It was another great month for psychedelic research. The BIMA study was the first to use MDMA-assisted psychotherapy for alcoholism (AUD) and showed very promising results. The participants lowered their drinking significantly and double-blind randomized studies are hopefully quickly done to confirm these excellent findings.

Many papers about ketamine passed our desk of which two stood out. One looked at ketamine in emergency rooms, the other looked at repeated dosages for chronic suicidal ideation (SI). Both found significantly lower scores, and this effect held up to four weeks after the six-week treatment for the second study.

Trends in psychedelic research show that more randomized controlled trials (RCTs) are being done, and more with psilocybin. The effect of the dosage is investigated in an analysis of more than 250 participants in previous research, which found that weight-based dosing is probably not optimal/necessary.

A paper investigated 22 policy instruments and gave recommendations for the Dutch government to follow, of course, these can (néé, should) be applied to other countries too. Testing, regulation, and information should always be part of this mix. And one more data point was found in online reports about the use of classical psychedelics (e.g. psilocybin, LSD) and lithium. The combination led to many complications and the risks about this specific combination should be more widely disseminated.

Where LSD has its effect, in the brain, has been more closely mapped in the first featured study this month. The blood plasma psilocin (the active metabolite of psilocybin) correlated with the subjective drug effects (SDI). And finally, a naturalist study with smoked DMT provides external validity of its effect outside the laboratory setting.

Transcriptomics-informed large-scale cortical model captures topography of pharmacological neuroimaging effects of LSD (paper)

This brain modelling study finds the topographic effects (where) LSD changes functional connectivity (FC) in the brain, via the modulation of serotonin 2A pyramidal cells.

Published (pre-print): 2 February 2021

Authors: Joshua B. Burt, Katrin H. Preller, Murat Demirtas, Jie Lisa Ji, John H. Krystal, Franz X. Vollenweider, Alan Anticevic & John D. Murray

“Psychoactive drugs can transiently perturb brain physiology while preserving brain structure. The role of physiological state in shaping neural function can therefore be investigated through neuroimaging of pharmacologically-induced effects. This paradigm has revealed that neural and experiential effects of lysergic acid diethylamide (LSD) are attributable to its agonist activity at the serotonin-2A receptor. Here, we integrate brainwide transcriptomics with biophysically-based large-scale circuit modeling to simulate acute neuromodulatory effects of LSD on human cortical dynamics. Our model captures the topographic effects of LSD-induced changes in cortical BOLD functional connectivity. These findings suggest that serotonin-2A-mediated modulation of pyramidal cell gain is the circuit mechanism through which LSD alters cortical functional topography. Individual-subject fitting reveals that the model captures patterns of individual neural differences in drug response that predict altered states of consciousness. This work establishes a framework for linking molecular-level manipulations to salient changes in brain function, with implications for precision medicine.”

Developing a new national MDMA policy: Results of a multi-decision multi-criterion decision analysis (paper)

This policy paper (2021) presents the case for a better drug policy concerning MDMA in the Netherlands (but could/should be read as applying to other countries too)

Published: 2 February 2021

Authors: Jan van Amsterdam, Gjalt-Jorn Y. Peters, Ed Pennings, Tom Blickman, Kaj Hollemans, Joost J. Breeksema, Johannes G. Ramaekers, Cees Maris, Floor van Bakkum, Ton Nabben, Willem Scholten, Tjibbe Reitsma, Judith Noijen, Raoul Koning & Wim van den Brink

Background: Ecstasy (3,4-methylenedioxymethamphetamine (MDMA)) has a relatively low harm and low dependence liability but is scheduled on List I of the Dutch Opium Act (‘hard drugs’). Concerns surrounding increasing MDMA-related criminality coupled with the possibly inappropriate scheduling of MDMA initiated a debate to revise the current Dutch ecstasy policy. Methods: An interdisciplinary group of 18 experts on health, social harms and drug criminality and law enforcement reformulated the science-based Dutch MDMA policy using multi-decision multi-criterion decision analysis (MD-MCDA). The experts collectively formulated policy instruments and rated their effects on 25 outcome criteria, including health, criminality, law enforcement and financial issues, thematically grouped in six clusters. Results: The experts scored the effect of 22 policy instruments, each with between two and seven different mutually exclusive options, on 25 outcome criteria. The optimal policy model was defined by the set of 22 policy instrument options which gave the highest overall score on the 25 outcome criteria. Implementation of the optimal policy model, including regulated MDMA sales, decreases health harms, MDMA-related organised crime and environmental damage, as well as increases state revenues and quality of MDMA products and user information. This model was slightly modified to increase its political feasibility. Sensitivity analyses showed that the outcomes of the current MD-MCDA are robust and independent of variability in weight values. Conclusion: The present results provide a feasible and realistic set of policy instrument options to revise the legislation towards a rational MDMA policy that is likely to reduce both adverse (public) health risks and MDMA-related criminal burden.“

Trends in the Top-Cited Articles on Classic Psychedelics (paper)

This review paper (2021) investigates the trends in the top-cited papers on psychedelics and finds more RCT studies on psilocybin being done that get cited more often.

Published: 4 February 2021

Authors: David W. Lawrence, Bhanu Sharma, Roland R. Griffiths & Robin L. Carhart-Harris

“This study was designed to identify trends in the top-cited classic psychedelic publications. The top 50 publications on classic psychedelics with the greatest total of number of citations and annual citation rate were identified and pooled. Unique articles (n = 77) were dichotomized by median year of publication (2010); the differential distribution of study characteristics between the “Recent Cohort” (n = 40) and “Older Cohort” (n = 37) were documented. The Recent Cohort had a greater annual citation rate (median 76.5, IQR 43.8 to 103.3) compared to the Older Cohort (median 8.8, IQR 4.2 to 17.2, p < .001). The Recent Cohort included a greater number of clinical studies (n = 27 [67.5%] vs. n = 10 [27.0%]) while the Older Cohort included more basic science and preclinical studies (n = 22 [59.5%] vs. n = 3 [7.5%], p < .001). Psilocybin was the predominant psychedelic studied in the Recent Cohort (n = 26 [40.6%] vs. n = 8 [17.4%]) while lysergic acid diethylamide (LSD) was predominantly studied in the Older Cohort (n = 26 [56.5%] vs. n = 19 [29.7%], p = .028). The Recent Cohort included more studies examining affective disorders (n = 16 [25.8%] vs. n = 1 [2.7%]) and substance use disorders (n = 6 [9.7%] vs. n = 1 [2.7%]), while the Older Cohort included a greater number of pharmacological outcomes (n = 26 [70.3%] vs. n = 11 [17.7%], p < .001). This study identified and documented trends in the top-cited classic psychedelic publications. The field is continuing to form a foundational understanding of the pharmacological effects of psychedelics and is now advancing with the identification of therapeutic uses within clinical populations.“

Low dose oral ketamine treatment in chronic suicidality: An open-label pilot study (paper)

This open-label study (n=32) with 6 dosages (weekly) of oral ketamine (35-210mg/70kg) found that it significantly reduced suicidal ideation in those with chronic suicidal thoughts, with clinically significant lower scores in 69% of participants at the end (which held at 50% 4 weeks later).

Published: 4 February 2021

Authors: Adem T. Can, Daniel F. Hermens, Megan Dutton, Cyrana C. Gallay, Emma Jensen, Monique Jones, Jennifer Scherman, Denise A. Beaudequin, Cian Yang, Paul E. Schwenn & Jim Lagopoulos

“Recently, low-dose ketamine has been proposed as a rapid-acting treatment option for suicidality. The majority of studies to date have utilised intravenous (IV) ketamine, however, this route of administration has limitations. On the other hand, oral ketamine can be administered in a range of settings, which is important in treating suicidality, although studies as to safety and feasibility are lacking. n = 32 adults (aged 22–72 years; 53% female) with chronic suicidal thoughts participated in the Oral Ketamine Trial on Suicidality (OKTOS), an open-label trial of sub-anaesthetic doses of oral ketamine over 6 weeks. Participants commenced with 0.5 mg/kg of ketamine, which was titrated to a maximum 3.0 mg/kg. Follow-up assessments occurred at 4 weeks after the final dose. The primary outcome measure was the Beck Scale for Suicide Ideation (BSS) and secondary measures included scales for suicidality and depressive symptoms, and measures of functioning and well-being. Mean BSS scores significantly reduced from a high level of suicidal ideation at the pre-ketamine (week 0) timepoint to below the clinical threshold at the post-ketamine (week 6) timepoint. The proportion of participants that achieved clinical improvement within the first 6 weeks was 69%, whereas 50% achieved a significant improvement by the follow-up (week 10) timepoint. Six weeks of oral ketamine treatment in participants with chronic suicidality led to significant reduction in suicidal ideation. The response observed in this study is consistent with IV ketamine trials, suggesting that oral administration is a feasible and tolerable alternative treatment for chronic suicidality.“

Psilocybin-induced changes in brain network integrity and segregation correlate with plasma psilocin level and psychedelic experience (paper)

This fMRI study (n=15) investigated the effects of psilocybin (14/21mg/70kg) on the brain and found that the higher the psilocin (active metabolite of psilocybin) and subjective drug experience (SDI) correlated with lower network integrity and segregation (less top-down, more bottom-up).

Published (pre-print): 5 February 2021

Authors: Martin K. Madsen, Dea S. Stenbaek, Albin Arvidsson, Sophia Armand, Maja R. Marstrand-Jorgensen, Sys S. Johansen, Kristian Linnet, Brice Ozenne, Gitte M. Knudsen & Patrick M. Fisher

“The emerging novel therapeutic psilocybin produces psychedelic effects via engagement of cerebral serotonergic targets by psilocin (active metabolite). The serotonin 2A receptor critically mediates these effects by altering distributed neural processes that manifest as increased entropy, reduced functional connectivity (FC) within discrete brain networks (i.e., reduced integrity) and increased FC between networks (i.e., reduced segregation). Reduced integrity of the default mode network (DMN) is proposed to play a particularly prominent role in psychedelic phenomenology, including perceived ego-dissolution. Here, we investigate the effects of a psychoactive oral dose of psilocybin (0.2-0.3 mg/kg) on plasma psilocin level (PPL), subjective drug intensity (SDI) and their association in fifteen healthy individuals. We further evaluate associations between these measures and resting-state FC, measured with functional magnetic resonance imaging, acquired over the course of five hours after psilocybin administration. We show that PPL and SDI correlate negatively with measures of network integrity (including DMN) and segregation, both spatially constrained and unconstrained. We also find that the executive control network and dorsal attention network desegregate, increasing connectivity with other networks and throughout the brain as a function of PPL and SDI. These findings provide direct evidence that psilocin critically shapes the time course and magnitude of changes in the cerebral functional architecture and subjective experience following psilocybin administration. Our findings provide novel insight into the neurobiological mechanisms underlying profound perceptual experiences evoked by this emerging transnosological therapeutic and implicate the expression of network integrity and segregation in the psychedelic experience and consciousness.“

Neural and subjective effects of inhaled N,N-dimethyltryptamine in natural settings (paper)

This naturalistic (open-label) EEG study (n=35) with smoked DMT (~40mg) confirmed earlier findings (but now outside the lab) that DMT significantly decreased alpha, and increased delta and gamma oscillations. The latter also correlated with subjective mystical-type experiences (MEQ).

Published: 10 February 2021

Authors: Carla Pallavicini, Federico Cavanna, Federico Zamberlan, Laura A. de la Fuente, Yayla Ilksoy, Yonatan S. Perl, Mauricio Arias, Celeste Romero, Robin L. Carhart-Harris, Christopher Timmermann & Enzo Tagliazucchi

“Background: N,N-dimethyltryptamine is a short-acting psychedelic tryptamine found naturally in many plants and animals. Few studies to date have addressed the neural and psychological effects of N,N-dimethyltryptamine alone, either administered intravenously or inhaled in freebase form, and none have been conducted in natural settings. Aims: Our primary aim was to study the acute effects of inhaled N,N-dimethyltryptamine in natural settings, focusing on questions tuned to the advantages of conducting field research, including the effects of contextual factors (i.e. “set“ and “setting“), the possibility of studying a comparatively large number of subjects, and the relaxed mental state of participants consuming N,N-dimethyltryptamine in familiar and comfortable settings. Methods: We combined state-of-the-art wireless electroencephalography with psychometric questionnaires to study the neural and subjective effects of naturalistic N,N-dimethyltryptamine use in 35 healthy and experienced participants. Results: We observed that N,N-dimethyltryptamine significantly decreased the power of alpha (8–12 Hz) oscillations throughout all scalp locations, while simultaneously increasing power of delta (1–4 Hz) and gamma (30–40 Hz) oscillations. Gamma power increases correlated with subjective reports indicative of some features of mystical-type experiences. N,N-dimethyltryptamine also increased global synchrony and metastability in the gamma band while decreasing those measures in the alpha band. Conclusions: Our results are consistent with previous studies of psychedelic action in the human brain, while at the same time the results suggest potential electroencephalography markers of mystical-type experiences in natural settings, thus highlighting the importance of investigating these compounds in the contexts where they are naturally consumed.”

Effects of ketamine on brain function during metacognition of episodic memory (paper)

This double-blind placebo-controlled fMRI study (n=53) on ketamine (r-ketamine, continuous iv) and cognition found that ketamine increased metacognitive bias, negatively impacted metacognitive sensitivity, and increased activation of posterior brain areas.

Published: 10 February 2021

Authors: Mirko Lehmann, Claudia Neumann, Sven Wasserthal, Johannes Schultz, Achilles Delis, Peter Trautner, René Hurlemann & Ulrich Ettinger

“Only little research has been conducted on the pharmacological underpinnings of metacognition. Here, we tested the modulatory effects of a single intravenous dose (100 ng/ml) of the N-methyl-D-aspartate-glutamate-receptor antagonist ketamine, a compound known to induce altered states of consciousness, on metacognition and its neural correlates. Fifty-three young, healthy adults completed two study phases of an episodic memory task involving both encoding and retrieval in a double-blind, placebo-controlled fMRI study. Trial-by-trial confidence ratings were collected during retrieval. Effects on the subjective state of consciousness were assessed using the 5D-ASC questionnaire. Confirming that the drug elicited a psychedelic state, there were effects of ketamine on all 5D-ASC scales. Acute ketamine administration during retrieval had deleterious effects on metacognitive sensitivity (meta-d′) and led to larger metacognitive bias, with retrieval performance (d′) and reaction times remaining unaffected. However, there was no ketamine effect on metacognitive efficiency (meta-d′/d′). Measures of the BOLD signal revealed that ketamine compared to placebo elicited higher activation of posterior cortical brain areas, including superior and inferior parietal lobe, calcarine gyrus, and lingual gyrus, albeit not specific to metacognitive confidence ratings. Ketamine administered during encoding did not significantly affect performance or brain activation. Overall, our findings suggest that ketamine impacts metacognition, leading to significantly larger metacognitive bias and deterioration of metacognitive sensitivity as well as unspecific activation increases in posterior hot zone areas of the neural correlates of consciousness.”

Single, Fixed-Dose Intranasal Ketamine for Alleviation of Acute Suicidal Ideation. An Emergency Department, Trans-Diagnostic Approach: A Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Trial (paper)

This double-blind placebo-controlled study (n=30) with intranasal ketamine (40mg) found significant reductions in suicidal ideation (SI, 80 vs 33% remission) and depressive symptoms (MADRS) 4 hours after administration for those with SI in the emergency department.

Published: 14 February 2021

Authors: Yoav Domany & Cheryl B. McCullumsmith

“Background: Suicidal patients often present to the emergency department, where specific anti-suicidal treatment is lacking. Ketamine, a Glutamate modulator and a rapidly acting antidepressant with anti-suicidal properties, might offer relief. Aims: Evaluation of single, fixed-dosed intranasal ketamine for acute suicidal ideation in the emergency department. Methods: Between August 2016 and April 2018, 30 eligible suicidal subjects, scheduled for psychiatric hospitalization, independently of their psychiatric diagnosis, were randomized to intranasal ketamine 40 mg or saline placebo. Safety and efficacy evaluations were scheduled for 30, 60, 120, and 240 min post administration and on days 1, 2, 3, 4, 5, 7, 21, and 28. Primary outcome was suicidal ideation. Results: Fifteen subjects were randomized for each study group. All were analyzed for primary and secondary outcomes. Four hours post administration, the mean difference in suicidal symptoms between the groups, measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) item of suicidal thoughts (MADRS-SI), was 1.267 (95% confident interval 0.1-2.43, p < 0.05) favoring treatment. Remission from suicidal ideation was evident in 80% for the ketamine group compared with 33% for the controls (p < 0.05). The mean difference in depressive symptoms, measured by MADRS, at the same time was 9.75 (95% confident interval 0.72-18.79, p < 0.05) favoring ketamine. Treatment was safe and well-tolerated. Conclusions: Single, fixed-dose, intranasal ketamine alleviated suicidal ideation and improved depressive symptoms four hours post-administration. We present here an innovative paradigm for emergency department management of suicidal individuals. Future larger-scale studies are warranted. “

Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo (paper)

This pre-print article shows that brain cells, specifically the layer five pyramidal neurons in mice, grew by 10% after the introduction of psilocybin. The effects were still present 30 days later, providing more evidence for brain plasticity as an underlying mechanism of psychedelic-assisted therapies’ long-lasting effects.

Published (pre-print): 17 February 2021

Authors: Ling-Xiao Shao, Clara Liao, Ian Gregg, Neil Savalia, Kristina Delagarza & Alex C. Kwan

“Psilocybin is a serotonergic psychedelic with untapped therapeutic potential. Here we chronically imaged apical dendritic spines of layer 5 pyramidal neurons in mouse medial frontal cortex. We found that a single dose of psilocybin led to ~10% increases in spine density and spine head width. Synaptic remodeling occurred quickly within 24 hours and was persistent 1 month later. The results demonstrate structural plasticity that may underpin psilocybin’s long-lasting beneficial actions.”

• Related new publication: Prolonged epigenetic and synaptic plasticity alterations following single exposure to a psychedelic in mice

First study of safety and tolerability of 3,4-methylenedioxymethamphetamine-assisted psychotherapy in patients with alcohol use disorder (paper)

This open-label study (n=14) with MDMA-assisted psychotherapy (2 sessions;187.5mg) found it to be well-tolerated and safe to use. The average consumption of alcohol at 9 months later was 18.7 units, versus 130.6 units before the detox (start of study).

Published: 18 February 2021

Authors: Ben Sessa, Laurie Higbed, Steve O’Brien, Claire Durant, Chloe Sakal, Daniel Titheradge, Tim M. Williams, Anna Rose-Morris, Elsa Brew-Girard, Sam Burrows, Chantelle Wiseman, Sue Wilson, James Rickard & David J. Nutt

“Background: 3,4-methylenedioxymethamphetamine (MDMA) therapy has qualities that make it potentially well suited for patients with addictions, but this has never been explored in a research study. We present data from the Bristol Imperial MDMA in Alcoholism (BIMA) study. This is the first MDMA addiction study, an open-label safety and tolerability proof-of-concept study investigating the potential role for MDMA therapy in treating patients with alcohol use disorder (AUD). Aims: This study aimed to assess if MDMA-assisted psychotherapy can be delivered safely and can be tolerated by patients with AUD post detoxification. Outcomes regarding drinking behaviour, quality of life and psychosocial functioning were evaluated. Methods: Fourteen patients with AUD completed a community alcohol detoxification and received an eight-week course of recovery-based therapy. Participants received two sessions with MDMA (187.5mg each session). Psychological support was provided before, during and after each session. Safety and tolerability were assessed alongside psychological and physiological outcome measures. Alcohol use behaviour, mental well-being and functioning data were collected for nine months after alcohol detoxification. Results: MDMA treatment was well tolerated by all participants. No unexpected adverse events were observed. Psychosocial functioning improved across the cohort. Regarding alcohol use, at nine months post detox, the average units of alcohol consumption by participants was 18.7 units per week compared to 130.6 units per week before the detox. This compares favourably to a previous observational study (the ‘Outcomes’ study) by the same team with a similar population of people with AUD. Conclusions: This study provides preliminary support for the safety and tolerability of a novel intervention for AUD post detox. Further trials to examine better the therapeutic potential of this approach are now indicated.”

Optimal dosing for psilocybin pharmacotherapy: Considering weight-adjusted and fixed dosing approaches (paper)

This analysis of psilocybin dosages given in 10 previous studies (n=288) found no effect of weight, nor gender, on the effects (acute or long-term) of the dosage (20-30mg) of psilocybin used. The authors recommend a fixed dosing approach going forward to simplify dosing regimes.

Published: 20 February 2021

Authors: Albert Garcia-Romeu, Frederic S. Barrett, Theresa M. Carbonaro, Matthew W. Johnson & Roland R. Griffiths

“Background: Growing evidence suggests psilocybin, a naturally occurring psychedelic, is a safe and promising pharmacotherapy for treatment of mood and substance use disorders when administered as part of a structured intervention. In most trials to date, psilocybin dose has been administered on a weight-adjusted basis rather than the more convenient procedure of administering a fixed dose. Aims: The present post hoc analyses sought to determine whether the subjective effects of psilocybin are affected by body weight when psilocybin is administered on a weight-adjusted basis and when psilocybin is administered as a fixed dose. Methods: We analyzed acute subjective drug effects (mystical, challenging, and intensity) associated with therapeutic outcomes from ten previous studies (total N=288) in which psilocybin was administered in the range 20 to 30mg/70 kg (inclusive). Separate multivariate regression analyses examined the relationships between demographic variables including body weight and subjective effects in participants receiving 20mg/70kg (n=120), participants receiving 30mg/70kg (n=182), and participants whose weight-adjusted dose was about 25mg (to approximate the fixed dose that is currently being evaluated in registration trials for major depressive disorder) (n=103). Results: In the 20mg/70kg and 30mg/70 kg weight-adjusted groups, and in the fixed dose group, no significant associations were found between subjective effects and demographic variables including body weight or sex. Across a wide range of body weights (49 to 113kg) the present results showed no evidence that body weight affected subjective effects of psilocybin. Conclusions: These results suggest that the convenience and lower cost of administering psilocybin as a fixed dose outweigh any potential advantage of weight-adjusted dosing.”

Classic psychedelic coadministration with lithium, but not lamotrigine, is associated with seizures: an analysis of online psychedelic experience reports (paper)

This analysis of online reports (n=96) found that the use of psychedelics in combination with lithium led to seizures (47%), bad trips (64%), and emergency medical treatment (39%). The authors express the caution people should take when self-medicating/combining psychedelics with antidepressants (with lithium being commonly used for bipolar disorder).

Published (pre-print): 24 February 2021

Authors: Sandeep Nayak, Natalie Gukasyan, Frederick S. Barrett, Earth Erowid, Fire Erowid & Roland R. Griffiths

“Introduction: Psychedelics show promise in treating unipolar depression, though patients with bipolar disorder have been excluded from recent psychedelic trials. There is limited information on the use of classic psychedelics (e.g.LSD or psilocybin) in individuals using mood stabilizers to treat bipolar disorder. This is important to know as individuals with bipolar depression may attempt to treat themselves with psychedelics while on a mood stabilizer, particularly given enthusiastic media reports of the efficacy of psilocybin for depression. Methods: This study analyzed reports of classic psychedelics administered with mood stabilizers from three websites (Erowid.org, Shroomery.org, and Reddit.com). Results: Strikingly, 47% of 62 lithium plus psychedelic reports involved seizures and an additional 18% resulted in bad trips while none of 34 lamotrigine reports did. Further, 39% of lithium reports involved medical attention. Most of the lamotrigine reports (65%) but few (8%) of the lithium reports were judged to have no effect on the psychedelic experience. Discussion: Although further research is needed, we provisionally conclude that psychedelic use may pose a significant seizure risk for patients on lithium.“