Psychedelics: The New Kid on the Block
Annals of Indian Psychiatry – January 01, 2024
Source: OpenAlex
Summary
Remarkably, 80% of 51 cancer patients maintained significant reductions in depression and anxiety six months after high-dose psilocybin. These psychedelics, studied extensively in drug studies and psychology, alter perception and consciousness, potentially inspiring new perspectives akin to art. Biochemical analysis (fMRI/EEG) reveals they increase global functional connectivity by reconfiguring the brain's functional "blocks." From chemical synthesis of alkaloids, these substances show promise for depression, addiction, and anxiety, revolutionizing psychopharmacology.
Abstract
HISTORY In the early part of twentieth century, these molecules were known as psychotomimetics, meaning that they create a state similar to psychosis. Later on, they were also termed as hallucinogens, but psychedelics usually do not cause hallucinations at a therapeutic dose. The name psychedelics for these substances was first given by Osmond in 1957, meaning that they reveal useful or beneficial properties of the mind.[1] However, the idea that psychedelics can have beneficial effects has had mixed response till recently among the medical fraternity. Psychedelics strictly mean substances that alter perception, mood, and consciousness by acting on brain 5-HT2A receptors mainly as an agonist in the layer 5 of pyramidal cells in the cortex. This definition excludes other agents such as cannabinoids, dissociative agents such as ketamine, and entactogens such as 3,4-methylenedioxymethamphetamine, although all of them may cause hallucination, but their mechanism of action is different. The classic serotonin psychedelics such as psilocybin, lysergic acid diethylamide (LSD), and N, N-dimethyltryptamine (DMT) cause brain processes that are significantly different compared with normal consciousness[2] mainly by reducing between-network synchrony and increasing the connectivity between brain networks. These changes in integrative functions of the brain may be demonstrated using investigations such as electroencephalography (EEG)/magnetoencephalography synchrony (decreased) and functional magnetic resonance imaging (fMRI) connectivity (increased).[2] The effect on brain connectivity is long lasting and may persist for months after single use. Contrary to popular belief, psychedelics do not produce physical dependence or withdrawal on repeated use. PSYCHEDELICS AS TREATMENT Use of plant-based psychedelics like psilocybin or eyote in religious/ritualistic practices has an ancient history particularly in the American continent.[3] Psilocybin mushrooms were used by the Aztec shaman in healing and in a variety of religious rituals. Peyote (Lophophora williamsii) is a small cactus found mainly in the South America and Northern Mexico that has been used since ancient times and is consumed as a sacrament during services of the Native American Church. Psychedelics are an exceptional category of mind-altering substances and has been in use in various cultures as Sacrament.[4,5] In this regard, Jaffe[6] has given a highly revered definition of psychedelics "…The feature that distinguishes the psychedelic agents from other classes of drug is their capacity reliably to induce states of altered perception, thought, and feeling that are not experienced otherwise except in dreams or at times of religious exaltation." Psychedelics played a substantial role in defining the youth culture of the 1960s and 1970s. The powerful psychological effect of LSD was accidently discovered in 1943 by Hofmann,[7] after 10 years of LSD discovery the detection of serotonin in the mammalian brain was done by Twarog and Page in 1953.[8] The discovery of LSD has greatly influenced the research in the field of Serotonin Neuroscience. One of the eminent LSD researchers[8] noted that "…One basic dimension of behavior… compellingly revealed in LSD states is "Portentousness" which is the capacity of the mind to see more than it can tell…. to believe in more than it can rationally justify, to experience boundlessness and "Boundaryless" events, from the banal to the profound." The word entheogen has been coined as a substitute for psychedelic to reduce the negative overtone. The word entheogen usually means a substance or material that generates God or the divine within someone. However, the effects produced by psychedelics are highly dependent on the set (mental expectation) of the user and the setting (environment).[9] RESEARCH WITH PSYCHEDELICS The initial research into psychedelics was done by the American and European physicians with peyote (Mescaline). Mescaline was identified in 1894 by the German chemist Arthur Heffter, then synthesized in 1919 by the Austrian chemist Ernst Späth. This opened the gate for Medical Research in psychedelics in North America and Europe. As early as in 1934, French psychiatrists Henri Claude suggested the possibility of using mescaline for the treatment of depression.[10] The discovery of the effects of the LSD in 1943 and the rediscovery of Mexican divinatory mushrooms in 1953 led to extensive medical research on psychedelics.[11] However, by 1960s, the research in psychedelics drastically declined due to various factors like anti-war demonstration by so-called hippies who used to abuse LSD, rejection of conventional social norms by adolescents and college students, public hysteria concerning drug-induced insanity, and experiments conducted at a renowned US university without institutional approval.[12] Interestingly, since the late 1980s, there was a gradual increasing interest in psychedelics with numerous publications in the field of neurobiology and neuroscience of psychedelics, which has been termed as "Psychedelic renaissance."[13] Initial clinical trials focused on the benefits of psilocybin to reduce anxiety and improve the mood of patients with cancer.[14] In this randomized, double-blind, cross-over trial, they investigated the effects of a very low dose (1 or 3 mg/70 kg) versus a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 weeks between sessions and a 6-month follow-up in 51 cancer patients with symptoms of depression and anxiety. High-dose psilocybin produced large decreases in measures of depressed mood and anxiety, improved quality of life, increased optimism, and decreases in death anxiety. At 6-month follow-up, these changes were maintained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety.[14] Many researchers have tested psychedelics in conjunction with psychotherapy for the treatment of anxiety and depression. A study compared psilocybin with escitalopram over a 6-week period in patients with moderate-to-severe major depressive disorder in a phase 2, double-blind, randomized, controlled trial. A total of 59 patients were enrolled: 30 were assigned to the psilocybin group and 29 to the escitalopram group. All the subjects received psychotherapy. The primary outcome was the change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report. At the end of 6 weeks, there was no significant difference in the antidepressant effects between escitalopram and psilocybin.[15] In a recent double-blind, randomized, placebo-controlled trial in 29 patients with treatment-resistant depression, a single dose of ayahuasca was compared against placebo.[16] Improvement in depression was assessed with the Montgomery-Åsberg Depression Rating Scale and the Hamilton Depression Rating scale at baseline, at 1, 2, and 7 days after dosing. Significant antidepressant effects of ayahuasca were seen when compared with placebo at all-time points. Ayahuasca is a brew that contains the psychedelic DMT and Harmine (RMAOi). This was a unique study which assessed the efficacy of a single-dose psychedelic in treatment-resistant depressed patients. Researchers have also investigated the effects of psilocybin in addiction disorders. Researchers conducted a proof-of-concept study to assess the effects of psilocybin in alcohol-dependent participants. Ten volunteers received orally administered psilocybin in one or two supervised sessions along with Motivational Enhancement Therapy. Abstinence increased significantly following psilocybin administration (P < 0.05) and was maintained at follow-up to 36 weeks. The magnitude of effects in the first psilocybin session also predicted decreases in craving. There were no significant treatment-related adverse events.[17] Since DMT can induce a rapid (3–5 min) intense altered state of consciousness with a sense of being transported to an alternative world, without any disturbances in wakefulness which subsides within 15–20 min, it is a very useful molecule to study consciousness. In a recent landmark study, they assessed the effects of single bolus dose of 20 mg intravenous DMT on human brain by doing simultaneous fMRI and EEG before (8 min prior), during, and after the DMT dose (20 min) on 20 healthy volunteers in a within group placebo controlled, pseudo-randomized setting. The fMRI results correlated with significant increases in global functional connectivity, network disintegration, and desegregation. DMT was associated with decrease modularity, especially for frontoparietal, salience, and default-mode networks. Analyses of EEG activity revealed widespread decreases in alpha under DMT and increases in both delta and gamma bands. The major finding of the study was dysregulation of activity in the brain's transmodal association cortex pole (TOP), so that TOP becomes less segregated from or more integrated with the rest of the cortex. This implies that brain functions mainly in entropic mode under psychedelics which may be the reason for their distinct phenomenology. This multimodal, multivariate EEG-fMRI study with DMT revealed a robust dysregulating effect on activity in the brain's TOP with increased communication between the TOP of the cortex and the rest of the brain. This may be interpreted as evidence of increased information processing and a hyper-associative style of cognition.[18] Researchers performed a scientometric analysis to assess the research trend on psychedelics over a period of 100 years. A scientometric approach objectively maps the scientific knowledge area and shows how research trends have evolved over time which is superior to bibliometric analysis. Total 31,867 documents cumulating 591,329 references from 2809 different sources in 22 different languages were found, with 95.5% being in English. The analysis revealed reveals two essential time periods. The first time period was from early 1900 to 1990 with maximum 171 articles in 1974. The second time period from 1990 to date presents consistently increasing trend of publications, from 190 publications in 1990 to 1538 in 2021. The topmost cited study was the randomised controlled trial of psilocybin use for life-threatening cancer patients with depression by Solmi et al. with depression was published in 2016. The research network analysis found 16,162 institutions, the top three institutions with highest number of publications were University of California (n = 929), the National Institutes of Health USA (n = 770), and the University of London (n = 740). The important trend saw an evolution from LSD effects to the therapeutic potential psilocybin and DMT.[19] Evidence has been accumulating on the efficacy of psychedelics in depression, several phase 2 trials have shown very promising results; both ayahuasca[20] and psilocybin[21] were superior to placebo, and psilocybin was comparable to escitalopram. Other than depression and anxiety new randomized controlled trials are ongoing to evaluate psychedelics in anorexia nervosa.[22] Interestingly, psychedelics seem to reduce the gap between pharmacological and nonpharmacological interventions, using the effects of the pharmacological intervention as a key to enhance psychotherapy.[23] CONCLUSIONS The use of psychedelics in otherwise treatment refractory conditions is perhaps the most promising development in Psychiatry. Multiple phase II and III clinical trials have proven the efficacy of psychedelics particularly Psilocybin in various mental and physical conditions like depression, addictions, anxiety, anorexia nervosa, and pain. Psychedelics are also a good adjunct to psychotherapy. If used responsibly and with proper caution the psychedelics may revolutionize the field of psychopharmacology. With the approval of esketamine in depression, it may not be too far when psilocybin will also be used in patients with various mental health conditions. The ethical and legal ramifications of the same will also have to be looked into and stringent guidelines will have to laid out.