Special Rewind: Psychedelics Edition. May 10, 2021

Section 1: Psychedelics as a potential therapeutic option for psychiatric conditions

Psychedelic drugs, such as lysergic acid diethylamide (LSD), was of interest to molecular psychiatry in the 1950s due to its considerable chemical similarity to serotonin (5-HT). In the context of a highly regulated system, the use of psychedelics in psychiatry is not necessarily novel, but a reemerging concept.^[1] They are generally considered Schedule I controlled substances (psilocybin, DMT, MDMA),^[2] which traditionally are considered to purport no medical value and high potential for abuse.^[3]

Despite this, psychedelic drugs such as psilocybin, in particular, have recently received increased attention with potential to treat a range of conditions.^[4] Through a better understanding of pharmacokinetics and 5-HT receptor subtypes, psilocybin has become known to have a significant impact on 5-HT_2A, specifically in the cerebral cortex as a non-selective serotonin agonist.^[5] This is believed to inhibit thalamic filtering via GABAergic projections, which permits cortical regions to receive more sensory information.^[5,6,7] However, the claustrum, a subcortical nucleus expressing high 5-HT_2A receptors and projecting glutamatergic inputs to the cerebral cortex, seems to also experience positive effects following psilocybin administration.^[7] There is also ample evidence that psilocybin, for example, reduces amygdalar reactivity and improves responses originating in the prefrontal and orbitofrontal cortices.^[8] Clinically speaking, the culmination of these findings have led to great excitement in the application of drugs such as psilocybin for the treatment of various psychiatric conditions. In terms of dosing, there is substantial convenience and reduction of costs in administering fixed doses. It has been found that body weight does not significantly impact effects and the benefits outweigh advantages of weight-adjusted dosing.^[9]

Concerns do exist regarding treatment with psychedelic drugs, with some reporting that terms such as consciousness and spiritual are misused and poorly defined.^[10] Further, one must be cautious with maintaining professional boundaries in the context of psychedelic drug treatment and therapy. The combination of these treatment modalities are currently viewed positively by many, such that conventional psychotherapy could be greatly enhanced through the use of psychedelic drugs^[11], effects that span the range of psychedelics and result in greater effect sizes than trials of pharmacotherapy or psychotherapy alone.^[12]  While much research remains regarding safety and efficacy, guidelines are in place that have resulted in very few persisting adverse reactions.^[13] Areas of improvement include but are not limited to ethics, trial design, and unambiguously defining outcomes.^[11] The current reality is that psychedelics demonstrate unique potential for the treatment of psychiatric conditions and are likely to become more widespread as research continues to explore this area.^[14]

Section 2: Psychedelics for depression & trauma-related disorders

Posttraumatic Stress Disorder (PTSD) and other trauma-related conditions are common across the globe and particularly pernicious among combat veterans. For patients who have not responded well to traditional first line pharmacotherapy or counselling, psychedelics may be considered as an alternative or adjunct treatment in the future. In some studies, the effects of psychedelics, such as lysergic diethylamide (LSD), psilocybin, and methylenedioxymethamphetamine (MDMA) suggest an ability to improve mood and help people recover from traumatic events.^[1] For example, racial minority groups are generally underrepresented in psychedelic drugs research, but it has been discovered that therapeutic doses of LSD, psilocybin, and MDMA reduced mental health and traumatic stress symptoms, even after controlling for level of racial discrimination.^[2]  One study investigated the psychological effects of ibogaine, a psychoactive indole alkaloid, among Special Operations Forces personnel. Substantial reductions in suicidal ideation, depression, anxiety, PTSD symptoms, and cognitive impairment were found. Regarding the psychedelic experiences themselves, 84% of the sample reported them as one of the top five personally meaningful experiences of their lives.^[3] An increase in psychological flexibility is noted in numerous studies as mediating the relationship between acute psychedelic effects and reductions in depression and anxiety, including international samples,^[3,4] suggesting that psychedelics may be of even greater value when used to enhance psychotherapy. For example, MDMA-assisted psychotherapy trial has completed Phase 3 with positive results for individuals with PTSD, with approximately 67% of participants no longer meeting criteria for PTSD two months after treatment.^[5,6]

In addition to PTSD, substantial research has recently been done investigating the potential usage of psychedelic drugs for anxiety and depression. A psychedelic drug less common in research is 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), is known for recreational use to achieve spiritual enlightenment and other subjective effects. In recent literature, there is evidence that up to 80% of participants with depression and anxiety experience significant reductions following use of 5-MeO-DMT. These improvements were not associated with the intensity of negative drug effects, though they were associated with positive, mystical drug effects.^[7] Users often associate these mystical outcomes to benefit enhancement strategies to reduce risk of negative drug experiences.^[8] These same mystical experiences, in the context of psilocybin, mediate positive effects on personal meaning up to 14 months after drug administration.^[9,10] These results extend to individuals with comorbid medical conditions such as terminal cancers, with depression and anxiety being common experiences. Psilocybin is one drug that showed improved mood and anxiety symptoms at five weeks, with approximately 80% of patients experiencing sustained improvements at six-month follow-up, with a dose-dependent effect.^[11,12] However, even a single dose of psilocybin has demonstrated ability to reduce negative affect and amygdalar responses, as well as increase positive affect and pre- and orbitofrontal cortices responses, when confronted with emotionally-conflicting stimuli.^[13]

In summation, there is a substantial and strong body of evidence supporting psychedelic drugs to benefit patients with mood disorders and trauma-related symptoms.

Section 3: Psychedelics for substance use disorders

Psychedelics are viewed by some as the perpetuation of drug misuse and abuse. However, literature tends to suggest that these treatments can reduce use of other drugs, such as opioids, cannabis, and stimulants.^[1] Both animal and human studies suggest that there is no potential for physical dependence on psilocybin, along with very low abuse risk.^[2] Further, treatment with psilocybin has resulted in increased insight into cigarette smoking, resulting in reduced use of nicotine.^[3,4] Lysergic acid diethylamide (LSD) has also demonstrated similar effects, with 38% of a 358-participant study quitting cigarette use. Of these, 74% maintained abstinence for at least two years.^[5] Opioid use is a significant problem, such that the ability of psychedelic drugs to reduce risk of future opioid abuse and dependence is an important clinical consideration.^[6,7] Alcohol use has also been studied with psilocybin treatment, suggesting that subjective experiences have resulted in greater insight into the addiction. This novel insight is purported to play a therapeutic role in subsequent reductions in alcohol use that may also involve psychedelic-induced serotonergic alterations and changes in mood.^[8] Both LSD and psilocybin have been shown to decrease alcohol consumption, with up to 83% of participants no longer meeting diagnostic criteria for Alcohol Use Disorder following treatment. Insight continued to be a major factor associated with the magnitude of decline in use.^[9] The synthetic 2,5-dimethoxy-4-iodoamphetamine (DOI), a psychedelic associated with significant mood improvements, also demonstrates effectiveness in reducing alcohol consumption via 5-HT_2A alterations. Further, the effects of DOI were associated with alcohol-preferring participants compared to controls.^[10] The culmination of this literature, although incomplete, appears to suggest that psychedelic drugs not only have a low potential for dependence when appropriately used, but can also be used to treat substance use disorders across the spectrum.

Section 4: Music and psychedelic drug experiences

In the context of improved insight and mystical and spiritual experiences among users of psychedelic drugs, it is important to consider how these subjective experiences translate to clinical care and enhanced well-being. It has long been suggested that music could be incorporated into psychedelic drug treatment,^[1] which may facilitate the demonstrated positive outcomes.^[2] Several studies have suggested that the environment of psychedelic drug treatment, such as support and comfort, is associated with its overall outcomes.^[3,4] Therefore, the ability for music to alter one’s state of consciousness, such as trances, may generate a more effective treatment environment. Subjective experiences of participants suggest that it may be possible to choose the appropriate music and determine the peaks that will result in improved outcomes during psychedelic drug treatment.^[5]

With lysergic acid diethylamide (LSD) treatment, broad effects on brain entropy and sensory networks are reported to improve psychedelic experiences and lower one’s ego defenses that may be exacerbating symptoms.^[6] The known serotonergic alterations associated with psychedelic drug use also appears to play a putative role in positive outcomes. Specifically, 5-HT_2A receptor subtype signaling is a key component of an individual’s ability to track tonal structure in music, which impacts feelings of connectedness, emotionality, and life meaningfulness.^[7]

In the context of smoking cessation, and possibly other substance use, some evidence suggests that music type may determine whether or not the psychedelic treatment is effective. For example, scoring of mystical experiences were higher during overtone-based music compared to Western classical sessions.^[8] The literature does suggest, however, that music can evoke negative imagery depending on its content, such that further research should investigate these suboptimal outcomes.^[9] Though individual-level experiences are difficult to predict due to unique musical interests, it does overwhelming seem to harbor potential in strengthening connection to the psychedelic experience, as well as promoting effects that last longer.^[10]

Section 5: Psychedelic use in the long-term

Serious adverse reactions have not been a recognized risk through ongoing research, though some are concerned about long-term use and the time at which psychedelic drug treatment should be considered.^[1] Psychotic disorders, when they occur in a very small group of people, they are generally transient,^[2] which is a commonly-reported concern in the area of psychedelic drug research. Some of this heterogeneity can be attributed to the environment and overall well-being at time of administration, such as promoting a safe and supportive environment during treatment. This results in more positive acute effects as well as more long-lasting reductions in symptoms.^[3] In a study comparing cannabis, psilocybin, and salvinorin, cannabis resulted in a greater number of participant-reported hallucinations, though the subjective reports suggested different hallucinatory experiences compared to the acute effects of the other traditional psychedelic drugs.^[4] In terms of age at psychedelic use, there is evidence that adolescence is a particularly sensitive time in brain development. The propensity to engage in impulsive and risky behaviors is often high, and dissociative effects may occur that are not therapeutic in nature.^[5] In fact, lifetime psychotic symptoms have been associated with lifetime use of psychedelics in Germany, though this result does not account for time of use, genetic risk for psychosis, or other potential confounding. However, our understanding of the serotonergic system suggests that depletion is also a risk factor for mood and substance use disorders, such that drugs offering prolonged activity on 5-HT_2A could be advantageous for some.^[6] In sum, there is currently limited evidence of long-term risks in adults. In animal studies, however, it appears that psychedelics offer prolonged epigenetic and cognitive improvements over time.^[7] As such, despite the promising potential that psychedelic usage appears to have for medical purposes, more studies are required to fully understand long-term outcomes.

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