The lack of papers in last month’s edition is overshadowed by the number of (high quality) papers this month. Next to many reviews (see the last section) there is research on alcoholism and psychedelics in animals, research into our brainwaves (with DMT and LSD), and the experience of ego dissolution. The latter didn’t predict less narcissistic behavior, but feelings of awe and connection did (survey).

Microdosing Psychedelics: Subjective Benefits and Challenges, Substance Testing Behavior, and the Relevance of Intention

Author: Joel Bornemann

Published: 2 May 2020

One sentence summary: Review of the current microdosing literature, reports positive effects but unreliable samples and possible placebo effect.

“Psychedelic substances are currently experiencing a renaissance in interest for both therapeutic as well as recreational applications. It has been proposed that microdosing, i.e., ingesting sub-perceptual doses of a psychedelic, could confer some of the benefits of these substances to users while minimizing the risks associated with full-dose use. This review aimed to summarize and examine the extant literature on psychedelic microdosing. Exploratory evidence published to date indicates a variety of benefits reported by microdosers including improvements in mood, focus, and creativity, with some null reports, and a minority of people reporting selective negative consequences such as increased anxiety and physiological discomfort. Methodological limitations of current evidence, however, make definitive conclusions hard to draw. Recommendations for future research are given.“

Psilocybin and LSD have no long-lasting effects in an animal model of alcohol relapse

Authors: Marcus W. Meinhardt, Cansu Güngör, Ivan Skorodumov, Lea J. Mertens & Rainer Spanagel

Published: 5 May 2020

One sentence summary: Three different regimens (macro and microdosing) of psilocybin and LSD showed no effect on alcohol use disorder (AUD) in mice.

“For most psychiatric disorders, including alcohol use disorder (AUD), approved pharmacological treatments are limited in their effectiveness, and new drugs that can easily be translated into the clinic are needed. Currently, great hope lies in the potential of psychedelics to effectively treat AUD. The primary hypothesis is that a single session of psychedelic-guided psychotherapy can restore normal brain function in AUD individuals and thereby reduce the risk of relapse in the long run. Here we applied three different treatment schedules with psilocybin/LSD in order to investigate relapse-like drinking in the alcohol deprivation effect (ADE) model. In contrast to the primary hypothesis, psychedelics had no long-lasting effects on the ADE in male and female rats, neither when administered in a high dosage regime that is comparable to the one used in clinical studies, nor in a chronic microdosing scheme. Only sub-chronic treatment with psilocybin produced a short-lasting anti-relapse effect. However, it is not a translatable treatment option to give psychedelics sub-chronically for relapse prevention. In conclusion, our results in the ADE model do not support the hypothesis that microdosing or high doses of psychedelic reduce relapse behavior. This conclusion has to be confirmed by applying other animal models of AUD. It could also well be that animal models of AUD might be unable to fully capture the therapeutic potential of psychedelic drugs and that only future large-scale clinical trials will be able to demonstrate the efficacy of psychedelics as a new treatment option for AUD.”

• It would be interesting, and challenging, to see if animal models of psychedelics use translate to humans. One would expect some receptor overlap (and therefore we use animal models anyways), but the mental processes might be very different (you can’t give the rat therapy during a macro dose)
• A proposed review (protocol) of psilocybin in animal research can be found here

Chronic pain and psychedelics: a review and proposed mechanism of action

Authors: Joel P. Castellanos, Chris Woolley, Kelly A. Bruno, Fadel Zeidan, Adam L. Halberstadt & Timothy Furnish

Published: 5 May 2020

One sentence summary: This review investigates the (limited) research on psychedelics for chronic pain and notes the limitations op opioids (and the current epidemic of use).

“The development of chronic pain is a complex mechanism that is still not fully understood. Multiple somatic and visceral afferent pain signals, when experienced over time, cause a strengthening of certain neural circuitry through peripheral and central sensitization, resulting in the physical and emotional perceptual chronic pain experience. The mind-altering qualities of psychedelics have been attributed, through serotonin 2A (5-HT_2A) receptor agonism, to ‘reset’ areas of functional connectivity (FC) in the brain that play prominent roles in many central neuropathic states. Psychedelic substances have a generally favorable safety profile, especially when compared with opioid analgesics. Clinical evidence to date for their use for chronic pain is limited; however, several studies and reports over the past 50 years have shown potential analgesic benefit in cancer pain, phantom limb pain and cluster headache. While the mechanisms by which the classic psychedelics may provide analgesia are not clear, several possibilities exist given the similarity between 5-HT_2A activation pathways of psychedelics and the nociceptive modulation pathways in humans. Additionally, the alterations in FC seen with psychedelic use suggest a way that these agents could help reverse the changes in neural connections seen in chronic pain states. Given the current state of the opioid epidemic and limited efficacy of non-opioid analgesics, it is time to consider further research on psychedelics as analgesics in order to improve the lives of patients with chronic pain conditions.”

DMT alters cortical travelling waves (pre-print)

Authors: Andrea Alamia, Christopher Timmermann, Rufin VanRullen & Robin L. Carhart-Harris

Published: 8 May 2020

One sentence summary: EEG study confirms hypothesis that prior beliefs are relaxed under psychedelics (more bottom-up, less top-down/central)

“Psychedelic drugs are potent modulators of conscious states and therefore powerful tools for investigating their neurobiology. N,N, Dimethyltryptamine (DMT) is a particularly interesting serotonergic psychedelic that can rapidly induce an extremely immersive state of consciousness characterized by vivid and elaborate visual imagery. In the present study, we investigated the electrophysiological correlates of the DMT-induced altered state, by recording EEG signals from a pool of participants receiving DMT and (separately) placebo (saline), intravenously, while instructed to keep their eyes closed (i.e. ‘resting state’). Consistent with our prior hypotheses, results revealed a spatio-temporal pattern of cortical activation (i.e., travelling waves) similar to that elicited by visual stimulation. Moreover, the typical top-down alpha-band rhythms of closed-eyes rest (i.e. a backward travelling wave) were significantly decreased, while the bottom-up ‘forward travelling wave’, was significantly increased. These results support a recent model proposing that psychedelics reduce the ‘precision-weighting of priors’, thus altering the balance of top-down versus bottom-up information passing, where properties of backward waves are considered correlates of this precision weighting. The robust hypothesis-confirming nature of the present findings imply the discovery of an important mechanistic principle underpinning psychedelic-induced altered states – i.e. reduced backward and increased forward travelling waves – and lend further support to prior assumptions about the functional significance of cortical travelling waves.“

• Related is ‘LSD flattens the functional hierarchy of the human brain’, also a pre-print in May 2020

Pharmacokinetics and subjective effects of 1P‐LSD in humans after oral and intravenous administration

Authors: Christina Grumann, Kerstin Henkel, Simon D. Brandt, Alexander Stratford, Torsten Passie & Volker Auwärter

Published: 15 May 2020

One sentence summary: 1P-LSD is a prodrug for LSD, now shown in humans.

“1‐Propanoyl‐lysergic acid diethylamide (1P‐LSD) appeared as a non‐controlled alternative to LSD a few years ago. Although evidence is beginning to emerge from in vitro and animal studies that 1P‐LSD might serve as a prodrug for LSD, an equivalent evaluation in humans is unavailable. Controlled oral and intravenous self‐administrations of 100 μg 1P‐LSD hemitartrate are reported in two human volunteers followed by analyses of urine and serum samples using a fully validated LC–MS/MS method. Psychometric evaluations included assessment of selected subjective drug effects and administration of the Five‐Dimensions of Altered States of Consciousness rating scale (5D‐ASC). In serum and urine, oral administrations of 1P‐LSD only led to the detection of LSD reflecting biphasic elimination with a terminal elimination half‐life of approx. t_1/2 = 6.4 h. 1P‐LSD could be detected for only up to 4.16 h in serum and 2.7 h in urine following intravenous administration, whereas LSD was detected in all serum samples (last sampling after approx. 24 h) and up to 80 h in urine. LSD showed first order elimination kinetics with an approx. t_1/2 = 5.7 h, whereas 1P‐LSD showed a rapid decrease in concentration within the first hour followed by a slower decrease, most probably due to hydrolysis. The bioavailability of LSD after oral ingestion of 1P‐LSD was close to 100%. The psychosensory effects of 1P‐LSD and their time course were comparable to those seen after uptake of LSD in other studies which further supports the prodrug hypothesis. The 5D‐ASC scores were higher after oral compared with intravenous administration of 1P‐LSD.“

• Related is this first (pharmacological) study on 2C-E in humans

Me, myself, bye: regional alterations in glutamate and the experience of ego dissolution with psilocybin

Authors: Natasha L. Mason, Kim P. C. Kuypers, Fabiola Müller, J. Reckweg, D. H. Y. Tse, S. W. Toennes, Nadia R. P. W. Hutten, J. F. A. Jansen, P. Stiers, Amanda Feilding & Jan G. Ramaekers

Published: 23 May 2020

One sentence summary: A dose of 11mg/70kg of psilocybin induced glutamate alterations that predicted changes in ego perception/dissolution.

“There is growing interest in the therapeutic utility of psychedelic substances, like psilocybin, for disorders characterized by distortions of the self-experience, like depression. Accumulating preclinical evidence emphasizes the role of the glutamate system in the acute action of the drug on brain and behavior; however this has never been tested in humans. Following a double-blind, placebo-controlled, parallel group design, we utilized an ultra-high field multimodal brain imaging approach and demonstrated that psilocybin (0.17 mg/kg) induced region-dependent alterations in glutamate, which predicted distortions in the subjective experience of one’s self (ego dissolution). Whereas higher levels of medial prefrontal cortical glutamate were associated with negatively experienced ego dissolution, lower levels in hippocampal glutamate were associated with positively experienced ego dissolution. Such findings provide further insights into the underlying neurobiological mechanisms of the psychedelic, as well as the baseline, state. Importantly, they may also provide a neurochemical basis for therapeutic effects as witnessed in ongoing clinical trials.“

• “Our data provide indirect evidence that psychedelics might have the potential to increase neuroplasticity in the human cortex via increased glutamatergic activity, but not in the hippocampus”
• One should note that the dosage in the study was medium (often they are 2 to 3 times higher), as were the effects on ego perception/dissolution

Psilocybin acutely alters the functional connectivity of the claustrum with brain networks that support perception, memory, and attention

Authors: Frederick S. Barrett, Samuel R. Krimmel, Roland R. Griffiths, David A. Seminowicz & Brian N. Mathur

Published: 23 May 2020

One sentence summary: Psilocybin modulates claustrum (brain structure that connects sub- & cortical regions) function in humans.

“The claustrum is a subcortical nucleus that highly expresses 5-HT_2A receptors and provides glutamatergic inputs to arguably all areas of the cerebral cortex. We therefore tested the hypothesis that psilocybin modulates claustrum function in humans. Fifteen healthy participants (10M, 5F) completed this within-subjects study in which whole-brain resting-state blood-oxygenation level-dependent (BOLD) signal was measured 100 min after blinded oral administration of placebo and 10 mg/70 kg psilocybin. Left and right claustrum signal was isolated using small region confound correction. Psilocybin significantly decreased both the amplitude of low frequency fluctuations as well as the variance of BOLD signal in the left and right claustrum. Psilocybin also significantly decreased functional connectivity of the right claustrum with auditory and default mode networks (DMN), increased right claustrum connectivity with the fronto-parietal task control network (FPTC), and decreased left claustrum connectivity with the FPTC. DMN integrity was associated with right-claustrum connectivity with the DMN, while FPTC integrity and modularity were associated with right claustrum and left claustrum connectivity with the FPTC, respectively. Subjective effects of psilocybin predicted changes in the amplitude of low frequency fluctuations and the variance of BOLD signal in the left and right claustrum. Observed effects were specific to claustrum, compared to flanking regions of interest (the left and right insula and putamen). This study uses a pharmacological intervention to provide the first empirical evidence in any species for a significant role of 5-HT_2A receptor signaling in claustrum functioning, and supports a possible role of the claustrum in the subjective and therapeutic effects of psilocybin.“

Ethics and ego dissolution: the case of psilocybin

Authors: William R. Smith & Dominic Sitsi

Published: 26 May 2020

One sentence summary: The authors critique the consent process and propose a more comprehensive informed consent process.

“Despite the fact that psychedelics were proscribed from medical research half a century ago, recent, early-phase trials on psychedelics have suggested that they bring novel benefits to patients in the treatment of several mental and substance use disorders. When beneficial, the psychedelic experience is characterized by features unlike those of other psychiatric and medical treatments. These include senses of losing self-importance, ineffable knowledge, feelings of unity and connection with others and encountering ‘deep’ reality or God. In addition to symptom relief, psychedelic experiences often lead to significant changes in a patient’s personality and worldview. Focusing on the case of psilocybin, we argue that the peculiar features of psychedelics pose certain novel risks, which warrant an enhanced informed consent process–one that is more comprehensive than what may be typical for other psychiatric medications. We highlight key issues that should be focused on during the consent process and suggest discussion prompts for enhanced consent in psychedelic psychiatry. Finally, we respond to potential objections before concluding with a discussion of ethical considerations that will arise as psychedelics proceed from highly controlled research environments into mainstream clinical psychiatry.“

Broadening Your Mind to Include Others: The Relationship Between Serotonergic Psychedelic Experiences and Maladaptive Narcissism

Authors: Valerie van Mulukom, Ruairi E. Patterson & Michiel van Elk

Published: 29 May 2020

One sentence summary: Feelings of awe, not ego dissolution, during psychedelic experience were associated with feelings of connectedness and empathy and in turn lower maladaptive narcissism.

“Rationale: Recent research has shown that classical serotonergic psychedelic (CSP) drugs may be used to ameliorate certain health issues and disorders. Here we hypothesised that CSP experiences, through their ability to induce awe and ego-dissolution, may result in a reduction of maladaptive narcissistic personality traits, such as a strong sense of entitlement and lack of empathy. Objectives: Our objective was to investigate whether high levels of awe and ego dissolution during recent CSP experiences are associated with currently lower levels of maladaptive narcissism. Methods: In this pre-registered high-powered (N = 414) study, we used an online retrospective survey asking participants to describe their ‘most awe-inspiring, impressive, significant, or emotionally intense experience’, as well as several validated scales to test our hypothesis. Results: A statistically significant mediation model indicated that recent CSP-induced experiences were associated with currently increased feelings of connectedness and affective empathetic drive, which in turn were associated with decreased exploitative-entitled narcissism. This relationship held even when taking into account sensation-seeking personality features. We found no evidence for feelings of ego dissolution to have the same effect. Conclusions: Feelings of awe, but not ego dissolution, during recent CSP experiences were associated with increased feelings of connectedness and empathy, which in turn were associated with decreased levels of maladaptive narcissism personality features. This suggests that CSPs hold therapeutic potential for disorders involving connectedness and empathy, such as the treatment of pathological narcissism, and that the induction of connectedness through awe appears to be the driving force behind this potential.”

Ketamine as a Mental Health Treatment: Are Acute Psychoactive Effects Associated With Outcomes? A Systematic Review

Authors: Meryem Grabski, Anya Borissova, Beth Marsh, Celia J A Morgan & H Valerie Curran

Published: 30 May 2020

One sentence summary: Systematic review (n=891 participants) of ketamine treatments that didn’t find dissociation as predictor of (mental health) outcomes, also critical on methodology of studies reviewed.

“Esketamine was recently licensed by the US Food and Drug Administration (FDA) and European Drug Agency (EDA) for use in treatment resistant depression (TRD), and promising research indicates ketamine as a possible treatment in other mental health conditions. While the underlying mechanisms remain unclear, it has been hypothesised that acute psychoactive effects during ketamine administration may be associated with psychiatric treatment efficacy. We systematically reviewed the evidence for this association. The databases Medline, Embase and PsychInfo were searched up to June 2019. Studies were included if they enrolled adults with a psychiatric diagnosis, assessed acute psychoactive effects using a quantitative measure, and reported on the relationship between acute effects and treatment outcome. We included 21 studies, involving 891 patients. Seventeen studies assessed patients with depression (TRD [k = 14]), three assessed substance use disorders, and one assessed social anxiety disorder. Overall, 41 associations were assessed, of which 26 % were significant. The studies reviewed displayed great variability in terms of methodology and quality of reporting. The most commonly assessed effect was dissociation, measured by the CADSS. Our results suggest that the CADSS total is not consistently associated with antidepressant outcomes. Apart from this, the current literature is too limited to draw definite conclusions on the presence of an association between acute psychoactive effects and mental health outcomes. The field would benefit from consistently employing a priori hypotheses, more transparent reporting and sufficiently powered statistical analyses. Furthermore, the use of a broader range of assessments tools of acute psychoactive effects during ketamine administration would be beneficial.“