Can psilocybin treat depression and help people quit smoking tobacco?
Can MDMA help treat PTSD?
Could LSD be used to treat autism?
In a meeting hosted by the NIH, leading scientists in psychedelic pharmacology gathered earlier this month to discuss some of the most exciting, troubling, and pressing questions in the field.
The workshop, titled “Psychedelics as Therapeutics: Gaps, Challenges, and Opportunities” was sponsored by the National Institute of Mental Health (NIMH), the National Institute on Drug Abuse (NIDA), and the National Institute on Alcohol Abuse and Alcoholism (NIAAA).
Held on January 12-13, 2022, the workshop brought together experts in the field of psychedelic pharmacology to discuss the gaps, challenges, and opportunities involved in developing psychedelics, including LSD, psilocybin / psilocin, and MDMA as therapeutics for a variety of psychiatric illnesses. The meeting organizers reported that 4,413 people registered for the event, and 2,935 people or groups from 72 countries attended at least one session.
According to Javier Muniz of the Food and Drug Administration, there has been a resurgence of interest in psychedelics as therapeutics since about 2006, dubbed the “psychedelic renaissance,” with about 700 publications per year in 2020.
Hallucinations and transcendent mood
People on psychedelics often report feelings of bliss and unity, spiritual experiences, hallucinations, and changes in consciousness and self-awareness. LSD is known to affect thalamocortical circuits.
According to Matthew Johnson from Johns Hopkins University, subjects on psilocybin describe experiencing feelings of interconnectedness, awe, curiosity, increased altruism, self-acceptance, gratitude, and appreciation of art. Some also reported changes such as viewing their self-identity as a construct and recontextualizing life as an adventure. These longer lasting subjective effects likely mediate their effects through changing the expression of genes involved in synaptic plasticity.
Classical psychedelics like psilocin, LSD, mescaline, and DMT act by binding to serotonin (5-HT) receptors (most notably the 5HT2A receptor), which are expressed throughout the brain. Serotonergic neurons originate in the raphe nuclei, which are found in the brainstem, particularly in the pons and midbrain.
There is discussion and debate among researchers about the role of 5HT2A receptor in psychedelic effects. It is considered necessary but not sufficient to generate hallucinations.
Psilocin acts on more than just 5HT2A receptors. It also acts on 5HT 1A, 1B, 2B, 2C, 6, and 7 receptors, Clint Canal from Mercer University explains. Psilocin is also a moderately potent D2 dopamine receptor agonist. Bryan Roth from University of North Carolina adds that psychedelics can also act on the melatonin receptors, MT1 and MT2. Thus, the psychedelic experience involves many mechanisms.
As Roth points out, L5 cortical pyramidal neurons express the 5HT2A receptor, leading to increased spinogenesis and plasticity in response to psychedelics. Importantly, people with different polymorphisms, or genetic variations, of these receptors could respond differently to the same psychedelics.
According to Scott Thompson from University of Maryland, psilocybin promotes excitatory synaptic growth in mouse models of depression. Mice treated with psilocybin display increased pyramidal cell dendritic spines and excitatory synapses, an effect that persists above baseline at day 34.
Are psychedelics safe? Potential cardiac risks
Roth and Canal display cautious optimism, stressing the concern about the hypertensive effects of psychedelics. As Roth points out, 5HT2B receptors are expressed in the heart and are thought to play a role in heart disease. Psilocin in particular has high affinity here. However, several attendees raised questions about doses required for these adverse outcomes, which were not discussed in the presentation.
When it comes to MDMA, the jury is still out on the safety profile. Many patients report side effects. In a study of MDMA as a treatment for PTSD, 13% of patients reported nystagmus, which are uncontrolled eye movements.
According to Johnson, psilocybin can increase dangerous behavior towards oneself or others, but it poses no addiction risk.
LSD mediates pro-social effects and learning
Gabriella Gobbi from McGill University discussed translational applications of psychedelics. In particular, LSD is being evaluated as a therapeutic for anxiety associated with end of life, alcoholism, and autism, for the ability to make individuals more sociable.
The medial prefrontal cortex (PFC), filled with excitatory glutamatergic neurons, is also rich in 5HT2A receptors, which are involved in social cognition, Gobbi explains.
In particular, LSD increases the sensitivity of 5HT2A receptors and excitatory AMPA receptors. LSD has been shown to increase phosphorylation of Akt and mTOR (a key signaling pathway that regulates cell growth and survival) (Watanabe, 2011). mTOR is important in prosocial behavior. In particular, LSD upregulates mTOR complex 1 (mTORC1), which is involved in CamKIIa signaling and addiction.
CaMKII is calcium-calmodulin kinase II–as the name suggests, it is activated by calcium and calmodulin. It is expressed by excitatory glutamatergic neurons. It is required for the induction of long-term potentiation and associated structural plasticity of dendritic spines; i.e., it is a key player in the process of learning and forming memories. This increase in mTOR/CaMKII is thought to mediate LSD’s effects on learning and memory.
In summary, LSD could be activating 5HT2A receptors to increase AMPA receptor expression, which influences mTOR signaling in glutamatergic neurons in the PFC, improving sociability and learning.
Psilocybin for depression and anxiety in cancer patients and alcoholism
Scott Thompson of University of Maryland discussed clinical trials of psilocybin for depression and anxiety in cancer. He presented evidence that psilocybin can induce antidepressant effects lasting 3 months, far outlasting its presence in the human body.
However, the mechanism of these antidepressant effects remain unknown. Does it involve 5HT2A activity? Based on preclinical research, it appears that 5HT2Rs are not required for anti-anhedonic effects. Mechanistic studies can help with discovering therapeutic targets and generating new leads.
Michael Bogenschutz of New York University described how subjective experience can be a mediator of the psychedelic experience. He described the use of psilocybin for depression and anxiety in cancer patients, as well as for treating addictions–particularly alcoholism and smoking cessation. Responders had decreased connectivity in the parahippocampus and PFC.
MDMA for PTSD
MDMA, made by Merck in 1912, has been shown to increase oxytocin, vasopressin, and serotonin signaling. Called an entactogen, or a substance that promotes affiliation and empathy, MDMA is being investigated as a potential treatment for PTSD, describes Jennifer Mitchell from University of California, San Francisco.
PTSD occurs in response to experiencing or witnessing a traumatic event. Trauma occurs in response to actual or threatened serious injury, death, and/or sexual violence. PTSD affects an estimated 7-8% of people, is twice as common in women as in men, and it doesn’t tend to resolve without treatment. Current treatment options, which often involve reappraising the traumatic event, include Zoloft, Paxil, and CBT, particularly prolonged exposure therapy or cognitive processing therapy.
People with PTSD tend to respond to trauma in one of two different ways: hyperarousal or dissociation. In the arousal subtype, patients have an increase in amygdala activity and decreases in hippocampal and PFC activity. The dissociative subtype tends to involve hypoarousal, emotional numbing, and difficulty with cognitive processing. Patients with the dissociative subtype and childhood trauma appear to respond more to MDMA.
MDMA could be combined with cognitive processing therapy to help with PTSD by inhibiting the reconsolidation of fear memories. This allows individuals to revisit the experience and stay emotionally engaged without being overwhelmed by anxiety.
Psilocybin and tobacco smoking cessation
Tobacco causes more US drug-related deaths per year than alcohol, prescription drugs, all illicit drug use, and over the counter medications combined, says Matthew Johnson from Johns Hopkins University.
In a clinical study on psilocybin for tobacco smoking cessation run by Johnson, those recruited had been smoking for an average of 25 years, at about 16-17 cigarettes per day. After 1 session with psilocybin, 59% were abstinent at 1 year, compared to 28% using the nicotine pack. This is considered a massive clinical effect.
Carbon monoxide, a marker of smoking, decreased over 3 sessions with psilocybin.
Psilocybin combined with CBT was 3.5 times more effective than bupropion (Wellbutrin) and 4.5 times more effective than nicotine replacement, with 50% continuously abstinent at 12 months.
Some participants also reported reduced withdrawal effects and that psilocybin changed their relationship with tobacco, saying that they were able to place any cravings in context, acknowledging that they will pass, which enabled them to resist cravings.
Johns Hopkins is also investigating whether psilocybin can be used to treat opioid addiction, Alzheimer’s disease, post-treatment Lyme disease, and anorexia nervosa.
Set and setting, confounds in study design and measurement
Ido Hartogsohn from Bar Ilan University in Tel Aviv, Israel emphasized the importance of set and setting in clinical trials. Often, there is a pre-session before the 8-hour session. In particular, each trial has to consider appropriate music, electromagnetic frequencies (e.g. visible light), and arrangements of physical space to create a relaxing environment. Additionally, they must offer the subjects a certain level of privacy, determine how they will set expectations for the experience, and provide high-quality support and containment.
Subjects may be instructed to lay on a couch and provided a blanket, headphones with music that is selected by those running the trial, and eye shades; they are told to trust, let go, and be open, as Johnson describes.
Some trials may go a step further in an effort to treat the medicine as a cultural sacrament rather than a commodity, offering communal environments, which are less controlled but more true to their historical usage among people.
Gitte Knudsen from University of Copenhagen adds that because of long-term effects, it is important to know a participant’s history with psychedelics, a consideration when designing robust clinical trials. There is also the possibility of medication interactions, Muniz notes.
Suresh Muthukumaraswamy of the University of Auckland discussed how to overcome confounds in clinical trials with design and measurement. Blinding is the monkey wrench in randomized controlled trials on psychedelics. The aim of blinding is to control for belief as a confounder. However, it is extremely difficult to control for belief in psychedelic trials because of the “dramatic functional unblinding,” as Muniz puts it, involved with such a profound experience. Participants are often abundantly aware of whether they got the treatment based on whether they’re tripping. (The story is more subtle with microdosing, or studies testing different dosages, which was not a focus of the workshop).
Participants who get the treatment may get excited and show increased psychoactive effects. Those who don’t may be disappointed, which can decrease the placebo effect. Staff can also provide differential therapy, treating participants differently such as providing more support for those who are tripping, dubbed the “therapeutic alliance.”
Additionally, the search continues for surrogate biomarkers, or biological correlates of consciousness, in order to measure subjective experiences, remove bias, and increase rigor and reproducibility of clinical trials.
Ethics and ethnopharmacology
Informed consent is an important ethical consideration in psychedelic research, says Paul Appelbaum of Columbia University. Participants should be aware of the nature and purposes of the study, the use of a placebo, and risks and benefits. Participants may feel more at ease if they know what to expect in terms of set and setting by seeing a demonstration video of the administration session, as well as a video clip testimonial of a past participant. The consent process should also be administered by a neutral colleague, not an enthusiast investigator, who may introduce biased expectations. It’s critical to manage expectations amidst hype, anecdotes, and popular culture influences.
There is also the important issue of boundaries. People under the influence of psychedelics are highly suggestible and vulnerable, and there have been reports of sexual exploitation in these settings. Thus, if investigators are going to use therapeutic touch, such as squeezing a hand to reassure a participant, they should ask for consent at the very beginning of the process. Muniz reminds us that drug trials should offer adequate training and certification for providers to protect participant safety.
Another important matter involves exclusion criteria and the choice of placebo controls. An important question is raised: is it ethical to deprive someone from a beneficial intervention? Perhaps the difference is more stark in a scenario involving therapeutic surgery and a sham surgery, but there exists a gray area in the rainbow patch of the psychedelic world.
Should clinical trials exclude people with a history or risk of psychosis, schizophrenia, or suicide, when there is a possibility that the therapeutic may be used for these populations in the real world? If vulnerable groups are excluded from trials, there will be a lack of data and a gap in the knowledge of effects in these groups. Thus, the question was posed: is it ethical to deprive these groups of potential therapeutics based on the existing data, when there is a high or even inevitable likelihood of off-label use? This critical issue spans access to treatment, legal liabilities, and risk evaluation.
Finally, and perhaps most importantly, there is the glaring ethical consideration of patenting sacraments which have been used for thousands of years, the same sacred medicines which have been demonized in our criminal justice system to the tune of billions of dollars and many people unjustly incarcerated, sometimes for decades. Countless families have been fragmented in a manner that places institutional racism on display. Pharmaceutical companies, such as Reset Pharma, are displaying considerable interest in developing and patenting psychedelic therapeutics. Is it ethical for companies to be profiting off of the use of naturally-originating psychedelics now when individuals have been paying with their lives in the decades following the War on Drugs? This appears to be more of a financial and political question rather than a scientific one, but it is one that implores the government to choose differently than it has in the past: to listen to reason, rather than the media hysteria and sensationalization that generated insensible and inhumane policies in the first place. Others would argue that the pharmaceutical industry is poised to enable widespread acceptance and use of psychedelics as therapeutics, which would be culturally beneficial to society.
Active areas of research
Many open questions in the field of psychedelic pharmacology continue to exist. Addressing these questions could help remove obstacles to widespread use:
Mechanisms: What are the pharmacokinetics / pharmacodynamics of psychedelics? How do psychedelics create hallucinogenic effects?
Safety and Efficacy: What is the risk profile in vulnerable populations? What is the therapeutic window / dose-response relationship? What’s the minimum microdose that can have a clinically meaningful effect?
Design: What are the safest, most relevant, bioactive, selective agonists and antagonists to serve as placebo controls?
Recordings of the presentations are now available on the NIMH website here.