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. The trial tested 25 mg of psilocybin in combination with talk therapy. 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 scores on the MADRS scale were comparable to that in COMPASS Pathways’ Phase 2b trial.
Most striking is the durability of the reduction in depression scores. The effects were seen on day eight (-17.8) and remained 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 Blossom’s 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 50 receiving psilocybin. The next largest trial for depression compared psilocybin to a common SSRI (59 total, 30 active). All this to say, this study adds a significant amount of data pointing 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 Blossom 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 remained on antidepressants (SSRIs). Many studies exclude patients on, or ask 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).
A meta-analysis searched for the optimal dose in psilocybin-assisted therapy for depression. 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.
Other Clinical Psychedelic Studies During Summer 2023
An open-label (meaning there was no placebo group; everyone knew they received the treatment) study examined 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).
The first 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 not likely to occur until 2025 at the earliest.
Outside of the research environment, polydrug use is common. Combining MDMA with LSD (candy flipping) or with psilocybin (hippie flipping), for example, is 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 potential benefits of microdosing. But what about the potential 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.
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.
With 50 articles added (and 200 more in Blossom’s 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 that Floris 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 syndrome for those with spinal cord injury using psychedelics.
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