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Journal Club: At Home LSD Microdosing

An exciting article, "Acute mood-elevating properties of microdosed LSD in healthy volunteers: a home-administered randomised controlled trial" by Murphy et al. was just published as a pre-proof. Naturally, we wanted to break it down for ya'll.


If you haven't been following along with Your Brain on Science, refer to our episode on microdosing, where we do a comprehensive breakdown on the current literature at the time of the episode. This episode also included the mention of a so-called white paper, which refers to non-published or peer reviewed findings that are typically sent to investors of a company that's sponsoring a trial. We discussed how the preliminary findings were interesting and the data showed was a little confusing, because well... you can listen to the episode.


Fast forward to today - the results are officially published! Some of the authors of this paper have received research funding from MindBio Therapeutics Ltd to conduct further

work in psychedelic microdosing, including this study. So keep that in mind when we're reading these results. Let's break it down...


Rationale/Hypothesis

  • Microdosing has been anecdotally linked to increased productivity, creativity and mood, with some preclinical evidence for plasticity following some psychedelics. Little research has been able to prove microdosing more than a placebo.

  • The goal of the study is to assess the potential therapeutic effects of microdosing LSD in a "naturalistic" environment, meaning a place where the participant is going about their daily life.

  • It's important to note this study was done in healthy participants with no underlying mental health conditions.

Methods

  • This trial is a randomized controlled trial, meaning that users are randomly assigned either the LSD or placebo (control) groups.

  • The participants were given either a 10 microgram dose of LSD in water, or an inactive placebo (water alone). The first dose was given in a clinical setting, followed by 13 doses at the participants home every 3 days for 6 weeks.

  • All participants were verified to be compliant with dosing schedule using self-recorded videos.

  • Pre-/post- intervention questionnaires and cognitive tasks were administered at Baseline (~1 week before the first dose) and a Final visit 6 weeks later (~2 days after the last dose).

  • Expectancy questionnaires were administered on the Treatment visit (prior to dosing) with a matching retrospective questionnaire of experience administered at the Final visit.

  • Adverse events (AEs), blinding data, and daily VAS measures were collected via questionnaires sent to participants by SMS every night.

  • Blinding was measured via a categorical guess of ‘Placebo’ (-1) , ‘Don’t know’ (0), and ‘LSD’ (+1) on each dose day, from which the Bang Blinding Index (BBI) was computed, as well as a continuous VAS rating of their confidence from ‘Definitely Placebo’ (-50) to ‘Definitely LSD’ (+50).

  • They also using a variety of questionnaires measure other aspects of the experience. These questionnaires include: the Big-Five Inventory, Detail and Flexibility Questionnaire, Five Facets of Mindfulness, Depression/Anxiety/Stress Scale, NIH toolbox emotion battery, Perceived Stress Scale, NIH Cognitive Battery and the Modified Tellegen Absorption Scale (which measures ‘absorption’, a construct which covers the tendency to get absorbed in sensory or imaginative experience)


What is the VAS?

This is is a form of a "visual analog scale" in which participants can rate their subjective experiences with things like pain, anxiety, anger, creativity, etc.


In the case of this study the VAS ratings are: Less than Usual’ (-50) to ‘More than Usual’

(+50), with ‘Usual’ (0) as the middle point. Data were analyzed using the categorical variable ‘Day’ with three levels, dose day and the two subsequent non-dose days, repeated 14 times through the trial. Keep this in mind when looking at the results.


Demographics & Adverse Events (Adverse events below)

  • All male participants with a mean age of 36 years old, majority educated above highschool, little ethnic diversity (mostly New Zealand/European)

  • Overall good compliance with study design, small number (<10 of missed doses, calls, etc.)

  • No severe AEs, most AEs included jitteriness and anxiety. Those feeling jittery were mainly in the LSD group (~32%) vs placebo (~7%), which was statistically significant.

  • Interestingly, following AE reports of a disruptive overstimulation, the protocol was amended to include a process for dose titration.

  • 7 trial participants experienced increased anxiety, which warranted dose titration (one in placebo). 4 participants ended up dropping out of the study due to this. It was reported these participants had relieved anxiety following two-weeks of light support from research staff.

Unblinding and Expectancy

  • The Placebo group was effectively blinded however, the LSD group was partially unblinded.

  • Some of the study team was unblinded throughout the trial, but this seems to be corrected after 30 participants were unblinded to the study team.


Figure S4: Bang Blinding Index for the MDLSD trial. The index ranges from -1 (complete unblinding) to +1 (incorrect guessing) with 0 indicating chance. Maintenance of blinding is indicated by a point estimate between -0.2 and 0.2 or the confidence interval crossing 0.







Figure S6. Expectancy predicator added to daily VAS scores.

  • Expectancy was found to play a significant role in the measures of: energy, happy, and connected.

  • Participants in the LSD group rated a greater belief that microdosing had caused a positive change in certain measures post-intervention (meditative, open, creative, well) than those in the placebo group did, and this belief exceeded their expectancy of a change pre-intervention.


Figure 4. Mean ratings of what was expected vs what was experienced. Ratings for both scales indicate participants' certainty on whether microdosing would/did change the construct and are centred on “Not sure” (0), with limits of “Definitely increase/d”(+50) and “Definitely reduce/d” (-50). Ratings towards “Definitely reduce/d” lie within the grey area, and those towards “Definitely increase/d” within the white area.


VAS Scores - Main Results

  • Effects of energy, connected, creative, happy and well were driven by slight increases on the dosing days, while the effects of anger and irritability appear to be driven by slight decreases on the dosing days but a return to ratings of usual on the following non-dosing days. This is similar for the effects of sad, stressed and tired. Most effects were acute and did not last more than the dosing day.

  • Analysis of those who weren't sure of their doses via blinding data, showed effects of LSD on energy and wellness being likely more than placebo effect.

  • Participants felt less creative and energetic in the laboratory environment than in their natural environments.

  • Despite significant mood effects on dosing days, no longitudinal psychometric questionnaires nor cognitive tasks produced effects that survived correction for multiple comparisons -- this means that when statistically correcting for using the same data for multiple tests, there were no significant effects of LSD on mood on dosing days.

Figure 2. Shows mean scores across participants in each group for their ratings. Remember, closer to 0 means usual for the participants, closer to 50 or -50 means a large effect of the LSD (more than usual or less than usual, respectively).


Issues/Limitations

  • Study claims that even though sex differences were found in previous studies, they only wanted to study males to simplify their analysis. This should have prompted for inclusion of women in the study to further elucidate potential differences in response to psychedelics, not the other way around. Methods state: "Male-only recruitment was used to reduce menstrual cycle confounds in two of the EEG paradigms that our laboratory has previously identified."

  • Data was collected following the height of the COVID-19 pandemic (April 2021- April 2022), which could confound results due to exacerbations in poor mental health and isolation.

  • When reading the supplemental material the study design seems messy and continuously changing, for example:

3 participants received 15 doses instead of 14
unblinding of study team only half-way through the study
participant let into trial despite fitting into exclusion criteria (wasn't discovered until completion)
  • Figure 2 in the main text is their main measure of the study. This figure is very hard to read considering all the axis are different scales, making it at first glance seem like there are more or less effects than actually present. Interestingly the other figure of the main text, which shows expected vs experienced shows similar data but the scales are all the same simplifying data. (just glad they didn't circle the graphs they wanted people to look at like their unpublished press release LOL)

  • large effect size range, suggesting that more research is needed

  • check out any supplemental materials here

Conclusions

Overall, this body of work adds an important contribution to the literature. The group reports that the use of at-home LSD in these participants is relatively safe both physiologically and psychologically, but there may be some increased risk of anxiety and overstimulation associated with the LSD.


The data suggests that there is a large blinding and expectancy effect, but hey were just happy someone finally tested it transparently. I wish some more of that analyses made it into the main text. I also appreciate that they explicitly recognize the current benefits and safety of microdosing are untested and caution should be taken with repeated use.

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