Research Briefing: No Blue Mondays after clinical MDMA use?

This research briefing is co-published with the excellent Report on Psychedelics.

December 20th, 2021

In The Research Briefing:

• New double-blind study doesn’t find benefits of microdosing

• The negative post-acute effects of MDMA appear to be absent in the clinical setting

The perceived benefits of microdosing remain unclear

The practise of microdosing, the use of sub-hallucinogenic doses of psychedelics, is currently garnering significant attention in the psychedelic community in wake of some recent publications. While we have become all too familiar with overwhelmingly positive anecdotal reports from self-reported microdosers in the media, survey studies and beyond, the exact science leading to these perceived benefits remains open to debate. Much of this debate stems from the lack of appropriately designed clinical trials as well as some important parameters being overlooked in the reporting of results.

The present study sought to explore the effects of microdosing 0.5g of dried Psilocybe cubensis mushrooms (roughly 0.9mg of psilocin, or 1/25th of a high dose) in 34 volunteers who were already planning to start their own microdosing protocol. The trial assessed these effects across a number of different aspects of human behaviour, cognition, perception, and convergent/divergent thinking. Importantly, the trial was designed in a double-blind placebo-controlled fashion, the gold standard in modern clinical research. Moreover, the effects of microdosing on measures of personality, anxiety, mood, cognitive flexibility, amongst a host of other measures were assessed.

In the trial, participants received two doses, one of the dried psychoactive mushrooms and the other dose being the placebo, which in this case was 0.5g of dried non-psychoactive edible mushrooms. On the first dosing day (Wednesday week 1), participants were instructed to randomly select one of two envelopes containing either the active or placebo dose. The unselected envelope was left for the following session one week later (Friday week 2). A number of different measurements were taken on different days of the two-week-long trial period. Participants completed self-report scales prior to each session in order to assess psychological traits and expectations as well as completing tasks and activities following dosing days. Electroencephalography (EEG) recordings were used to investigate brain function.

The main findings:

• The overall acute effects induced by the microdose (measured using the Visual Analog Scale) reached significance, however, these findings were not consistent across participants, i.e results were subjective in nature
• Reported acute effects were significantly higher for the active dose which the researchers attributed to unblinding, i.e. the participants knowing which one was the microdose
• A trend toward cognitive impairment was observed in some cognitive tasks but overall, microdosing did not significantly impact any of the measured domains
• EEG results showed that the active dose decreased the theta band spectra power, which is consistent with the findings in studies using higher doses of psilocybin

The present paper adds to the somewhat scarce literature on rigorously designed microdosing trials. Although significant subjective effects were observed in some participants, most effects were negligible and across some of the measured domains, even indicative of impaired performance.

Furthermore, the findings of this study support the idea that expectancy plays a role in the anecdotal benefits of microdosing. Given that people tend to microdose for periods much longer than two weeks, future research should explore the effects of microdosing over a longer time period using a study design similar to the research at hand.

‘Blue Mondays,’ is there any evidence in clinical MDMA research?

Many tend to associate the substance MDMA, also known as Ecstasy, with a decline in mood and cognition after the acute effects of the substance have worn off. In layman’s terms, these potential neurotoxic effects are widely known as ‘come downs’ and anecdotal reports from recreational users characterize these ‘come downs’ with a state of depressed mood a few days after MDMA use. Given that research is well underway into the therapeutic benefits of MDMA, unearthing the nature of these adverse effects is imperative for MDMA to become a viable therapy option for those in need.

The present paper explores these adverse reactions in the context of clinical research in which participants have been treated with MDMA. Furthermore, the paper seeks to delineate these effects in the clinical setting from reports of users self-administering MDMA in the recreational context. The paper at hand is part of a wider study in which 14 individuals with alcohol use disorder (AUD) were treated with MDMA-assisted therapy.

In the alcoholism study, participants received 10 psychotherapy sessions, with 125mg of MDMA being administered at sessions three and seven. A 62.5mg booster dose was also administered two hours following the initial dose in these sessions. While the wider study focused on the ability of MDMA-assisted therapy on alcohol consumption, the present paper focused on outcome measures related to post-acute mood and sleep quality as well as illicit MDMA use and anecdotal reports.

The main findings:

• Participants maintained a positive mood during the week after each MDMA session. This was measured each day following the two dosing sessions using the Profile of Mood States (POMS).
• The Pittsburgh Sleep Quality Index (PSQI) was administered at baseline, 3 months post-MDMA administration and 6 months post-MDMA administration to assess changes in sleep quality. Sleep quality was improved at the 3- and 6-month follow-ups relative to baseline measurements.
• No participants had any desire to illicitly use MDMA at 3-, 6- and 9-month follow-ups.
• Negative side effects, or come downs, may be explained by confounding variables associated with recreational use.

The results of the present study support the idea that the post-acute effects that have been associated with MDMA may not be relevant when this substance is administered in the clinical setting. Thus, this study further emphasizes the overall safety and tolerability of MDMA administered in the clinical context.

The anecdotal reports from recreational users may stem from the fact that MDMA is generally taken in nightlife settings in the UK (where this study took place) and post-acute may be explained by a combination of dehydration, overheating, exhaustion and sleep and dietary disruption from extended periods of dancing in crowded venues and the illicit sourcing and high dosing of MDMA.

Although the current study doesn’t help explain why ‘Blue Mondays’ do happen, it shows that within a controlled clinical setting, for those with alcoholism, it doesn’t happen. But, this study does contradict earlier finding by Matthias Liechti and colleagues (2001) that reported a third of participants having some depression of mood, lack of energy, and bad dreams in the days after MDMA dosing. A possible explanation for the difference posed by the authors is that in the earlier study there is no therapy given, another reason might be a reduced ‘after glow’ for those participants, wherein the present study new insights into their drinking behaviour could keep their mood elevated for the subsequent days.

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