Psychedelic Research Recap May 2023
Psychedelic Research Recap May 2023
May was another busy month for psychedelic research, with 30 papers added to the database (and four times that to the May link overview). It was also a busy month for your reviewer, who moved house and then immediately went to speak at Psychedelic Science 2023.
Still, it was such a packed month that I didn’t want to merge it with (also eventful) June. So here is the recap of a month filled with comparative studies (psychedelics vs each other & SSRIs), MDMA as a research tool, and aesthetic changes after ayahuasca use.
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. Known as a candy flip, the combination is loved by many psychonauts. But, 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.
A 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 wants 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.
A 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 agency.
Interesting findings of ketamine research
Ketamine is the best-studied psychedelic(-like) compound out there. It’s 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 insurance. 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).
Bolstering 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.
A 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. And 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 who 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 this year.
The other psychedelic studies that came out in May 2023
Here are the other psychedelic studies – with enough significance that they have been added to the database – from May 2023: A 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 colour 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.
A report on the Fireside Project finds that 66% of those who called experienced a de-escalation of psychological distress.
A re-analysis of DMT brain imaging data shows reduced global control energy, as is seen with LSD and psilocybin too.
A 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. A final study that I want to highlight is one that looked at control conditions in psychedelic trials. I mentioned it in my Psychedelic Science talk, but only 20% of ‘double-blind’ studies even tested the blinding (and found it to be poor). The researchers looked at 86 trials (RCTs). They also found that most used inert (inactive) placebo controls. I’ll touch more on this in an upcoming Lucid News article, but the quality of psychedelic research is something that is top-of-mind.
Papers Published in May 2023
26 studies from the Blossom database published this month.
Acute effects of MDMA and LSD co-administration in a double-blind placebo-controlled study in healthy participants
In a double‑blind, placebo‑controlled crossover study in 24 healthy adults, co‑administration of MDMA (100 mg) with LSD (100 µg) did not change the quality of LSD’s acute subjective effects but prolonged them and increased LSD plasma concentrations and elimination half‑life. The combination produced greater cardiovascular and pupil effects and higher oxytocin than LSD alone and therefore offered no advantage in efficacy or safety for psychedelic‑assisted therapy.
Ayahuasca in the treatment of bipolar disorder with psychotic features-A retrospective case study
This case study (n=1) examines the therapeutic use of ayahuasca in a woman in her late thirties suffering from complex trauma, bipolar disorder, borderline personality disorder, and suicidality. Participation in multiple ayahuasca ceremonies led to significant alleviation of distress, resolution of suicidality, and recognition of her bipolar disorder diagnosis, though core trauma remained partially unresolved. A subsequent follow-up showed continued reduction in dissociative symptoms and noted positive effects of ayahuasca on other instances of psychosis and bipolar disorder. The study contributes to a better understanding of ayahuasca's potential in treating bipolar disorder and severe traumatization.
Bridging the translational neuroscience gap: Development of the ‘shiftability’ paradigm and an exemplar protocol to capture psilocybin-elicited ‘shift’ in neurobiological mechanisms in autism
This protocol summary introduces the shiftability paradigm and the study 'PSILAUT' which aims to bridge the translational gap in autism research. The authors suggest that current pharmacological approaches targeting autism have failed due to the lack of direct experimental evidence on how neurochemical systems modulate information processing in the human brain. To tackle this, 'PSILAUT' uses psilocybin as a pharmacological probe to directly test the hypothesis that the serotonin system functions differently in autistic and non-autistic adults.
Chronic 3,4-Methylenedioxymethamphetamine (MDMA) use is related to glutamate and GABA concentrations in the striatum, but not in the anterior cingulate cortex
Chronic MDMA users showed elevated glutamate–glutamine (GLX) in the left striatum but not in the medial anterior cingulate cortex (ACC), and although overall GABA did not differ by group, striatal GABA was negatively associated with MDMA use frequency. GLX estimates from MEGA-PRESS were more robust than short–echo-time PRESS, suggesting MDMA-related striatal glutamatergic and GABAergic alterations that may contribute to cognitive deficits.
Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants
In a randomized, double‑blind, placebo‑controlled cross‑over study in 32 healthy volunteers, mescaline (300/500 mg), LSD (100 µg) and psilocybin (20 mg) produced comparable acute subjective effects with no qualitative differences in altered states of consciousness at psychoactive‑equivalent doses. Pharmacokinetic differences explained duration differences (mescaline ≈11.1 h, LSD ≈8.2 h, psilocybin ≈4.9 h), with modest autonomic and oxytocin effects (mescaline and LSD increased oxytocin) and similar tolerability apart from slightly more subacute adverse effects after mescaline.
Transpersonal Ecodelia: Surveying Psychedelically Induced Biophilia
Surveying 272 people who had used psychedelics, thematic analysis found that psychedelic experiences—particularly transpersonal feelings of interconnectedness—either re‑established or newly produced passionate, protective biophilic bonds and attendant pro‑environmental attitudes and behaviours, with natural settings reported as especially beneficial. The authors conclude psychedelics can foster nature connection even in previously non‑nature‑oriented individuals, but call for more research on effects outside laboratory settings.
Phenomenology and therapeutic potential of patient experiences during oral esketamine treatment for treatment-resistant depression: an interpretative phenomenological study
This qualitative interview study (n=17) of those receiving esketamine (35-210mg/70kg, 12x over 6w) for depression explores patients' experiences. Findings reveal highly variable effects of ketamine with common psychological distress, and central themes include perceptual effects, detachment, stillness and openness, mystical-type effects, fear and anxiety, feeling hungover and tired, and a neutralizing mood effect post-session. While patients reported several esketamine effects with psychotherapeutic potential such as increased openness, detachment, and mystical-type experiences, the study identifies a need for additional support due to the frequency and severity of the perceived distress during the treatment.
Unlocking the self: Can microdosing psychedelics make one feel more authentic?
In a month-long study of 18 Dutch microdosers, microdosing days (and the day after) were associated with higher state authenticity and with increases in the number and satisfaction of daily activities, suggesting that enhanced feelings of authenticity may help explain microdosing's reported wellbeing benefits.
Acute effects of intravenous DMT in a randomized placebo-controlled study in healthy participants
In a double-blind, randomised, placebo-controlled crossover trial in 27 healthy participants, intravenous DMT produced very rapid, intense psychedelic peaks within 2 minutes after 15–25 mg boluses and slower, dose-dependent plateaus after 0.6–1 mg/min infusions, with effects resolving within 15 minutes due to a short plasma half-life. Boluses induced more negative/anxious experiences than infusions, and continuous infusion showed acute tolerance despite rising plasma concentrations, indicating that infusion regimens offer a controllable way to tailor DMT-induced psychedelic states for therapeutic use.
Changed Substance Use After Psychedelic Experiences Among Individuals in Canada
This cross-sectional online survey (n=1639) investigated self-reported changes in substance use associated with past or current psychedelic use. Results indicate that 43% reported decreasing or ceasing alcohol, cocaine, or antidepressant use. Conversely, the highest rates of increased use were reported for cannabis and tobacco products (10%). Key reasons for substance use reductions included increased self-connection, less anxiety or depression, and connection with nature and others. Factors leading to reduction in any substance use included the motivation to treat a medical condition, the number of psychedelics used, younger age, and using both microdoses and macrodoses.
Ketamine-assisted psychotherapy treatment of chronic pain and comorbid depression: a pilot study of two approaches
This observational pilot of ten people with chronic pain and comorbid major depressive disorder compared a high‑dose intramuscular "psychedelic" KAPT protocol with a low‑dose sublingual "psycholytic" protocol and found reductions in depression, pain, anxiety and PTSD symptoms overall, with larger and more consistent decreases in the psychedelic group though differences were not statistically significant given the small sample. The authors conclude KAPT may be beneficial for chronic pain/MDD comorbidity and recommend larger controlled trials to determine optimal dosing and administration.
Concomitant medications associated with ischemic, hypertensive, and arrhythmic events in MDMA users in FDA adverse event reporting system
This survey (n=17) investigates cardiovascular adverse events (AEs) associated with MDMA-assisted therapy sessions, utilizing the FDA Adverse Event Reporting System. The study finds that all cases of cardiovascular AEs involved using additional substances alongside MDMA, all of which had been previously associated with cardiovascular AEs. MDMA was not marked as the primary suspect in any of the reports.
Real-world effectiveness of repeated intravenous ketamine infusions for treatment-resistant depression in transitional age youth
In a retrospective matched analysis of 52 transitional age youth (18–25) with treatment‑resistant depression, four intravenous ketamine infusions over two weeks produced significant, moderate‑sized reductions in depressive symptoms, suicidality and anxiety (QIDS‑SR16, SI item, GAD‑7). Clinical benefits, safety and tolerability were comparable to a matched general adult sample (30–60), with only mild, transient adverse effects.
Esketamine nasal spray for major depressive disorder with acute suicidal ideation or behavior: description of treatment access, utilization, and claims-based outcomes in the United States
This real-world (n=269) analysis of esketamine (Spravato) use finds nearly 50% of patients had their first pharmacy claim approved. Of those approved, 45% had eight or more treatment sessions (as recommended), though spread over 85 days (versus 28 per the label). Patients had lower health utilization, but this could be due to factors outside of the esketamine treatment (e.g. regression to the mean).
ARC: a framework for access, reciprocity and conduct in psychedelic therapies
This theory-building article (2023) presents the ARC (Access, Reciprocity and Conduct) framework, a culturally informed ethical infrastructure for psychedelic-assisted therapy (PAT). The ARC framework emphasizes equitable access to PAT for mental health treatment needs, ensures safety in clinical contexts, and acknowledges the traditional and spiritual uses of psychedelic medicines. Developed using a dual-phase co-design approach, it invites contributions and feedback from stakeholders across research, industry, therapy, community, and indigenous settings to address the complex ethical questions arising in the rapidly expanding field of PAT.
A Retrospective Study to Determine the Impact of Psychedelic Therapy for Dimensional Measures of Wellness: A Quantitative Analysis
In a retrospective study of 65 adults who self‑administered psychedelic medicines for non‑recreational purposes, participants reported perceived improvements across pain, function, mood and overall quality of life—largest for mental health and QoL—with strong correlations between domains and no significant differences between psychedelic types. The findings suggest psychedelics may broadly enhance dimensions of wellness, but the small, retrospective, anonymous design and lack of baseline data limit causal inference.
Control Conditions in Randomized Trials of Psychedelics: An ACTTION Systematic Review
This systematic review (2023, s=86) of psychedelic RCTs (up to May 2020) finds that for placebo, 61% used an inert control, 20% active comparators (e.g. niacin), 15% both, and 4% a lower psychedelic dose. Of the 21 therapeutic trials, only 3 (14%) compared different amounts of therapy. Most studies were blinded, but less than 20% tested blinding (generally poor).
Dose-response relationships of LSD-induced subjective experiences in humans
This study (n=322) analyses data from previous studies to assess the dose-response relationship and outcomes on the Altered States of Consciousness Rating Scale (ASC) and the Mystical Experience Questionnaire (MEQ) following LSD (25μg to 200μg) administration. Increasing doses were positively correlated with ratings on most factors and scales of the questionnaires, with the strongest responses for visionary phenomena such as audio-visual synesthesia and altered imagery, followed by positively perceived ego dissolution comprising depersonalization and derealization phenomena.
Rapid neuroplasticity changes and response to intravenous ketamine: a randomized controlled trial in treatment-resistant depression
In a randomized trial of 98 treatment‑resistant depressed adults, a single intravenous ketamine infusion produced 24‑hour decreases in gray‑matter DTI mean diffusivity in prefrontal and limbic regions that correlated with larger improvements in depression scores, with left BA10 and left amygdala effects driven mainly by ketamine and right BA10 effects seen across groups, while hippocampal changes showed an opposite pattern on the MADRS. These findings suggest the acute antidepressant effects of ketamine are partly mediated by rapid neuroplasticity detectable with DTI.
One-Year Outcomes Following Intravenous Ketamine Plus Digital Training Among Patients with Treatment-Resistant Depression
This secondary analysis of a randomised clinical trial examines whether automated self‑association training prolongs the antidepressant effect of a single intravenous ketamine infusion in patients with treatment‑resistant depression, reporting outcomes over a one‑year follow‑up.
Dosing and Therapeutic Conduct in Administration Sessions in Substance-Assisted Psychotherapy: A Systematized Review
This systematized review (s=82) examines the current evidence for best therapeutic practices during administration sessions with serotonergic psychedelics and entactogens (e.g. MDMA) as adjuncts to psychotherapy. The study finds that the effects of different therapeutic models, methods, techniques, and more complex interventions on therapeutic outcomes have not been investigated rigorously, with most available evidence being anecdotal.
Case report: Prolonged amelioration of mild red-green color vision deficiency following psilocybin mushroom use
This case report describes a person with mild red–green colour vision deficiency (deuteranomaly) who showed partial objective improvement on self‑administered Ishihara testing after ingesting 5 g dried psilocybin mushrooms, with peak effect at eight days and persistence for at least 16 days. The authors suggest a single psilocybin exposure may produce sustained post‑acute improvements in colour discrimination and call for systematic studies to confirm, generalise and elucidate the mechanism.
A complex systems perspective on psychedelic brain action
This commentary (2023) discusses the potential transdiagnostic efficacy of psychedelic-assisted therapy and its impact on brain function. It proposes that psychedelics induce a mode of brain function that is more dynamically flexible, diverse, integrated, and tuned for information sharing, which is consistent with greater criticality, and suggests that a complexity science perspective may help in understanding the inconsistencies in previous findings and guide towards compelling mechanistic models.
Pilot study of single-dose psilocybin for serotonin reuptake inhibitor-resistant body dysmorphic disorder
This open-label study (n=12) of patients suffering from Body dysmorphic disorder (BDD), an obsessive preoccupation with misperceptions of appearance, finds that psilocybin (25mg) plus psychological support (6 sessions) resulted in a response (>30% decrease in BDD-YBOCS) in 58% of participants. Secondary measures such as negative affect, disability, and conviction of belief also significantly decreased.
Real world effectiveness of repeated ketamine infusions for treatment-resistant depression with comorbid borderline personality disorder
This retrospective analysis (n=100) of the effectiveness of ketamine (35mg/70kg) for borderline personality disorder (BPD) in those with treatment-resistant depression (TRD) finds that intravenous ketamine significantly reduces symptoms of depression, borderline personality, suicidality, and anxiety in patients with comorbid BPD and TRD. Both BPD-positive and BPD-negative groups showed significant improvements in the primary outcome measures, with no significant difference between groups.
TMS-EEG and resting-state EEG applied to Altered States of Consciousness: Oscillations, Complexity, and Phenomenology
This double-blind cross-over brain imaging study (n=22) of psilocybin combined EEG with transcranial magnetic stimulation (TMS) to reveal that psilocybin produces a chaotic pattern of brain activity (versus placebo; LZc complexity under eyes closed). Using TMS, the authors could measure the Perturbational Complexity Index (PCI) due to the stimulation. The difference between psilocybin and placebo on PCI wasn't significant.