical neuron atrophy is a hallmark of depression and includes neurite retraction, dendritic spine loss, and decreased synaptic density. Psychoplastogens, small molecules capable of rapidly promoting cortical neuron growth, have been hypothesized to produce long-lasting positive effects on behavior by rectifying these deleterious structural and functional changes. Here we demonstrate that ketamine and LSD, psychoplastogens from two structurally distinct chemical classes, promote sustained growth of cortical neurons after only short periods of stimulation. Furthermore, we show that psychoplastogen-induced cortical neuron growth can be divided into two distinct epochs: an initial stimulation phase requiring TrkB activation and a growth period involving sustained mTOR and AMPA receptor activation. Our results provide important temporal details concerning the molecular mechanisms by which next-generation antidepressants produce persistent changes in cortical neuron structure, and they suggest that rapidly excreted psychoplastogens might still be effective neurotherapeutics with unique advantages over compounds like ketamine and LSD.”

Further analysis.

Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor

Authors: Kuglae Kim, Tao Che, Ouliana Panova, Jeffrey F. DiBerto, Jiankun Lyu, Brian E. Krumm, Daniel Wacker, Michael J. Robertson, Alpay B. Seven, David E. Nichols, Brian K. Shoichet, Georgios Skiniotis & Bryan L. Roth

Published: 17 September 2020

One-sentence summary: This study reveals structurally how psychedelics, including LSD, psilocin, mescaline, and various N-BOH analogs, mediate their therapeutic and hallucinogenic effects by binding to and activating their molecular target, the serotonin (5-HT) 2A receptor coupled with G-protein Gaq.

“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-HT_2A 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.”

Further analysis.

Hallucinations Under Psychedelics and in the Schizophrenia Spectrum: An Interdisciplinary and Multiscale Comparison

Authors: Pantelis Leptourgos, Martin Fortier-Davy, Robin L. Carhart-Harris, Philip R. Corlett, David Dupuis, Adam L. Halberstadt, Michael Kometer, Eva Kozakova, Frank LarØi, Tehseen N. Noorani, Katrin H. Preller, Flavie Waters, Yuliya Zaytseva & Renaud Jardri

Published: 18 September 2020

One-sentence summary: This review article highlights the commonalities (reduced integration & stability of functional networks, strong metaphysical meaning) and differences (overactivation of associative networks vs primary sensory cortices, visual vs auditory hallucinations, ‘normal’ insight vs poor reality monitoring) of hallucinations under schizophrenia spectrum disorders (SCZ) and psychedelics.

“The recent renaissance of psychedelic science has reignited interest in the similarity of drug-induced experiences to those more commonly observed in psychiatric contexts such as the schizophrenia-spectrum. This report from a multidisciplinary working group of the International Consortium on Hallucinations Research (ICHR) addresses this issue, putting special emphasis on hallucinatory experiences. We review evidence collected at different scales of understanding, from pharmacology to brain-imaging, phenomenology and anthropology, highlighting similarities and differences between hallucinations under psychedelics and in the schizophrenia-spectrum disorders. Finally, we attempt to integrate these findings using computational approaches and conclude with recommendations for future research.”

Further analysis.

The Emerging Role of Psilocybin and MDMA in the Treatment of Mental Illness

Authors: Hartej Gill, Barjot Gill, David Chen-Li, Sabine El-Halabi, Nelson B. Rodrigues, Danielle S. Cha, Orly Lipsitz, Yena Lee, Joshua Daniel Rosenblat, Amna Majeed, Rodrigo B. Mansur, Flora Nasri, Roger Ho & Roger S. McIntyre

Published: 21 September 2020

One-sentence summary: This narrative review shines a positive light on psychedelic-assisted therapy.

“Introduction: Mental illness has a chronic course of illness with a number of clinical manifestations. Affected individuals experience significant functional, emotional, cognitive and/or behavioral impairments. The growing prevalence of mental illness has been associated with significant social and economic costs. Indeed, the economic burden of mental illness is estimated to exceed $1.8 trillion USD over the next 30 years. A significant number of individuals affected by mental illness fail to respond to first-line treatment options. Therefore, there remains an unmet need for rapidly attenuating therapeutic options for mental health disorders with minimal social and economic burden. Areas covered: The paucity of novel treatment options warrants a renewed investigation of psychedelic-based psychotherapy. Herein, the authors will evaluate the therapeutic potential of traditional psychedelics, psilocybin and MDMA, in the treatment of mental illness with a narrative review of available literature. Expert opinion: Psychedelics, such as psilocybin and MDMA, offer an alternative avenue of therapy for many mental health disorders. Available evidence indicates that psychedelics may offer a single-dose, rapid effect model that have robust effects with treatment-resistant mental disorders and a unique advantage as a possible monotherapy for mental illness. Novel clinical trials that evaluate the safety, tolerability and efficacy in clinically representative populations are warranted.”

Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study

Authors: Brian T. Anderson, Alicia Danforth, Robert Daroff, Christopher Stauffer, Eve Ekman, Gabrielle Agin-Liebes, Alexander Trope, Matthew Tyler Boden, James Dilley, Jennifer Mitchell & Joshua Woolley

Published: 23 September 2020

One-sentence summary: This open-label feasibility study (n=18) showed that psilocybin-assisted group(!) therapy was safe and effective for the treatment of demoralization in older long-term AIDS survivors.

“Background Psilocybin therapy has shown promise as a rapid-acting treatment for depression, anxiety, and demoralization in patients with serious medical illness (e.g., cancer) when paired with individual psychotherapy. This study assessed the safety and feasibility of psilocybin-assisted group therapy for demoralization in older long-term AIDS survivor (OLTAS) men, a population with a high degree of demoralization and traumatic loss. Methods Self-identified gay men OLTAS with moderate-to-severe demoralization (Demoralization Scale-II ≥8) were recruited from the community of a major US city for a single-site open-label study of psilocybin-assisted group therapy comprising 8–10 group therapy visits and one psilocybin administration visit (0·3–0·36 mg/kg po). Primary outcomes were rate and severity of adverse events, and participant recruitment and retention. The primary clinical outcome was change in mean demoralization from baseline to end-of-treatment and to 3-month follow-up assessed with a two-way repeated measures ANOVA. Findings From 17 July 2017 to 16 January 2019, 18 participants (mean age 59·2 years (SD 4·4)) were enrolled, administered group therapy and psilocybin, and included in intent-to-treat analyses. We detected zero serious adverse reactions and two unexpected adverse reactions to psilocybin; seven participants experienced self-limited, severe expected adverse reactions. We detected a clinically meaningful change in demoralization from baseline to 3-month follow-up (mean difference -5·78 [SD 6·01], ηp2 = 0·47, 90% CI 0·21–0·60). Interpretation We demonstrated the feasibility, relative safety, and potential efficacy of psilocybin-assisted group therapy for demoralization in OLTAS. Groups may be an effective and efficient means of delivering psychotherapy pre- and post-psilocybin to patients with complex medical and psychiatric needs.”

Further analysis.

A (positive) commentary can also be found ‘Psilocybin-assisted group therapy: A new hope for demoralization‘

Pharmacokinetics and pharmacodynamics of lysergic acid diethylamide microdoses in healthy participants

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

Published: 25 September 2020

One-sentence summary: This double-blind, placebo-controlled study (n=23) found that 10µg (vs 5µg) of LSD microdosing produced psychedelic (psychotropic) effects (even more so at 20µg), the peak effects were at 2.5h and ended at 5 hours.

“”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 h 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 h. The mean elimination half-life was 2.7 h (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 h after 10 µg LSD administration, peaked at 2.5 h, and ended at 5.1 h. 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 h. The threshold dose of LSD base for psychotropic effects was 10 µg.”

Further analysis.

Related papers

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

• The Ayahuasca Experience: A Phenomenological Study of Tourists in Iquitos, Peru (master thesis, field work study)
• Psychiatric Medications and Hypertension (esketamine and hypertension review, no contraindications found)
• Ketamine, but not guanosine, as a prophylactic agent against corticosterone-induced depressive-like behavior: Possible role of long-lasting pro-synaptogenic signaling pathway (in mice)
• Ketamine potentiates TRPV1 receptor signaling in the peripheral nociceptive pathways (in rats)
• NICE reconsiders esketamine for depression (second rejection of esketamine, because too costly, by NICE (UK))
• Intranasal delivery of rapid-onset antidepressants: a new trend of treating major depressive disorder (review of ketamine and delivery pathways)
• GABAB receptor intracellular signaling: novel pathways for depressive disorder treatment? (impact of ketamine on GABAergic synaptic transmission)
• Marginalization, stigma and abandonment of LSD in medicine (French, history of LSD use/abandonment in psychotherapy)
• Psychotherapy assisted by psychedelics, intense and unusual exposures therapy (French, overview of how and why psychedelic-assisted psychotherapy works)
• Re-evaluation of the discriminative stimulus effects of lysergic acid diethylamide with male and female Sprague-Dawley rats (studying sex differences, in mice, uhh rats)
• Efficacy of Psychoactive Drugs for the Treatment of Posttraumatic Stress Disorder: A Systematic Review of MDMA, Ketamine, LSD and Psilocybin (more review articles, this one is more critical and ranking ketamine(-assisted psychotherapy) as very low, MDMA as moderate, based on nine included trials)
• Psychedelic Telepathy: An Interview Study (interviews with people explaining their telepathic abilities on psychedelics, not my area of interest/expertise)
• Meetings with Mother Ayahuasca: The effects of the spiritual experience on mental processes and physiological responses (thesis)
• Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders (review, by Vollenweider & Preller)
• Classic Psychedelics as a Psychotherapeutic Aid in the Treatment of Stimulant Use Disorder: a Case Report (positive case report on how someone used psychedelics (outside/next to therapy) to stop using stimulant drugs)
• Culture and psychedelic psychotherapy: Ethnic and racial themes from three Black women therapists (good discussion and experiences on cultural issues and blindspots for expanding psychedelic-assisted psychotherapy)
• Total Recall: Lateral Habenula and Psychedelics in the Study of Depression and Comorbid Brain Disorders (neuroscience perspective on psychedelics and depression)
• Phytochemical, Cytotoxicity, Antioxidant and Anti-Inflammatory Effects of Psilocybe Natalensis Magic Mushroom (magic mushrooms are anti-inflammatory, a sub-field that will yield very interesting results over the coming years)
• Immunochemical monitoring of psilocybin and psilocin to identify hallucinogenic mushrooms (making it easier for anyone? to find which mushrooms contain psilocybin and psilocin)
• Development of an improved psilocybin synthesis (thesis)
• Dr. Valentina Wasson: Questioning what we think we know about the foundations of psychedelic science (critique on equity, access, and history of psychedelic science)
• Chemical Composition of Traditional and Analog Ayahuasca (information about the composition of different ‘strains’ of ayahuasca)
• Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy (the safety of MDMA (physiological and mental) may not be perfect, this review article offers suggestions for alternative (classes of) drugs)
• Identification of psychedelic new psychoactive substances (NPS) showing biased agonism at the 5-HT _2A R through simultaneous use of β-arrestin 2 and miniGα _q bioassays (investigating why/how novel psychedelics work)
• The Antidepressant Effect of Ketamine Is Dampened by Concomitant Benzodiazepine Medication (ketamine x benzodiazepine)
• What is the drug of choice of young festivalgoers? (MDMA is the most popular)
• N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo (in mice)
• The Importance of Ritual Discourse in Framing Ayahuasca Experiences in the Context of Shamanic Tourism (looking at the ritual, especially the shaman’s speeches)
• Tropane-Based Ibogaine Analog Rescues Folding-Deficient Serotonin and Dopamine Transporters (in cells and flies)
• Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis (meta-analysis that favors racemic – intravenous ketamine over esketamine)