Balazs Szigeti and colleagues ran the largest self-blinding experiment to date (191 participants) and found that the placebo and microdosing groups both experienced similar improvements in self-rated psychological well-being and cognitive function (e.g. mood, energy, creativity) after four weeks. This study provides more evidence that microdosing benefits can be attributed to expectancy (placebo) effects.
The researchers faced the crowd on the microdosing subreddit and explained the benefits, the low costs, and the possible drawbacks of a study with this design. Their findings are in line with other clinical studies in healthy populations that don’t show changes in mood or cognition while microdosing. However, these findings diverge from many studies on the experiences of people engaging in microdosing regimens, who often report benefits: from better mental health to increased productivity.
Besides the expectancy effect, it may also be the case that microdosing is more beneficial for specific populations. That is what MindMed is studying in their phase 2 clinical trial of microdosing for ADHD. If successful, microdoses of LSD could become a replacement for the current stimulant-based drugs. The trials are currently ongoing and data should be available by early 2022.
A lack of clinical data, and reliance on anecdotal reports, isn’t stopping others from offering psychedelic microdoses online. One of the companies moving into this space is Red Light Holland, which recently acquired SR Wholesale to boost the distribution of its products. Will placebo-controlled studies help validate the claims that microdosing companies are apparently making? Only time will tell.
Research with MDMA has mostly been conducted with a fixed dose of 125mg. Research from 2014 showed very similar effects across the fixed and body-weight adjusted (1.5mg/70kg) dosages and different study sites. The biggest difference highlighted in this study was the smaller subjective effects experienced by those who had taken MDMA more often.
But are there differences between men and women in their reaction to MDMA? And, do bodyweight or personality measures matter? That is what a new analysis of 194 participants in double-blind studies, funded by MindMed, investigated. The results may help future clinical trials and companies that will provide psychedelic therapies offer more individualized dosing regimens.
The study found that the weight of participants predicted both the physiological (e.g., heart rate) and psychological (e.g., feelings of closeness) effects of MDMA. When adjusting for bodyweight, there were no differences between men and women.
Another predictor is the level of CYP2D6 activity, an enzyme that is more or less active in different people. As this is genetically determined, a test could help hone the dose needed for each participant even further. A test, for this gene and others, has just been released by Entheon Biomedical via HaluGen.
The mental state of participants also predicted their subjective experience. Those who were scored higher on measures of anxiety before the experiments also experienced more anxiety, fear of losing control and ego dissolution during the trial.
These results won’t change the current phase 3 trials led by MAPS. They do provide some evidence for a more personalized dosing schedule. However, a similar pooled-analysis of those suffering with PTSD and their long-term outcomes (vs weight, dosage, and genetic profile) could help make dosing more precise in the future.
Other studies this month also investigated dosing regimens and predictors of the intensity of psychedelic experiences. The dose of psilocybin, from 3 to 27mg, predicted how positive changes in perception (e.g., ego dissolution) were. As was found in the MDMA study, several personality traits (absorption, openness, acceptance) predicted the level of positive effects and mystical-type experiences on psychedelics. And finally, baseline theta oscillations (associated with mind-wandering) predicted the intensity of mystical-type experiences after smoking DMT. The authors suggest that reducing theta waves, through mindfulness training, could enhance the therapeutic effects of psychedelics.
Mescaline, made famous in The Doors of Perception, has historically been understudied. A new survey study with 452 participants might spark interest in this natural psychedelic. A whopping 86% of participants who were experiencing symptoms of depression said that recreational use of the drug had helped them.
Journey Colab is, to our knowledge, the only company developing mescaline as a medicine. It is doing this for alcohol use disorder and is currently in phase 1 trials. Although the study above is lacking placebo, and is carried out retrospectively, 76% of those suffering from alcoholism said their trip helped them. Journey Colab is going with a synthetic source of mescaline, so if their trials are positive, it should not put extra strain on the dwindling supply of peyote.
Other studies published this month
A systematic review argues that breaking blind (participants learning which intervention they received) in randomized controlled trials of psychedelic therapies is leading to an over-estimation of the outcomes (outside of clinical trials). The authors suggest measures to tackle this and to use caution interpreting the existing RCTs. This is especially relevant for companies that, in time, will start treating patients that have fewer expectancy effects, might have less involved therapists, or just have less time available per patient. Controlling for these factors now may give a more realistic image of what to expect from psychedelic therapies.
A placebo-controlled, randomized, crossover study with 17 participants investigated the impact of LSD (100 μg/70kg) and the counteracting influence of the 5-HT2A receptor antagonist ketanserin (40mg/70kg) on the autonomic nervous system within healthy subjects. LSD predominantly increased sympathetic activity, while ketanserin increased the parasympathetic influence, thus antagonizing the effects of LSD on the autonomic nervous system completely. Although this study administered ketanserin before LSD, future studies by MindMed will aim to see if this blocking effect persists when someone is already under the influence.
A meta-analysis of 41 studies found ketamine to be effective up to 6 weeks later when ketamine was used for the treatment of depressive episodes. The effects found, at all three follow-up points, were large (g = -1.28 to -1.36). This paper argues for the longer-term positive effects of ketamine, which is usually thought to be effective up to 7 days. Lessons from this meta-analysis may help optimize treatment outcomes, and provide encouragement for using ketamine to buy more time while finding longer-term solutions.
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