Psychedelic Research Recap July & August 2023

Psychedelic Research Recap July & August 2023

Even as many of us took time off for summer vacations, researchers in the field of psychedelics persisted in their efforts. They delved deeper into understanding the healing properties of these substances. The big psilocybin for depression (MDD) by the non-profit Usona was published, we got new insights into candy flipping (MDMA + psychedelic) from two groups, and the risks of prolonged microdosing.

In case you had some downtime over the summer, hopefully, this overview will get you up to speed with anything you may have missed.

For all the latest papers, check out our [database](/papers) and the ones that weren’t added in our July and August Link Overviews.

Treating Depression with Psilocybin + Therapy

The long-awaited Phase II clinical trial by the Usona Institute was finally published in August. The results are positive and on par with earlier trials (or arguably better than the COMPASS trial, which involved ‘psychological support’ only). The trial tested 25 mg of psilocybin in combination with talk therapy (confusingly called psychological support but involved about 20 hours of therapy in total). The key finding of the 104-person trial is a reduction of 12 points on the MADRS scale (a common measure of depression scores) over placebo (niacin). Interestingly, most participants would not qualify for the label ‘treatment-resistant depression’ (TRD), though initial (before starting treatment) scores on the MADRS scale were comparable to that in the COMPASS trial.

Most striking is the durability of the reduction in depression scores. The effects were seen on day eight (-17.8) and stayed there until the endpoint on day 43 (-19.1). For the placebo group – which received niacin (arguably not the best placebo as participants are likely to guess that ‘feeling flushed’ isn’t the full-on trip) – the depression score reduction was about 7 points (thus leading to the headline figure of 12 points difference). In the psilocybin group, 42% had a sustained response (>50% reduction) and 25% were in remission (<10 score on MADRS between days 8 to 43).

If we take a look at our Originals database (freely accessible), we see that this is the second-largest trial with psilocybin for depression. The COMPASS trial had 233 participants, with 79 receiving the high dose. This study had 104 participants, with eventually 50 receiving psilocybin. The subsequent biggest trial for depression is the one comparing psilocybin head-on to a common SSRI (59 total, 30 active). All to say, this study adds a significant amount of data points towards the understanding of psilocybin in the treatment of depression. A prominent European trial (EPIsoDE) and the Phase III COMPASS trials are likely the next two, which will help us make sense of this treatment modality.

Sticking with the COMPASS studies, a pre-print we previously covered is now out, looking at using Natural Language Processing (NLP) to predict who will respond to treatment. It states that the model can predict who will respond to treatment with 85% accuracy. The implications of this research signal that audio recordings can be used to predict who will respond to treatment and possibly aid in helping identify who would need more support.

A smaller open-label study – also by COMPASS – with 19 participants investigated the effects of psilocybin treatment if people stayed on antidepressants (SSRIs). Many studies before this excluded patients, or asked them to taper off SSRIs, but this study found no serious treatment-emergent adverse events or increased suicidality. It did report a significant reduction in the MADRS score of 15 points (falling in the middle of the previously discussed Usona and COMPASS trials).

Looking at the most effective dose for psilocybin-assisted therapy for depression, a meta-analysis searched for the optimal dose to give. For primary depression, 25mg (as was used in the studies we just covered) seemed to be the optimal dose.

Finally, a meta-analysis of three studies (102 participants) assessed the risks of symptoms worsening in psilocybin for depression trials. It reports that clinically significant symptom worsening occurred in approximately 10% of participants in the psilocybin and escitalopram conditions, and in 63.6% of participants in the waitlist condition. Psilocybin showed a lower likelihood of symptom worsening compared to waitlist, and no difference compared to escitalopram.

The Other Clinical Psychedelic Studies During the Summer of 2023

An open-label (meaning there was no placebo group; everyone knew they received the treatment) studyexamined the effect of psilocybin (25mg) on patients with Anorexia Nervosa (AN; anorexia) or those in partial remission. Results show that the treatment was safe, tolerable, and acceptable, with no significant changes in ECG, vital signs, or suicidality. However, two participants developed asymptomatic hypoglycaemia (low blood sugar), which resolved within 24 hours. No significant changes in BMI were found. Several larger trials are currently underway, hoping to find positive treatment effects.

A review (pre-print) of clinical studies investigated reported practices, e.g. disclosing details on the intervention, number of therapy sessions, etc. The researchers looked at 33 studies and found many lacking in reporting vital details such as what therapy manual was used (52%) or assessment of treatment fidelity (82%).

A new paper came out on a study conducted a few years ago comparing psilocybin to dextromethorphan (DXM) in healthy volunteers. This article reports on the enduring psychological effects, arguing that psilocybin’s effects were dose-dependent and more favourable, while DXM had poorer physical tolerability.

Peering inside the brain, a functional mapping study compared the effects of psilocybin versus methylphenidate (Ritalin). The pre-print shows that psilocybin led to a persistent decrease in connectivity between the anterior hippocampus and cortex, especially the DMN, lasting weeks but normalizing after six months, potentially explaining its pro-plasticity and anti-depressant effects. A re-analysis of data on LSD, MDMA, and d-amphetamine also unveiled changing brain dynamics.

Moving on to the body, a detailed study by the University of Basel group investigated the pharmacokinetics and -dynamics of LSD in healthy participants. It details how LSD reached peak concentration (in the bloodstream) after 1.7 hours and that only 1% of LSD was found unchanged in urine 24 hours later. The effects lasted about 11 hours for the high dose (170 μg).

Thefirst article of July brought up a controversial topic: giving MDMA to adolescents. Though the study hasn’t taken place yet, the goal is to see if an earlier intervention (for trauma/TPSD) could be effective. The article outlines adaptations that would need to be made, such as family involvement, though an actual study is likely to occur in 2025 at the earliest.

Candy Flipping – A Boon or Irrelevant

Outside of the research environment, polydrug use is the norm. Ask around at a festival, and you will find people drinking a beer or two whilst enjoying the effects of MDMA (XTC). Combining MDMA with LSD (candy flip) or with psilocybin (hippy flip) is also not uncommon.

Still, when researchers investigated the combination last May, they found no enhancement in the quality of subjective effects compared to LSD alone. The researchers gave participants 100mg of MDMA and 100µg of LSD, and this is what we currently can say within the lab. A prospective survey of nearly 700 people argues that co-use of psilocybin/LSD with a low dose of MDMA was linked to significantly reduced challenging experiences (like grief and fear) and enhanced feelings of self-compassion, love, and gratitude.

Many different hypotheses can explain the difference, e.g. those within the lab have fewer challenging experiences because the environment had much better controls than being out at a festival. A blog post on Qualia Computing dives much deeper into the possible synergy of the candy flip.

The Dangers of Microdosing

There is a widespread discussion in the academic literature (and beyond) about the benefits of microdosing. But if we flip things on its head, what about the dangers of microdosing? A review that covers cell, animal, and human studies provides the most up-to-date picture of the potential risks of valvular heart disease (VHD).

The review focused on LSD, psilocybin, mescaline, DMT, and MDMA due to their interaction with the serotonin 5-HT2B receptor. Findings show that all these compounds, except mescaline (due to low potency), were partial agonists at the 5-HT2B receptor. While safety margins from typical microdoses were greater than known valvulopathogens, there remains a potential risk. Or put differently, microdosing likely won’t lead to VHD, but other evidence reviewed by the researchers shows that chronic high doses of MDMA might be more dangerous to heart health (among other things).

Turning back to the benefits of microdosing, an observational study with 17 participants fails to find positive effects on a battery of cognitive tests. The study concludes that microdosing psychedelics might influence psychological pathways rather than neurocognitive ones, leading to a subjective feeling of performance enhancement.

Looking at the methodology of microdosing studies, a computational analysis investigates the difference between ‘placebo group’ and ‘placebo control’. The study introduces the Correct Guess Rate Curve (CGRC), a tool to estimate the results of a perfectly blinded trial using data from an imperfect one, and re-analysed the ‘self-blinding psychedelic microdose trial’ dataset (n=191) to demonstrate that placebo-microdose differences may be susceptible to ‘activated expectancy bias’ (AEB).

Finally, a survey looked at the effects of psychedelics on pain, including the use of microdoses. It found a positive impact of microdoses on migraines, with comparable results (to conventional treatments – some of which come with many more side effects) on three other pain conditions.

All Other Studies of This Summer

With 50 articles added (and 200 more in our link overviews), the number of studies this summer was too great to fully capture everything in this recap. So, here are a few of the other themes I identified, with links to the studies if you want to investigate further: Two studies looked at psychedelics and creativity, one in the films of Fellini, another reviewing the literature and finding an impairment in cognition and creativity after a high dose.

Four studies crossed the intersection between (psychedelic) healthcare providers and the general population. The first is a theory-building article investigating the therapeutic alliance. The second is a survey of medication prescribers and their experience with psychedelic use. The third and fourth are surveys that look at how many people disclose psychedelic use to healthcare providers.

Five studies investigated the effects of (es)ketamine on depression (1,2,3,4,5), reporting on real-world data, comparing esketamine and ketamine, and repeated dosing.

Three studies reported on subjects we haven’t covered (in detail) before. One looks at olfactory improvements after psychedelic use in 3 case studies. A second study looks at the effects of psychedelics on intimacy; the survey likely also provides the researchers with data for a planned clinical trial on this topic. The third study looks at serotonin-like syndromefor those with spinal cord injury using psychedelics.