Pharmacology

Psychedelics are substances that impact brain function. To grasp the chemistry behind psychedelics, it’s essential to consider serotonin. Serotonin (5-HT) is a neurotransmitter pivotal for transmitting signals within the brain. It plays a role in numerous functions such as mood regulation, sexual desire, sleep, appetite, memory, and learning.

While attributing conditions like depression solely to low serotonin levels is overly simplistic, there exists a correlation; increased serotonin levels can alleviate symptoms. This is why many antidepressants are SSRIs (selective serotonin reuptake inhibitors), which elevate serotonin levels by blocking their reabsorption.

What about psychedelics? A range of these substances (including LSD, psilocybin, mescaline, and DMT) act as serotonin receptor agonists: “receptor” indicates they primarily attach to the serotonin 5-HT2A receptor sites in the brain, and “agonist” signifies they elicit a response akin to that of the natural chemical. (However, the specific mechanisms by which psychedelics alter perception and cognition via the 5-HT2A receptor remain unclear.) These compounds also interact with different receptors to varying degrees, contributing to the distinct effects of various psychedelics.

The following image is derived from a 1999 Yale study titled “Serotonin and Hallucinogens” [1], which highlights the structural similarities between serotonin (5-HT), LSD, and psilocin (the latter being the form psilocybin takes after digestion).

Applications

Psychedelics offer a vast array of applications. Let's examine these across a continuum, ranging from wellness to illness:

This extensive list may seem overly optimistic. (Like those posts shared on Indian WhatsApp claiming lemon juice and turmeric can cure everything from chronic heart disease to cancer — a cheeky reference!) The commonality among these conditions is notable, and we can simplify our understanding through neuroscience.

Neuroscience

Research suggests that the crux lies in an area known as the Default Mode Network (DMN) (this is still emerging research, making definitive conclusions premature) and the brain’s neuroplasticity. The DMN consists of a network of structures within the brain (including the prefrontal cortex) responsible for many higher-level functions — such as self-reflection, memory, emotions, and planning. This region is evolutionarily advanced, distinguishing humans from other mammals, and has been described by one neuroscientist as the conductor of our neural orchestra.

Consider these various functions; they shape our identity and form the basis of our ego! A common thread among the mental health issues previously mentioned is that they often involve repetitive thought patterns and harmful narratives. A healthy brain is flexible and adaptable, while conditions like depression, anxiety, and addiction arise from a brain that has become too rigid in its pathways — a brain with excessive order. Imagine a snowy hill, where the entrenched tracks prevent the formation of new paths, a situation exacerbated by an overactive DMN.

In a 2012 study by Robin Carhart-Harris at Imperial College London’s Center for Neuropsychopharmacology, it was found that the DMN is subdued during a psychedelic experience. This suggests that individuals are less prone to overthinking, rumination, or anxiety about the future, allowing them to be more present and connected. Since the DMN is linked to our sense of self, reducing its activity may lead to what some describe as “ego death.”

A follow-up study by Carhart-Harris in 2014 revealed that brains under psilocybin exhibit significantly different activity compared to those under placebo [2]. Specifically, there were enhanced connections among various brain regions, leading to more innovative thinking, whether related to personal insights or professional creativity.

This highlights the significance of neuroplasticity. The new neural pathways formed during psychedelic experiences can be lasting. Reflect on Mendel Kaelan’s sledges in the snow metaphor; these new tracks symbolize the brain's natural adaptability.

Dr. Henry Fisher, Chief Scientific Officer at Clerkenwell Health, stated that “enhanced neuroplasticity is central to the therapeutic benefits of psychedelics; it aids individuals in developing new thought patterns and coping mechanisms while also helping to dismantle harmful cognitive patterns.”

Research

Tim Schlidt and Daniel Goldberg from Palo Santo VC pointed out that dating back to the 1960s, thousands of research papers involving over 40,000 patients have been published on psychedelics. While many older studies may lack rigor (e.g., not being double-blind), they indicate an extensive and growing body of evidence supporting the efficacy of psychedelics. (For clarity, a double-blind study means that neither the participants nor the researchers know which treatment has been administered until the study concludes, reducing the risk of bias.)

The UK has a notable history in psychedelic research during this new renaissance, beginning in 1998 with Amanda Fielding’s establishment of the Beckley Foundation, an NGO aimed at drug policy reform and scientific exploration. This foundation has fostered research teams at King's College London and UCL, leading to the emergence of companies like Compass Pathways and Small Pharma.

Research efforts are rapidly accelerating. Notably, 2019 marked the establishment of two centers dedicated to studying psychedelic substances: the Centre for Psychedelic Research at Imperial College London and the Center for Psychedelic and Consciousness Research at Johns Hopkins University. Other academic institutions contributing to this field include UCL, Berkeley, and Yale.

Before discussing specific studies, let’s briefly outline the drug development process. Once a new compound is identified for its therapeutic potential, it undergoes several phases: preclinical studies (laboratory and animal testing), Phase 1 trials (initial tests on healthy human volunteers), Phase 2 trials (testing on a small group of patients with the target condition), Phase 3 trials (large-scale, multi-site trials), and finally approval.

The industry resource Psilocybin Alpha has created an informative tool called the “Psychedelics Drug Development Tracker,” which outlines key drug discovery and development activities, including the compounds being tested, the organizations involved, and their progress stage.

Currently, 46 trials are listed on the tracker in Phase 1, 2, or 3. Only one of these is in Phase 3. There are 22 trials in Phase 2, three in combined Phase 1/2, and 20 in Phase 1, followed by 24 at the preclinical stage. This may not be an exhaustive list. Additionally, Clerkenwell Health reports that over 60 companies are exploring psychedelic compounds, with more than 100 clinical trials ongoing — a remarkable figure!

The sole trial in Phase 3 is the MAPS investigation into MDMA-assisted psychotherapy for treating post-traumatic stress disorder (PTSD). This case study is significant. Industry insiders indicate that MAPS’ founder, Rick Doblin, strategically chose PTSD in war veterans as a research focus to garner bipartisan support in the USA. This Phase 3 trial commenced in 2017 and is projected to conclude in 2021, potentially allowing FDA approval by 2022.

The most advanced trials predominantly involve MDMA and psilocybin (as well as synthetic variants of psilocybin). Trials are also being conducted for LSD, ketamine (already approved for therapeutic use), and ibogaine.

Understandably, the most pressing health conditions are prioritized for deregulation efforts, leading to trials focused on PTSD, treatment-resistant depression (TRD), eating disorders, anxiety, cluster headaches, alcohol use disorder, and opioid use disorder. Allowing patients suffering from these serious illnesses to legally access effective treatments will represent a significant shift in paradigms. Following progress in these areas, we can anticipate increased exploration of the “wellness” aspects of psychedelics, focusing on creativity, productivity, social attitudes, happiness, and empathy. Personally, I am enthusiastic about this forthcoming phase.

The organizations spearheading these trials are predominantly startups and for-profit pharmaceutical companies, with a few non-profits involved. Major players include:

Non-profit organizations: - MAPS - Usona Institute

For-profit companies: - Compass Pathways - MindMed - Cybin - Awakn - Small Pharma - Eleusis - Beckley Psytech

We’ve undertaken a comprehensive journey through the science of psychedelics. To summarize, we explored their diverse applications, skimmed the surface of their pharmacological and neuroscientific impacts, and reviewed the extensive research occurring in this domain.

Next, click here to read Part 4 of the series, focusing on the safety of psychedelics.

Special thanks to Sean McLintock, Tom McDonald, Alastair Moore, Dr. Henry Fisher, Sjir Hoeijmakers, and Andre Marmot for their contributions and feedback on earlier drafts.

[1] Aghajanian, G., Marek, G., Nature. https://www.nature.com/articles/1395318#author-information [2] Homological scaffolds of brain functional networks, The Royal Society, December 2014 (https://royalsocietypublishing.org/doi/full/10.1098/rsif.2014.0873)