Psychedelic Therapy Renaissance
“Last Friday, April 16, 1943, I was forced to stop my work in the laboratory in the middle of the afternoon and to go home, as I was seized by a peculiar restlessness associated with a sensation of mild dizziness. On arriving home, I lay down and sank into a kind of drunkness which was not unpleasant and which was characterized by extreme activity of imagination. As I lay in a dazed condition with my eyes closed <...> there surged upon me an uninterrupted stream of fantastic images of extraordinary plasticity and vividness and accompanied by an intense, kaleidoscope-like play of colors. This condition gradually passed off after about two hours”  - This is the first-ever recorded experience of an diethylamide of lysergic acid (LSD)-induced psychedelic state. The latter diary entry was made by the father of LSD, a swiss Chemist, Alfred Hofmann. At the time, Hofmann was looking for a series of compounds structurally similar to ergot alkaloids which could potentially act as an analeptics - stimulate the respiratory system of the patient when administered. Hofmann accidentally came into contact with LSD when his fingertips absorbed a microscopic amount of it. The extreme potency of the drug meant that even a small amount sent his mind wandering like it has never before. The accidental exposure to the drug prompted the chemist to self-experiment some more which, interestingly made him think of its psychiatric application.
Hofmann sent out a couple of LSD samples to his colleagues from the field of psychiatry. Quite soon psychiatrists started to experiment with the drug in their practices. The altered state of consciousness produced by LSD intrigued psychiatrists because they thought that it allowed them to peer into the unconscious, the thoughts that hide in the back of the human consciousness and that are usually repressed. Other psychiatrists thought that by self-experimenting with the drug they could get a better understanding of how their schizophrenic patients feel and accustom their treatments accordingly. Medical experiments into addiction, anxiety, alcoholism, OCD, schizophrenia, and depression were carried out. It seemed that psychiatry is at a cusp of a major revolution.
Psychedelic drugs soon were also “tripping” people outside of the psychiatrist’s cabinet. When one thinks of the 60s and psychedelics, one sees pink-and-orange swirls, naked people with flowers in their hair and the shimmer of a sitar . “Dropping acid” impacted the minds of generational artists like of Bob Dylan, the Beatles, and Jimi Hendrix. The counter-cultural movement that opposed the war in Vietnam was partly inspired by slogans like “turn on, tune in, drop out”  by the notorious Harvard psychologist Timothy Leary. The rebellious anti-establishment free-spirit of the 60s provoked a moral panic that has by the mid 70s resulted in a classification of LSD and other psychedelic substances as a schedule I drug. Schedule I means that there is no practical medicinal use for this drug. Psychedelics were now classified alongside methamphetamine and heroin. Research into the psychiatric applications of psychedelics were stifled by a myriad of bureaucratic obstacles that made research into them both time and cost-prohibitive.
We are living in what is now called a psychedelic renaissance. Everything started when a study at John Hopkins university in the U.S. investigated the effects of psilocybin (the active ingredient in magic mushrooms). That paper titled “Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance” in 2006 found that subjects would rank their psychedelic experience as one of the most formative experiences of their lives alongside child birth or death of a parent . This study then inspired psychedelic therapy to be investigated at other places like NYU, Imperial College London, Oxford, Harvard and many other universities. Psychedelics combined with conventional psychotherapy measures like cognitive behavioral therapy have been used as potential remedies for late-life anxiety in cancer patients, eating disorders, OCD, post-traumatic stress disorder, and treatment-resistant depression. This week’s blogpost will zoom in on psychedelic applications of depression treatment and talk about how the scientists think psychedelics produce their antidepressant effects.
Classical psychedelic drugs include mescaline, psilocybin (“magic mushrooms”, trufles), ayahuasca, dimethyltryptamine (DMT) and D-lysergic acid diethylamide (LSD). These classical psychedelics are also often called the “serotonergic psychedelics” due to a lot of them targeting the 5-HT2a receptor (5-HT is just another name for serotonin receptor). 3,4-Methylenedioxymethamphetamine (MDMA) and ketamine are also sometimes referred to as having psychedelic properties, but as you might recall from last week’s blogpost, they are “dissassociative anesthetics”, meaning that their mode of action is distinct from classical psychedelics.
Classical psychedelics like mescaline have been used in entheogenic (I love this word  ), shamanistic practices for centuries. In such settings, an experienced spiritual guide would carefully administer the psychedelic through eating or smoking and create an atmosphere of spirituality that enhances the effects of the psychedelic experience. The “trip” would be facilitated by the shaman to make the experience as transformative and therapeutic as possible. This is actually not too far off from how psychedelic therapy is done in a modern clinical setting. In this case, the psychotherapist will be acting as the spiritual guide that will steer the patient’s mind from “bad experiences” if that comes up. There is also a medical team on stand-by that is carefully monitoring the physiological response of the patient to the psychedelic drug. Often the spaces where psychedelic therapy happens have mythological, spiritual paintings on the walls, statues of the psilocybin mushroom and other artefacts (see figure 1). This is meant to create a favourable “setting” where the patient feels like he is safe, but also where he can achieve spiritual revelations.
A recent study administered a high-dose of psilocybin alongside a therapist to 19 treatment-resistant depression patients . All 19 patients showed very significant antidepressant effects 1 day after treatment. Remember that conventional Serotonin Reuptake Inhibitors (SSRIs) usually take up an average of 4-6 weeks - so, this fast acting result is impressive. Even more remarkably, 5-weeks post treatment, 18 out of 19 patients showed “after-glow” like effects where they reported statistically significant changes in mood on a 16-item Quick Inventory of Depressive Symptoms (QIDS-SR16) survey. Think about it - a single drug intake, can change you for 5 weeks? Isn’t that just completely strange? How can a single pill do this? How does neuroscience explain it?
The previously described study at Imperial College London were also trying to look at the brains “on” psilocybin (active ingredient of “magic mushrooms”) with neural imaging. Functional magnetic resonance imaging (fMRI) was used in this study. This technique tries to see cerebral blood flow which is a proxy for neuronal activity in the brain. By asking a patient to take a certain drug, one can compare the neural activity of brains of a drug-taker and a control patient who took a placebo to see the effects of a drug. One can take it a step further and try to see if there are correlations in brain activity between different brain regions. This is what is called functional connectivity analysis. What this correlation revealed was nothing short of amazing.
Psilocybin expands your mind. Connectivity analysis found that psilocybin makes your higher-level brain regions “talk” to each other more. In practical terms this looks like increased correlation between brain regions that were not showing neural activity together before. This effect is also accompanied by a decrease in modular connectivity - parts of the brain that “talk to each other” more often, are now seen to be “connected” less. See figure 2 for a brilliant visualization of this phenomenon. Same color individual blobs are to represent locally (or modularly) connected brain regions. A brain on psychedelics will have way more cross-talk between regions that are not of the same color and less between the same color blobs. This shows the global increase and the modular decrease in connectivity. It is interesting because this increase in globular connectivity has been shown to be self-reported to co-occur with “ego-dissolution” - when the sense of self is lost, fear of death disintegrates and feelings of unity with the universe overwhelm.
Okay - so what? How does this globular connectivity, “expansion of the mind” lead to antidepressant effects? The truth is - we still do not know. A popular hypothesis is that of the “reset” mechanism. The idea here is that in certain mental illnesses like depression our thoughts and beliefs become more “rigid”. These higher-level ideas can be relaxed if one is forced (with the help of psychedelics) to recruit parts of your brain that are not normally recruited. In other words, it sort of lets you get out of the mental hole in which one is trapped as one can access “new perspectives”. With psychedelics, the “rigid” beliefs are “relaxed” and recalibrated. While this theory still relies on a lot of assumptions, some evidence can be found in the study with psilocybin as the antidepressant effects were correlated with the intensity of the mystical experience . It is almost like the more you “expand your mind” with psychedelics, the more likely you are to “relax” your depressive thoughts.
What is in the future for psychedelic therapy? Psilocybin, the active ingredient in “magic mushrooms”, is legal in Oregon, Oakland and Santa Cruz in California. These are probably going to be the first places where synthetically synthesized pure psilocybin will be used in therapy. Experts say it will happen in year 2023 . There are companies such as “Synthesis” in the Netherlands who have been exploiting the legal loophole where truffles, the fungus of the psilocybin mushroom, contain the hallucinogenic chemical psilocybin and can be used in facilitating therapy. This service is happening even now but the service is kind of price - for a 3-day Core retreat, you will have to pay 3000$. Nevertheless, it does seem that the Dutch company is serious. Recently, they have recruited the former lead clinical psychologist that worked at Imperial College London (the group that did the study on psilocybin). I personally think it is very important that the private endeavors in the psychedelic industry be driven by clinical professionals as opposed to amateur psychonauts.
Chances are that in about 10 years’ time it will be widely regarded that psychedelic therapy is one of the greatest breakthroughs in modern psychiatry. I am constantly amazed in the new applications of it in so many mental illness treatments. Again, I just want to reiterate that psychedelics can be used in treating alcoholism, OCD, late-life anxiety, depression, eating disorders, and many other diseases. I think it just speaks to the fact that mental illnesses could be having a common mechanism that could be tackled through holistic interventions such as psychedelics. Unraveling the mechanism of action of psychedelics could also help us understand why a lot of psychiatric disorders co-occur with each other (e.g. depression with anxiety; chronic pain with insomnia). The future of psychiatry is bright, but it is important to proceed with caution so that major setbacks like the one experienced in the 60s would not happen again.
The article was prepared on behalf of INA by Matas Vitkauskas
Sources of images:
Cover image https://www.news.com.au/technology/science/human-body/psychedelic-therapy-the-patients-paying-2k-to-get-high-with-their-doctor/news-story/5bfa32905c5cbfacdaaf783bfe38cdad
Illustration 1 https://doi.org/10.1038/news.2008.934
Illustration 2 https://royalsocietypublishing.org/doi/full/10.1098/rsif.2014.0873