Summer is officially here, and psychedelic researchers are continuing their efforts to turn these medicines into viable therapy options. Despite relatively few clinical trials published in June, we’re continuing to learn more about the effects of psychedelics through the reanalysis of existing datasets and surveys. Moreover, researchers continue to hypothesise how psychedelics work on the brain and discuss their potential for treating many disorders.
Psychedelics put to the test
Over the past month, researchers published several clinical trials with human participants. Most notably, they explored the antidepressant effects of DMT. Also, some early evidence suggests that LSD can have a nootropic effect. One rodent study worth highlighting found that ketamine and psilocybin did not elicit any antidepressant or anxiolytic effects in rats.
Deepak D’Souza and his team at Yale University carried out an open-label dose-escalation study exploring the effects of intravenous DMT in healthy volunteers (n=3) and participants with major depressive disorder (n=7). Across both groups, DMT was well tolerated and led to significant reductions in depression scores the day after the high dose. Despite the positive results, a larger sample is needed to confirm the antidepressant effects.
A double-blind placebo-controlled study (n=25) assessed the effects of LSD on metabolic pathways associated with neural plasticity in both humans and rodents. LSD treatment in humans (50μg, small/moderate dose) enhanced performance in a visuospatial memory task in humans. And in a novel object recognition task in rodents indicated that LSD has a nootropic effect. LSD-induced neural plasticity may underlie these cognitive gains in rats and humans.
In a blinded doses-escalation study with Salvinorin A in healthy participants (n=10), salvia produced psychotomimetic effects and perceptual alterations including dissociative and somaesthetic effects, increased plasma cortisol and prolactin and reduced resting EEG spectral power but did not produce euphoria, cognitive deficits or changes in vital signs.
A proof-of-concept study (n=58) assessed the association between participation in an ayahuasca retreat in a traditional indigenous Amazonian context and how it’s linked to nature-relatedness. Retreat participation was associated with increases in nature-relatedness, mindfulness and improvements in depression and anxiety.
In this posthoc analysis, six repeated ketamine infusions (0.5mg/kg) in anxious depressed patients were associated with a relatively lower antianhedonic response (47.8 % versus 51.2 %, p > 0.05) and remission (17.4 % versus 27.9 %, p > 0.05) than their non-anxious counterparts. Across both groups, a significant reduction in anhedonic symptoms was observed from the first infusion to the last infusion and at a 2-week follow-up.
In this rodent study, ketamine and psilocybin increased the levels of dopamine, serotonin, glutamate and GABA extracellular levels in the frontal cortex, while psilocybin also increased GABA in the reticular nucleus. However, contrary to many findings in human (and other rodent) participants no antidepressant or anxiolytic effects were observed.
A fresh perspective on existing data
This study analysed data from two Phase II and one Phase III trials from MAPS where MDMA-assisted therapy (MDMA-AT) was used to treat PTSD in order to compare the efficacy and safety of MDMA-AT between Black, Indigenous, and People of Color (BIPOC) and non-Hispanic White participants. No significant ethnoracial difference in CAPS-5 scores was observed while BIPOC participants trended toward greater reductions following MDMA-AT.
In this meta-analysis, the effectiveness of ketamine for treatment-resistant depression (TRD) using real-world data was explored. While the mean antidepressant effect of ketamine was found to be significant, there are high levels of variability between patients. Treatment effects were found to be similar following repeated treatments.
This meta-analysis explored the association between baseline levels and longitudinal changes in blood-based biomarkers and response to ketamine/esketamine. Over 460 individual biomarkers were examined and there were no consistent associations between baseline levels of blood-based biomarkers and response to ketamine
Using machine learning models, researchers assessed 11,821 publicly available natural language testimonials from Erowid (public registry of psychedelic experiences) using three machine learning models to help quantify changes in conscious awareness optimal for treatment by psychedelics. Together, the models showcase a neurobiologically-informed, temporally-sensitive portrait of drug-induced subjective experiences.
In a separate study, a machine learning model was applied to an EEG dataset from a study involving ayahuasca to investigate the ability of machine learning and complex network measurements to automatically detect changes in brain activity. Machine learning proved to be consistent with the current literature and showed the highest accuracy in detecting the correlation of the EEG time series.
David Glowacki and his team introduced us to “Isness-D” – a VR framework which harnesses the unique affordances of distributed multi-person VR to blur conventional self-other boundaries. They reanalysed data from self-report scales previously applied to analyse subjective psychedelic drug phenomenology finding that Isness-D scores were indistinguishable from recently published studies with psychedelic drugs.
Insights from surveys
The team at Johns Hopkins used a survey (n=2,374) to characterise a broad range of psychedelic-induced changes in beliefs. Upon analysis, five key factors – on which they scored higher after psychedelic use – were identified: dualism, paranormal/spirituality, non-mammal consciousness, mammal consciousness, and superstition.
Using the eudaimonic perspective of well-being, this survey (n=750) found that perceived benefits to narrative self-functioning are one pathway through which integration of psychedelic experience may promote optimal well-being for both clinical and non-clinical populations.
This survey assessed the relationship between microdosing and trait anxiety through an online survey with current microdosers (n = 186), former microdosers (n = 77) and microdosing-naïve controls (n = 234). Current and former microdosers reported lower STAI-T scores compared to microdosing-naïve controls while associations of current and former microdosing with trait anxiety were mediated by trait mindfulness.
This review of surveys that quantified the self-reported efficacy of two or more cluster headache (CH) treatments found that the consistently reported efficacy of psilocybin and LSD in the treatment of CH in these surveys indicates the need for clinical studies in this area.
Reviews and the rest
This systematic review explores the potential mechanisms by which combined psilocybin and mindfulness treatment could adjust neural activity underlying social anxiety disorder (SAD) and exert therapeutic effects. Proposed mechanisms include changes in cognitive processes like biased attention to threats linked to SAD by modulating connectivity of the salience network.
Upon reviewing the neurocognitive effects of subanesthetic doses of intravenous ketamine in pharmacological studies among healthy subjects and patients with PTSD or depression, no significant impairment in cognitive function was found in patients with depression and possible in those with PTSD.
This review explored the use of structured associated psychotherapeutic interventions in psychedelic clinical research to construct a picture of what models of psychedelic-assisted psychotherapy are currently adopted in such research.
A review of the role of neuroimaging techniques in the development of psychedelic therapy suggests that the modern development of psychedelic therapy has benefitted greatly from these techniques. It is suggested that current knowledge gaps in the field could be addressed using combined Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) methods, and more.
In this paper, eighteen experts reformulated the Dutch MDMA policy with a science-based approach. Implementation of the optimal policy model, includes regulated MDMA sales, decreasing health harms, MDMA-related organised crime, and environmental damage, as well as, increasing state revenues, and quality of MDMA products and user information.
A new book chapter from Matthew Johnson reviews the use of psilocybin in the treatment of addiction with a specific focus on smoking cessation.
This paper makes the case for using MDMA to treat symptoms of schizophrenia and proposes possible mechanisms of action. The role of psychedelics in the treatment of postpartum depression is also explored.
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