Last month, the latest instalment of the International Society for Research on Psychedelics (ISRP) conference took place in New Orleans, Louisiana. The conference is very much one for scientists, with a refreshing mix of psychedelic research heavyweights and early career investigators alike.
Alaina M. Jaster, PhD and Jessica Maltman, who both work at Virginia Commonwealth University, attended the three-day conference and—luckily for us—took detailed notes. Below, they share some of their highlights from each day, along with insights from the poster session.
The second annual International Society for Research on Psychedelics (ISRP) conference was held on February 16-18th in New Orleans, Louisiana. The conference, originally set to occur biannually following its inaugural event in 2019, was eagerly anticipated after a COVID-precipitated hiatus.
ISRP welcomed approximately 150 guests, with over 50 presentations and 30 posters showcasing a wide range of expertise and levels of training, including talks from graduate students, postdocs and principal investigators. The agenda was split across disciplines covering topics from basic science and drug discovery, to preclinical models, survey studies and clinical trials. This conference also featured work from folks studying psychedelics outside the predominant realm of mental health and substance use disorders, including work with macular degeneration, Lyme Disease, Autism Spectrum Disorder, Fragile X Syndrome, and more. The most alluring thing about this conference is its guiding ethos: for scientists, by scientists.
To give an idea of the scope of research, this synopsis aims to highlight some of the exciting work that is helping to advance the field of psychedelics. While this commentary is nowhere near exhaustive, the authors want to share a selection of presentations from each day of the conference they found intriguing.
Day One Highlights
Pre-clinical/Basic Sciences
To start off the conference, Dr. Kevin Murnane, Associate Professor at Louisiana State University (LSU) Health Sciences Center Shreveport, presented parallel research on methamphetamine use disorder in animal models and human studies to demonstrate the potential efficacy of psychedelics for this indication. Rodent studies produced some promising evidence suggestive of psychedelics’ ability to reduce methamphetamine administration while also increasing cognitive flexibility and not affecting rodents’ natural response to food. By using a translational approach, in which animal models are reflective of multiple aspects of a human study design, we can further understand the processes involved.
In the basic sciences, Dr. Umed Boltaev, Associate Research Scientist at Columbia University, presented a talk on quantifying neuronal morphology and whether psychedelics truly modulate TrkB and induce dendrite growth (which produced quite the conversation over the course of the weekend). Their data showed that with their analysis pipeline, which used many different assays to study morphological changes using primary neuronal cultures, psychedelics were not able to produce the same effects on spine growth that was showcased in a variety of recent publications. They suggested that this may be due to a variety of factors including the lack of adequate 5-HT2A receptor expression in these cortical neurons. This begs the question of whether the cell systems we are using accurately reflect the true biological processes of psychedelic-induced plasticity.
Continuing the focus on animal models, but shifting gears to fear-associated behaviors, Dr. Sam Woodburn, postdoctoral researcher at Cornell University, discussed how 2,5-dimethoxy 4-iodoamphetamine (DOI), 3,4-Methylenedioxymethamphetamine (MDMA), and psilocybin had differing efficacies and longevities for accelerating fear extinction and maintaining extinction in generalizable contexts. In a paradigm where the psychedelic was administered 30 minutes prior to testing extinction, all three led to increased rates of fear extinction acutely. However, only MDMA and psilocybin produced sustained effects and showed generalizability of this extinction to other contexts. This is a common research goal for post-traumatic stress disorder (PTSD)-like conditions seeing as cognitive processes and behaviors learned in therapy should ideally extend to contexts outside of the clinic. To further assess the effect of psilocybin on the learning or retention of fear conditioned behaviors, in a separate study psilocybin was administered before conditioning or after extinction and neither of these manipulations affected the learning or extinction of freezing behaviors. These findings indicate that the acute effects must be important for the extinction process. Overall this research suggests that the timing, subjective effects and specific pharmacological profile of the psychedelic are a critical consideration for treating fear-conditioned disorders with psychedelic-assisted therapy.
Another presentation that stood out was delivered by Dr. Gonzalo Hernandez of Universidad de la República in Montevideo, Uruguay, who discussed the use of nuclear magnetic resonance and chromatography-mass spectrometry/mass spectrometry to assess the chemical compositions of natural products and novel compounds. He showed data from ayahuasca brew samples from various sources, which included several different natural products. When separating the solid and aqueous parts of the brew, they were able to assess the different alkaloids and chemicals in each phase and discovered, for the first time, that fructose was a major component. They also showed that harmine, an alkaloid previously known to be in ayahuasca, was found in large quantities within the solids suspended in the beverage, while other alkaloids such as the active psychedelic component N,N-dimethyltryptamine (DMT), tetrahydroharmine, harmaline, and harmol were present in all extracted samples. These assessments of the composition of ayahuasca may provide greater insight into the physiological aspects of the ayahuasca journey, specifically the role of fructose.
Human/Clinical Studies
Stepping into the realm of human studies, Dr. David Rosen, a postdoctoral researcher from Johns Hopkins University, presented his research on associations between psychedelic use and aspects of social decision-making. In a world consumed by “us versus them” mentality due to our natural and sometimes subconscious fear of death, Rosen’s research suggests that psychedelics may be a useful tool for increasing acceptance of other world views and reducing terror associated with death. In this online survey study combined with a mortality salience exercise, they found that psychedelic use was associated with ego dissolution and increased openness, but their mortality salience paradigm proved unsuccessful and therefore conclusions about how it is affected by psychedelics couldn’t be drawn. While the data suggests psychedelics may encourage people to be more tolerant and open, more research is needed to understand whether psychedelics could encourage a more idyllic world by reducing people’s fear of death.
Also focusing on the human psychedelic experience, Director of Data & Analytics for the Johns Hopkins Center for Psychedelic and Consciousness Research, Dr. Nathan Sepeda, shared research on whether psychedelics can lead to changes in personality. After performing a meta-analysis using longitudinal clinical trial data on the 5 key personality traits (neuroticism, extraversion, openness, agreeableness, and conscientiousness), Sepeda found that only clinical populations (individuals with depression, anxiety, and/or an eating disorder) saw changes in any of these traits with psychedelic therapy. Notably, neuroticism and extraversion were the most changed. Furthermore, changes were dependent on whether the individual had a mystical experience from the psychedelic. Seeing as these changes were not observed in non-clinical control individuals, the presenter was hesitant to claim whether psychedelics modify personality, and suggested that these changes may be reflective of a change in symptoms (state-change) rather than personality (trait-change). More studies with larger sample sizes are needed to draw more definitive conclusions about non-clinical populations and the significance of these changes in clinical populations in regards to whether studied ‘personality traits’ correlate with decreased disease burden.
Dr. Natalie Gukasyan, Assistant Professor at Columbia University Medical Center, presented her research on a very interesting and under-studied condition, hallucinogen-persisting perceptual disorder (HPPD). While HPPD is included in the Diagnostic and Statistical Manual of Mental Disorders, it is poorly studied and there are no established guidelines for treatment. In her presentation, Dr. Gukasyan discussed results from a survey given to over 500 participants asking them how they have attempted to treat their HPPD and whether different pharmacological treatments improved or worsened their symptoms. Interestingly, the most anecdotally reported improvements followed the use of benzodiazepines and non-drug interventions like yoga and meditation, whereas antipsychotic medications seemed to worsen symptoms. Other pharmacological interventions such as mood stabilizers, ketamine, amphetamines and buspirone all had mixed results on symptom improvement and exacerbation. This research is a much-needed first step towards a better understanding of the symptomatology of HPPD and potential treatment options.
Day Two Highlights
Special Presentation: FDA Guidelines for Psychedelic Research
At the start of Day 2, Dr. Katherine “Kit” Bonson of the Federal Drug Administration (FDA) presented on the recent guidelines put forth for clinical trials with psychedelic drugs. A portion of her talk touched on how psychedelics have been heavily characterized in preclinical models and survey studies throughout the 20th century, potentially reducing the burden put on researchers to conduct abuse-related studies. She also noted many times that psychedelics are different from other drugs coming through the FDA approval pathway, and that it is difficult for the agency to assess these compounds given their strong subjective effects.
One large problem with psychedelic abuse-related studies is that serotonergic psychedelics have no usable positive controls. The FDA requires that a positive control be an FDA-approved drug with a similar mechanism to the test drug. However, due to the existing compounds with similar pharmacology being Schedule I or not FDA-approved, this is especially challenging for psychedelic programs. The only suggestion provided by Bonson was the use of ketamine as a positive control, but this was a cause for concern since the mechanism of action is completely different from serotonergic psychedelics and they produce different side effects.
As if her talk wasn’t interesting enough, the ensuing discussion provided even more food for thought. Someone raised the point that many drugs that cause euphoria, subjective effects and have potential for abuse are available over the counter (e.g., dextromethorphan or diphenhydramine-containing medication), so could psychedelics ever be available over the counter as well? Bonson met this question with an immediate “absolutely not.”
Translational Research (preclinical/clinical)
One presentation that was particularly intriguing due to its deviation from common psychedelic topics was LSU Associate Professor Tim Foster’s research on the role of serotonin and the 5-HT2A receptor in ocular disease. Due to the anti-inflammatory properties of psychedelics and the expression of the 5-HT2A receptor on the retina, ciliary body, and iris, the researchers hypothesized that psychedelics may be a useful tool for combating eye infections that are particularly hard to treat, such as viral infections. In rabbits, after scoring and infecting the eye with herpes simplex virus, psychedelics were administered and found to significantly clear up the viral infection whereas the current standard treatment for viral eye infections, steroids, significantly worsened the infection compared to untreated animals. While the work suggested a psychedelic eyedrop could be a great treatment alternative in the future, continued efforts in the field are needed to find non-hallucinogenic 5-HT2A receptor agonists that retain their therapeutic effects. Thomas Galbato, a graduate student in the Foster lab, also presented their research showing that the 5-HT2A receptor plays a significant suppressive role in age-related macular degeneration; once again indicating that psychedelics should be a continued consideration for eye-related disorders.
The prevalence of autism spectrum disorder (ASD) has been increasing for decades and it is clear that more research is needed to understand it, along with various components of neurodivergence. While some may think that autism would be difficult to replicate preclinically, Dr. William Fantegrossi, Professor at University of Arkansas for Medical Sciences, presented the similarities between a mouse model (BTBR mouse line) and symptoms of autism, such as social deficits, overgrooming, and behavioral inflexibility. While this model isn’t all-encompassing, it does represent core features of the condition. Interestingly, the animals also have no corpus callosum, which has been observed in some human cases of ASD. Furthermore, they showed that R-MDMA, but not S-MDMA, can increase social and novelty preference in the BTBR mice versus non-mutant mouse controls. While these results may be exciting for those with social anxiety and other social deficits, it is still unknown how MDMA may affect other symptoms of autism, such as sensory issues.
One of the contentious questions in the psychedelic field is whether or not the psychedelic experience is necessary for the therapeutic effects of psychedelics. Dr. Matthew Banks, Professor at University of Wisconsin-Madison, is exploring this question through a pilot study that co-administered the benzodiazepine amnestic midazolam and psilocybin, enabling the psychedelic experience to occur but reducing memory of the experience itself. Preliminary findings demonstrated that the combination of drugs was shown to be safe and effective with psilocybin producing its effects as measured by EEG and midazolam effectively reducing memory of the experience. Midazolam not only reduced memory of the experience, it also blocked behavioral changes produced by psilocybin alone, as evidenced by an inverse relationship with measures of insight and emotional salience of the psychedelic experience at day 1 or 8 post-dosing. While this work is a great first step in understanding the role of subjective experience, it is also important to note that benzodiazepines can alter neuroplasticity which is also thought to be involved in the therapeutic mechanisms of psychedelics.
Drug Discovery
One reason for the attractiveness of psychedelics for the treatment of depression is their apparent rapid-acting nature and potentially long-term durability, whereas current medications for depression can take several months to work. Additionally, patients may have to try several types before they find one that works best for them. Dr. Mark Rasenick, Distinguished Professor at University of Illinois College of Medicine, is interested in solving this problem by identifying an early-treatment biomarker that correlates with long term symptom relief. This may help physicians identify efficacious medications earlier, thereby saving the patient time and frustration.
Researchers observed long-term increases in cAMP, p-CREB, and BDNF in individuals whose symptoms improved with selective serotonin reuptake inhibitors (SSRIs), as well as mobilization of G proteins from lipid rafts. This can occur after several months of ketamine or psilocybin treatment as well, whereas lysergic acid diethylamide (LSD) colocalizes with the lipid raft and mobilizes G Proteins rapidly. In addition, 1 hour of psilocin or LSD treatment in cells produced a similar GTPɣs signal as a 3-day treatment with fluoxetine. Lastly, they found that PGE1-activated adenylyl cyclase decreases in depression and increases in treatment-responsive populations. This data all points towards the importance of this specific Gɑs signaling cascade as a biomarker of antidepressant success. As well as being a helpful measure for physicians to gauge and anticipate medication success, this could also help us design/screen for biased agonists for this therapeutic cascade, potentially identifying non-hallucinogenic 5-HT2A receptor agonist analogs.
Biased agonism was a considerable topic of interest throughout the conference. Currently, many researchers are trying to produce non-hallucinogenic potentiators of the serotonin system. Director of the Center for Addiction Sciences and Therapeutics at University of Texas Medical Branch, Dr. Kathryn Cunningham, presented on the design and testing of novel compounds that act as allosteric modulators of the 5-HT2A receptor, rather than full or partial agonists. It was discovered that some of these positive allosteric modulators (PAMs) do not produce the classic head twitch response associated with serotonergic psychedelics, but they do indeed enhance signaling through a different binding pocket than the agonists. This talk was quite interesting because there isn’t much in the way of PAMs in the psychedelic space, or even with class A G protein-coupled receptors (GPCRs). Taking an amphipathic structure, with a polar head and polar tail, and constructing a novel compound through cleaving unnecessary components makes way to a novel structure that is quite large, but has the ability to modulate the receptor in a different manner than the classical psychedelics. This work is an important addition to the field of psychedelic drug development and in turn may lead to more focus on lipophilicity and lipid involvement in psychedelic action.
Day Three Highlights
Human/Clinical Studies
Dr. Matt Johnson, Professor at Johns Hopkins University, started the last day on a strong note by getting the audience to laugh at one of his light-hearted jokes, followed by a presentation on some very promising data comparing psilocybin-assisted therapy to the use of a common intervention, the nicotine patch. In this open label study, participants were randomly assigned to either the psilocybin group or the nicotine patch group. Both trial arms were provided cognitive behavioral therapy for smoking cessation that lasted 13-weeks during the study. Smoking status was assessed using breath carbon monoxide, urinary cotinine, and self-report 6 months after the target-quit-date. While the study is still ongoing, the results suggest that, compared to a common intervention, psilocybin is producing exponentially better results. At the 6-month follow up, over 50% of the participants in the psilocybin group were biologically verified as abstinent, compared to only 25% in the nicotine patch group. Considering abstinence isn’t the only measure of progress, Johnson also pointed out that while some participants did not remain fully abstinent, there was still a reduction in smoking in those who received psilocybin.
Staying with the topic of nicotine and smoking cessation Dr. Gideon Naude, postdoctoral researcher at Johns Hopkins University, discussed the use of behavioral economic demand principles and how they apply to drug use in human populations. Behavioral economics is commonly used in preclinical models of food versus drug choice self-administration models, as well as human research understanding the cost/benefit ratio of substance use. However, it has not been assessed in studies using psychedelics as an intervention. Using hypothetical purchase tasks, an instrument designed to quantify and characterize demand (or a person’s desire to purchase goods and their willingness to pay a specific price), they assessed how demand of cigarettes would predict abstinence at the 6-month follow-up and whether this would be a better predictor than baseline daily cigarette use or dependence measures. Using a multiple logistic regression analysis, the data suggested that higher amplitude of cigarette demand measured at baseline was a significant predictor of abstinence at the 6-month follow-up. These findings suggest that economic demand measures may be more useful in predicting outcomes than measures of use or dependence and could be easily implemented across studies.
Pre-clinical/Basic Sciences
Switching over to the preclinical side, PhD candidate at Virginia Commonwealth University Belle Buzzi discussed the effects of psilocybin on models of withdrawal across drug classes in male and female mice. Many preclinical studies focus on reducing the rewarding aspects of drugs, but one important aspect of the cycle of drug dependence that is seen across species is somatic and affective signs of withdrawal. Her presentation focused on the question of whether psilocybin is able to reduce withdrawal-related behaviors, and whether the therapeutic effects of psychedelics are dependent on activation of 5-HT2A receptors. To get at these two questions, physical dependence to either nicotine or oxycodone was established and following cessation of drug administration, a single dose of psilocybin was given. Withdrawal was measured using well-characterized models, including somatic signs and hyperalgesia-based signs. A single dose of psilocybin was able to reduce somatic signs of physical dependency in male but not female mice, while psilocybin reduced thermal hyperalgesia due to nicotine withdrawal in both male and female mice. Interestingly, the effects of psilocybin on somatic signs were 5-HT2A receptor-dependent, as evidenced by a lack of effect seen in animals not expressing the receptor, whereas the effects on hyperalgesia were not. Important findings from this work include the fact that these positive effects of psilocybin happened after the drug had dissipated from the system, suggesting a lasting effect; and that these changes in withdrawal symptoms are present across at least two very different substances.
One of the more unique talks of the conference was from TRIP Center Clinical Research Coordinator Rhianna Rich, whose research focuses on the therapeutic potential of altered states of consciousness. Her talk had a primary focus on increased connectedness, which has been reported across a variety of domains in several psychedelic studies including both anecdotal reports and through surveys measuring the experience such as the Mystical Experiences Questionnaire. In her work, a large focus is on how to enhance the set and setting of a psychedelic experience to promote increases in connectedness and well-being. This study utilized visual healing, whereby participants viewed nature videos during the preparation session and the ascent and descent phases of the psilocybin dosing session. In those exposed to visual healing, it was discovered that their connectedness to nature increased from baseline to 2-weeks post-psilocybin, but social connectedness was unchanged. This study provides important insights into set and setting and how suggestion and environment plays an important role in therapeutic outcomes of psychedelics. Moving forward, it would be interesting to show videos that are more social in nature, to see if they altered the social connectedness outcome versus the nature video.
Poster Session Highlights
Emma Bonniwell, PhD candidate at Medical College of Wisconsin, shared her poster which focused on GPCR biased signaling and structure-based drug design of psychedelic compounds. Using bioluminescence resonance energy transfer (BRET) assays, she was able to measure G protein activation and β-arrestin recruitment at serotonin receptors in vitro. While several research efforts are aiming to understand signaling at the 5-HT2A receptor, her research is looking into designing biased agonists at the 5-HT2C receptor, which is also activated with high affinity by several classical psychedelics.
Bo Jarrett Wood, PhD candidate at LSU, presented on the rewarding and reinforcing effects of methamphetamine and how psychedelics can be a potential therapeutic for reducing these effects in rodent models. Utilizing both a phenethylamine psychedelic, DOI, and the tryptamine psilocybin, he was able to demonstrate therapeutic efficacy for these compounds in significantly reducing methamphetamine conditioned place preference as well as producing decreases in operant responding for methamphetamine on a fixed ratio 4 schedule of reinforcement.
Dr. Jason Younkin, a postdoctoral researcher at Virginia Commonwealth University and adjunct professor at Virginia State University, gave a talk and displayed interesting findings with quipazine analogs during the poster session. Quipazine is a unique psychedelic as its chemical structure includes a piperazine group. While it produces psychedelic effects, it is not used as frequently as other serotonergic psychedelics due to its effects on the gastrointestinal tract via 5-HT3 receptor activation. The goal of this study was to find analogs of quipazine that do not produce these negative side effects or the hallucination-like effects of all classical psychedelics using a battery of molecular and pharmacological techniques.
Dr. Jeremie Richard, postdoctoral researcher at Johns Hopkins University, had a different lens on addiction-related behavior from the usual substance disorders, as his focus is primarily on gambling disorder and other behavioral addictions. His poster reflected a recent scoping review that identified records investigating psychedelics in the treatment of such behavioral addictions. Out of 150 publications identified, only 21 were relevant to gambling disorder with the other 129 being related to substance use disorders. This suggests the potential utility of psychedelics as a treatment for behavioral disorders, as well as a heightened need for more research in this area.
Brittany Youseff, an MS student at University of Southern California, focused on mystical experiences in patients with alcohol use disorder. Her work primarily aimed to understand how multiple doses of a psychedelic can alter a participant’s overall experience; specifically, how a second dose of psilocybin may alter responses in the dimensions of mystical experience and transcendence of time and space. She found that repeated administration in this open-label pilot study may enhance the mystical experience and transcendence of time and space, but more research is needed to determine if there is a sweet spot of therapeutic efficacy and dosing in those with alcohol use disorder.
Zarmeen Zahid, PhD Candidate at University of Wisconsin-Madison, is investigating the prevailing hypothesis that psychedelics are acting as catalysts for behavioral change via changes in structural and functional plasticity. Using electrophysiology methods to test the plasticity and metaplasticity of various psychedelics and non-psychedelic serotonergic agonists, she’s found increased plasticity in the hippocampus but no evidence for plasticity in the medial prefrontal cortex at acute time points. This highlights the complex nature of circuit level changes, suggesting that plasticity changes may be occurring at specific brain regions rather than have uniform changes across the entire circuit.
