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Psychedelic Research Bulletin: May 2023

Comparing psychedelics

Talk to any psychonaut and they will tell you there are (significant) differences between LSD, psilocybin, and mescaline. Look at brain scans and animal studies; these too will say to you that each has a distinct pharmacological profile (though all in the same direction). But ask study participants in a cross-over study, and their experiences are too familiar (besides duration) to distinguish between these classical psychedelics.

The study gave comparable doses of mescaline (500mg), LSD (100µg), and psilocybin (20mg) to 32 participants who rated the experiences analogously. The safety profile of the three psychedelics looked similar, with mescaline taking the longest to reach peak plasma levels (pharmacological activity).

So, what happens if you give people both MDMA and LSD simultaneously? That is another question the research group at the University of Basel had. The combination, known as a candy flip, is loved by many psychonauts. However, in this study with 24 participants, no extra beneficial effects were seen when they compared the combination to LSD alone.

The researchers were expecting that MDMA might improve the safety profile of LSD, which they didn’t find. By adding MDMA, they expected to see lower anxiety levels and enhanced mood. But – at least in this case – half of the participants incorrectly guessed that they had only received LSD when both were given. Both drugs were ingested simultaneously, so another setup with MDMA administered later in the trip might see different results.

third study in May looked at data from over 300 trial participants to better map out the acute LSD experience. The dosing ranged from 25µg to 200µg (with 100µg being the most commonly used amount in studies – like the previously covered ones). One possible finding is that there might be a plateau effect going on, with – on some measures – 200µg not showing a massive difference to the dosings lower than that.

The one-and-only direct comparison of psilocybin and an antidepressant (SSRI, Escitalopram/Lexapro) has been re-analysed showing that ‘experiential avoidance’ reduction might be the mechanism driving positive change in the psilocybin group. Still, a non-significant difference between both treatment groups was found on the primary measure.

Finally, two studies investigate the safety profile of MDMA. The first does so by studying the brains of those who regularly – but not currently – used MDMA and non-users. This study finds elevated glutamate & glutamine (GLX) levels in the striatum, though, as it’s correlational, it’s difficult to say this is causative of (again correlational) lower cognitive scores by regular MDMA users. The second study investigates adverse cardiovascular events reported to the FDA, concluding MDMA was not marked as the primary suspect in any of the 17 reports.

Using psychedelics to probe what’s going

When I think about MDMA, my mind immediately goes to its medical application in helping those with PTSD. But a novel study puts things in a new perspective by using MDMA as a provocation test. A biochemical and psychoactive provocation test is a medical procedure that involves administering specific substances or stimuli to provoke a physiological or psychological response to evaluate the function of specific systems or assess certain conditions.

In this case, MDMA was used to see if those with arginine vasopressin deficiency (AVD, a rare condition where the body doesn’t produce enough of the hormone arginine vasopressin) would be similarly affected as healthy controls. Those with AVD had no (or little) reaction to MDMA (in peak concentration of oxytocin nor anxiety levels). This tentatively gives insight into how AVD works, but also the central role of oxytocin in MDMA’s (subjective) effects.

Similarly a study proposal intends to use psilocybin to test if the serotonin system functions differently in those with autism (ASD). The study hopes to bridge the translational gap in autism research.

pre-print examines the sense of self and how this differs between those with psychosis, experienced psychonauts, and control participants. Though the second group experienced enduring subjective changes to the sense of self, only those with psychosis exhibited reduced ‘body ownership’ and ‘sense of angency’.

Interesting findings from ketamine research

Ketamine is one of the more widely studied psychedelic(-like) compounds out there. Ketamine is widely available and easy to use in studies (cheap, short-lasting, etc.). This also means that there is a lot of contradictory evidence out there. Some large trials find effectiveness for treating depression, whilst others fail to see any positive effects beyond the first seven days.

Esketamine is the only ‘approved’ psychedelic that is reimbursed by some insurance providers. A real-world study finds that nearly 50% of patients had their first pharmacy claim approved. Though treatment often (more than half) included fewer than the eight recommended doses, and these were spread out over an average of 85 days (vs the recommended 28 days). Still, follow-up data shows lower utilisation of healthcare services (which insurers like to see, but without a control group, this could be a regression to the mean – meaning this would have happened anyway without an intervention).

Supporting the positive long-term effects of ketamine is a one-year follow-up where a single ketamine infusion was combined with ‘automated self-association training’ (ASAT). Adding this four-day training helped participants for up to three months but failed to show enduring effects in months four through 12.

study of more than 2500 participants in repeated ketamine infusions also finds that nearly 50% of patients respond to treatment and do so better than those treated with SSRIs. Further, a study of youth (18-25 years old) finds that ketamine is generally safe and leads to clinically relevant improvements in depression, anxiety, and suicidal ideation.

When comparing two different dosing regimes of ketamine, no difference was found between the high and low-dose groups. Patients suffered from chronic pain with associated depression improved in both regiments. Although there were only ten participants (five per group), psycholytic (low-dose) ketamine-assisted therapy might have even done better (on some measures, non-significant).

But treatments with ketamine don’t come entirely without risks and hardship. An interview study with 17 patients finds psychological distress in many, with central themes including detachment, fear and anxiety, and tiredness after the experience. The researchers call for additional support for those undergoing (repeated) ketamine treatments.

We end the ketamine section with the first study published (pre-print) in May, looking at the “Trail of Ketamine Masked by Surgical Anesthesia in Depressed Patients“. Whilst under anaesthesia, patients were given either a single infusion of ketamine (35mg/70kg; the most commonly used dose) or a placebo. No significant difference between the groups was found, but both decreased by an average of 13 points on the MADRS scale (out of 60 max).

Why both groups decreased so significantly on the scale without having the acute psychedelic experience is now a question that is actively being asked. Some commentators point towards expectancy effects, whilst others may attribute the antidepressant effects to other factors around the treatment (e.g., the anaesthetic used or general relief after surgery). Without going into depth much further, the study is one of the more unique ones conducted thus far this year.

Other psychedelic studies that came out in May 2023

Here are other psychedelic studies from May 2023:

  • case study of using ayahuasca in treating bipolar disorder finds alleviations of distress and resolution of suicidality. The report might be the first one to describe this treatment positively.
  • Another case report describes the amelioration of mild red-green color vision deficiency after someone used psilocybin mushrooms.
  • Next to experimental studies, an online survey now also finds people to be more connected to nature after using psychedelics.
  • People on an online survey (1600 participants) also felt more connected to themselves and reduced substance (e.g. alcohol, cocaine) use after psychedelic use.
  • After an ayahuasca retreat, participants increased in aesthetic experience, though this didn’t correlate with the intensity of the acute trip.
  • After personal non-recreational use, veterans and civilians both reported improvements in wellness.
  • On the microdosing day itself, those who microdose feel more authentic, a small (18 people) survey finds.
  • report on the Fireside Project finds that 66% of those who called experienced a de-escalation of psychological distress.
  • re-analysis of DMT brain imaging data shows reduced global control energy, as is seen with LSD and psilocybin too.
  • framework relating to access, reciprocity and conduct (ARC) is presented.
  • What therapy is best used in psychedelic-assisted therapy is still an open question. A review finds no clear evidence of using one over the other.

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