Author: Gary Jackson

Psychedelic and Dissociative Drugs

Psychedelics have certain effects, such as mystical experiences, that make them attractive for recreational use. Limited research suggests that they may also have medical uses, such as reducing depression and anxiety, as well as promoting abstinence from smoking and alcohol. This demonstrates pharmacological interference with memory reconsolidation may allow overwriting of maladaptive drinking memories with clinical benefits. In June 2022, NIDA’s Office of Translational Initiatives and Program Innovations also announced a new program to support small businesses to develop psychedelic-based therapies for substance use disorders.

For more than 50 years, prohibition effectively ceased clinical research into psychedelic compounds as a result of their placement in schedule 1 of the 1971 convention on psychotropic substances by the United Nations (UNODC, 1971). This ban states that these drugs have “no evidence of medical value” (UNODC, 1971) and has heavily impacted “an otherwise promising development of a novel treatment paradigm in mental health” (31). Despite these restrictions, the collection of real-world evidence for the therapeutic use of psychedelics has continued, in the form of retrospective, observational and naturalistic studies. Importantly, such real-world evidence can complement lab-based RCTs by indicating an intervention’s effectiveness in a more ecologically valid fashion and with more external validity than formal clinical trials can provide (32). Further, this data allows for the assessment of patients with multiple morbidities, with doses tailored to their clinical needs, which subsequently provide researchers with novel insights into parameters to design future studies (32). Below we summarize the evidence from such studies in individuals with addiction using classic and non-classic psychedelics for therapeutic purposes and have summarized these findings in Table 1.

The Johns Hopkins Center for Psychedelic and Consciousness Research

This lends support to theory that psychedelics allow individuals to process threat and actively engage with their emotional environment as opposed to adopting avoidant coping mechanism strategies to reduce stress, such as drug seeking in patients with addiction. Intriguingly, one Single Photon Emission Computed Tomography (SPECT) neuroimaging case study in an individual with alcohol use disorder (AUD) combined ibogaine at day one with 5-MeO-DMT at day three and found cessation of alcohol use, reduced cravings, and improved moods at day five post-treatment. Increases in brain perfusion were seen in the left putamen, and right insula, as well as temporal, occipital, and cerebellar regions, compared to the patient’s baseline scan.

• We argue that biomedical and neuropsychopharmacological techniques that have traditionally been used in addiction research over the last 40 years should now be redeployed to the study of psychedelic therapies adjunctive to clinical trials in humans with addiction disorders.
• The emergency and referral resources listed above are available to individuals located in the United States and are not operated by the National Institute on Drug Abuse (NIDA).
• Recent work has demonstrated this radiotracer to be sensitive to endogenous serotonin following administration of oral dexamphetamine in healthy humans (163) and in clinical populations including depression demonstrating reductions in serotonin release capacity in the latter when compared with healthy controls (172).
• Used for surgical anesthesia since the 1970s, it has since shown promising results for pain relief [for review see (24)], treatment-resistant depression [for review see (25)], and addiction [see review by Ivan Ezquerra-Romano et al. (26)].
• Addictions have been consistently linked to strong negative affective states, withdrawal and emotional dysregulation with several regions of the brain, including the amygdala and frontal cortex, found to play a role in driving these responses (97).
• Psychedelic drugs—once promising research subjects that were decades ago relegated to illicit experimentation in dorm rooms—have been steadily making their way back into the lab for a revamped 21st-century-style look.

The current clinical treatment paradigm for addictions is a psychosocial intervention with adjunctive pharmacotherapy. These current treatments and interventions for addictions provide limited success with 20% of individuals relapsing within 1 month and a further 40% within 6 months (11). The effectiveness of treatments for alcohol addiction is among the lowest of all mental health disorders, with only 3 licensed pharmacotherapies available and only 9% of individuals with this disorder receiving such treatments (12). The situation is arguably worse for individuals with other substance or behavioral addictions, which have fewer or no clinically efficacious medications available (11). While more research is being conducted on the use of psychedelics as therapeutic treatment, it is vital to move ahead with care and to focus on the scientific rigor of the research. Further clinical research is necessary to establish which psychedelic drugs are most effective, how they should be administered, and who is most likely to benefit.

Are psychedelic and dissociative drugs addictive? Can people experience withdrawal?

It is crucial for treatment providers and others to be aware of the current state of research in order to have informed conversations with their clients and provide the best care possible. Given the mixed research findings, it is important to proceed with care and focus on scientific rigor and transparency. There is a need to better establish which of these drugs are most effective, how they should be administered, and who is most likely to benefit. New and future research efforts may benefit from exploring the underlying therapeutic mechanisms of the chemical component(s) of psychedelics in the brain. Such studies could facilitate the development of personalized medicines in the treatment of behavioral health disorders and provide needed data on potential abuse or side effects.

The quasi-experimental case-study data from Russia (27) has prompted the modern clinical exploration ketamine in RCTs. Another recent double-blind placebo-controlled phase II clinical trial in the UK included 96 patients with AUD randomizing patients to four possible treatment arms; ketamine or placebo infusion and mindfulness psychotherapy or psychoeducation, respectively. The treatment was well tolerated and the most positive effects were demonstrated in the group receiving three infusions of 0.8 mg/kg ketamine plus psychotherapy, who had more days of abstinence at 6 months follow-up than the placebo infusion plus psychoeducation group (68). The added value of this study is that it suggests the possible adjunctive therapeutic effect of psychotherapy combined with ketamine. Psychedelic-assisted therapy [e.g., with lysergic acid diethylamide (LSD)] has shown promising results as treatment for substance use disorders (SUDs).

Reclassification recommendation for psilocybin

Her report furthers the calls from NIDA’s 2019 medication development priorities paper, highlighting the pressing socio-economic need for the development of more effective treatments through innovative and mechanistic scientific programs to improve translation to the clinic (10). To be diagnosed with a substance use disorder, a person must meet specific diagnostic criteria for continued substance use despite negative consequences. While short-term positive and negative mood changes are common with psychedelic and dissociative drugs, more research is needed to better understand the long-term effects these substances may have on mental health. Armed with these promising results, Griffiths and his colleagues turned their attention to other clinical applications.

Another long-term effect is a phenomenon called hallucinogen persisting perception disorder (HPPD). This involves flashbacks of a prior drug experience that can happen without warning and cause significant distress or impairment. Dependence refers to a physical reliance on a drug, whereas addiction refers to a behavioral change arising from a compulsion to continue taking a drug. In addition to producing visual hallucinations, euphoria, and mystical experiences, psychedelics have other effects that underlie their recreational use.