Researchers in the field of psychedelics hit the ground running at the turn of the new year. January brought with it the largest published clinical trial with psilocybin to date. While ketamine was shown to effectively treat patients with alcohol use disorder, the same can’t be said for PTSD. A host of reviews provide food for thought on a range of psychedelics and their mechanism of action.
Participants in the Lab
Over the past month, a substantial amount of research involving human participants has been published. A plethora of research papers exploring the therapeutic effects of ketamine have emerged, notably for alcohol use disorder and PTSD.
This trial (n=96) assessed the effectiveness of 1) three weekly ketamine infusions (0.8 mg/kg i.v. over 40 minutes) plus psychological therapy, 2) three saline infusions plus psychological therapy, 3) three ketamine infusions plus alcohol education, or 4) three saline infusions plus alcohol education, in people with alcohol use disorder (AUD). Participants in the ketamine groups abstained from alcohol for a significantly longer number of days at 6-month follow-up, while the greatest abstinence was in the ketamine plus therapy group. A positive outcome for the team at Awakn Life Sciences.
A similarly designed study (n=158) assessed eight repeated doses of intravenous ketamine administered twice weekly at a low dose (14mg/70kg; n=53), standard dose (35mg/70kg; n=51) ketamine or placebo (n=54) in veterans and active service members with PTSD. The standard dose of ketamine reduced MADRS scores significantly more than placebo. However, the trial failed to find a significant dose-related effect of ketamine on PTSD symptoms measured using the CAPS-5.
One of the many endeavours of COMPASS Pathways, a Phase I RCT found that 10mg and 25mg doses of psilocybin are generally well-tolerated when administered to up to 6 participants simultaneously. Participants (n=89) each received one-to-one psychological support during the sessions in the largest published trial with psilocybin to date.
Elsewhere, adult couples (n=8) who self-reported active MDMA use were interviewed. Couples collaborated on becoming “set” for their experience and described positive effects on communication, intimate bonding, and providing a relationship “tune-up,” among other durable changes to the relationship. These findings suggest the possibility of informed, non-problematic adult use of MDMA for cognitive and relational enhancement.
A meta-analysis assessed patient-level data on the effects of psychedelics on suicidality across seven clinical trials. It was found that, relative to baseline, psychedelic therapy was associated with large effect sizes and sustained decreases in suicidality. The effect size was medium at six months, while reductions in suicidality were significant at all time points except 7-8 weeks.
Positives for Safety
Researchers analysed data from participants (n=142) in clinical trials who had received LSD and psilocybin to assess the prevalence of recurring drug-like experiences in the days after administration of these substances. 13 participants (9%) reported recurring drug-like experiences (LSD: 7, psilocybin: 2, both: 4) which were considered mild and perceived as neutral to pleasant. No reports met the criteria for hallucinogen-persisting perception disorder (HPPD).
In another study, researchers assessed the occurrence of serotonin syndrome (SS) associated with MDMA use and reported it to the FDA Adverse Event Reporting System (FAERS). In each of the 20 reported cases of SS, people had also taken one or more substances with serotonergic properties in addition to MDMA, including amphetamines, stimulants and opioids. There were no reports of sole MDMA use leading to SS.
What’s going on in the brain?
A neuroimaging study (n=4) used positron emission tomography (PET) with a 5-HT2A receptor agonist radioligand (that would light up on scans) and cortical regions of interest (ROIs) to determine the regional occupancy of 5-HT2A receptors after oral administration of a psychoactive dose of psilocybin (10mg/70kg). Three areas with the greatest occupancy were within the default mode network (DMN). There was high variability across individuals.
In an open-label study (n=15), the dynamic organisation of spontaneous cortical activity during wakefulness and altered consciousness induced by both subanaesthetic and anaesthetic doses of ketamine were assessed using EEG. The anaesthetic doses of ketamine tended to shift the configuration toward brain states with low spatial variability. In contrast, subanaesthetic ketamine was associated with a richer repertoire of spatially distributed patterns of brain activity.
Researchers at Imperial College London developed and validated a new scale to measure psychological insight gained during a psychedelic experience: the Psychological Insight Scale (PIS). A survey study (n=279) found the PIS is complementary to current measures used in psychedelic studies. As measured by the PIS, insight was found to mediate the long-term psychological outcomes after a psychedelic experience.
Franz X. Vollenweider and John W. Smallridge explore the neurobiological mechanisms through which psychedelics exert their effects in light of recent research in a new review. The pharmacological and neuroplastic effects are discussed as well as the hypothesised functional network models of psychedelic states.
David E. Olson discusses the biochemical signalling pathways activated by psychedelics and related neuroplasticity-promoting molecules in a separate review. The ability of psychedelics to promote structural and functional plasticity in the prefrontal cortex (PFC) and the implications this has for stress-related disorders are discussed.
A systematic review of clinical trials included a total of 705 individuals that were treated with either ibogaine or noribogaine. It was found that such interventions may be useful for treating substance use disorders, alleviating withdrawal symptoms and cravings. Importantly, a number of severe adverse effects, including death, that have been recorded in the trials are discussed.
Another review explored the positive and negative aspects of different formulations and routes of administration of DMT. Alternative ways to oral administration in tandem with a monoamine oxidase inhibitor (ayahuasca/pharmahuasca) are discussed as well as the role of endogenous DMT in normal brain function.
Finally, this review focuses on using ketamine to treat mood disorders in women. Some of the topics discussed are the cause of depression in women, the preclinical research on the neurobiological effects of ketamine and how these effects interact with ovarian hormones.
Outside of the Lab
A retrospective analysis (n=537) assessed the effectiveness of intravenous ketamine therapy in community-based practices, i.e. real-world care settings. Over half of the participants showed a response at 14-31 days post-infusion and 28.9% remitted, whilst 73% exhibited a reduction in suicidal ideation. However, remission status was weakly inversely correlated with depression severity.
A case is made for the inclusion of psychedelic-using communities in bioethical discussions that guide normative elements of psychedelic medicalisation. It is argued that these communities have a degree of epistemic expertise regarding psychedelics and that these communities are uniquely and heavily affected by psychedelic medicalisation.
Eduardo E. Schenberg and Konstantin Gerber question the epistemic authority of western science and medicine in over 30 years of research on ayahuasca. Given the traditional use of ayahuasca, the researchers propose new approaches to maintain epistemically fair research and ensure these peoples traditional knowledge and biocultural heritage is maintained. Without adequate regulation, the rights of indigenous people, as well as the sustainability of the Amazon itself, face threat.
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