September was an exciting month for many psychedelic researchers. Over the past month, we gained some positive insights into the effectiveness of ketamine infusions and esketamine using real-world data (i.e. data not from clinical trials). The official results of the first trial using LSD to treat generalised anxiety disorder (GAD) were published, and researchers continue to learn more about what psychedelics are doing in the brain.
What’s going on in the real world?
Even if clinical trial results are positive, it doesn’t necessarily mean that the results can be replicated in a real-world setting. While most psychedelics are yet to move beyond the clinical trial setting for reasons surrounding their current scheduling and safety, ketamine is widely used as an off-label treatment for many mental health disorders.
For the first time, researchers explored the effectiveness of esketamine (Spravato) in patients with treatment-resistant depression (TRD) in a naturalistic setting. While the study was open-label, the overall response (64%) and remission rates (41%) were similar to the positive outcomes found in clinical trials with esketamine. Esketamine was also found to be safe and well tolerated.
A separate study exploring the effectiveness of ketamine infusions for TRD from a sample of patients attending a private clinic found similar positive results. Of the 424 patients, 72% experienced a clinical response while 38% achieved remission. The infusions also had positive effects on scores of suicidal ideation and anxiety.
Using data from clinical trials and real-world effectiveness estimates, researchers compared the cost-effectiveness of esketamine to intravenous ketamine. Using the quality-adjusted life years (QALYs) metric, it was found that esketamine is not cost-effective compared to intravenous ketamine for patients with TRD. Both types of ketamine add roughly two QALYS, but the cost of esketamine is disproportionately higher.
Sticking with ketamine, a recent meta-analysis assessed the moderators underlying the antidepressant effect of intravenous ketamine in the clinical trial setting. Moderators of the robust antidepressant effect were the level of treatment resistance (i.e. more failed SSRIs) and studies that used a cross-over design (smaller placebo effect).
An open-label study exploring the effects of subcutaneous esketamine on suicidal ideation (SI) in patients with major depressive disorder (MDD) and bipolar depression (BD) finds that esketamine led to significant reductions in SI at the end of the study. However, there was no statistically significant difference between the two subpopulations.
A look inside the brain (and gut)
An interesting theory put forward is that psychedelics can increase serotonin production from the gut (where 95% is made), which can then move more easily into the brain by making the blood-brain barrier (BBB) more permeable.
At the University of Zurich, researchers conducted a follow-up analysis of a randomised-controlled trial (RCT) with psilocybin. Using MRI techniques, they found that self-inhibition of visual areas of the brain (EVA, FG) leads to the complex imagery seen by participants. The results align with the REBUS model and highlight (again) how the bottoms-up processes of the brain are amplified under the influence of psychedelics.
The same researchers also found that psilocybin led to a pattern of decreased top-down effectivity between the default mode network (DMN), salience network (SN), and central executive network (CEN) to the amygdala in a separate analysis.
Using fMRI data from veterans and first-responders who underwent MDMA-assisted therapy, this follow-up analysis finds a correlation between reductions in PTSD and increased amygdala-hippocampal connectivity and reduced amygdala-precuneus connectivity during memory recall.
Classic psychedelics have been known to promote neuroplasticity. However, the mechanisms remain unknown. This review explores specific aspects of psychedelic-induced neuroplasticity, such as the effects on particular proteins, receptors, and the areas of the brain involved.
Using data from a DMT study, this follow-up describes how it’s metabolised in the brain. Researchers also employed a simulation (100 people at doses from 1-10mg) to delineate further DMT’s effects (both the chemistry and the subjective effects) in the first study to explore DMT’s pharmacokinetics -dynamics.
Psychological insights
This analysis of the psilocybin vs escitalopram for depression study finds that those in the psilocybin arm of the study experienced significantly decreased rumination. Only those in the psilocybin arm who responded (>50% symptom reduction) had reduced thought suppression. Ego dissolution and psychological insight, for the psilocybin group, correlated with decreases in rumination and thought suppression.
An analysis of 15 studies finds that ego-dissolution and connectedness (during psychedelic-assisted therapy) lead to a higher chance of improving mental health and well-being. The mechanism of ego-dissolution doesn’t seem to continue after the acute session, whilst connectedness is more sustained. Interestingly, the scores on both measures weren’t correlated, indicating two distinct processes.
This review hypothesises how changes due to psychedelics and psychosis have different (positive and negative) outcomes. Through the lens of self-entropic broadening theory (broader attentional scope, hyperassociative thinking), psychedelics lead to low self-focus (awe, ego dissolution, mystical experiences), whilst psychosis leads to high self-focus (hyperreflexivity, self-referential processing).
A review investigating the subjective (experiential) measures used in psychedelic trials found good correlations between mystical experiences (MEQ), oceanic boundlessness and therapeutic/mood outcomes. Similar results (with fewer participants studied) are also found for challenging experiences, psychological insight, and emotional breakthroughs. However, not much comment is made about the construct validity of the measures.
LSD for anxiety, psychedelics for pain, surveys & the rest
Early this year, researchers at the University of Basel completed the world’s first trial using LSD to treat anxiety, and now the official results are here. It was found that LSD (200 μg) significantly reduced anxiety (STAI-G) scores up to three months after treatment. The patients, both with and without a life-threatening illness, also improved on measures of depression (HAM-D, BDI). Those with more subjective drug effects and mystical-type experiences had better outcomes.
If you’re interested in discovering more about psychedelics and anxiety, check out our previous article exploring this particular area of research and why it is lacking.
This case series highlights how low doses of psilocybin have been able to help those suffering from chronic pain conditions. All individuals were not helped by conventional treatments and achieved robust relief through psilocybin (with minimal cognitive and somatic adverse effects).
This case study describes how a teenager self-treated their psychosis (accompanied by complex PTSD and suicidal ideations) through high-dose LSD and low-dose DMT sessions. The hypothesis argues that psychedelics were able to break down the defensive system and allow for the integration of traumatic memories.
A survey of psychologists found that several factors make it more likely for psychologists to have a positive attitude towards psychedelics. These include younger age, male, more knowledge about psychedelics, not religious, (in)direct experience.
This re-analysis of a national drug survey found that those who use classical psychedelics reported fewer sick leave than the general public. Though a relatively small change (3%), the cost savings could theoretically be $2-$3 billion for the United States economy (this is a thought experiment, many other factors not in the model could also explain this correlation).
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