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Psychedelics as Therapeutics

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.