With the Food and Drug Administration designation in 2017 of 3,4-methylenedioxymethamphetamine (MDMA) as a breakthrough therapy in post-traumatic stress disorder and psilocybin in treatment-resistant depression, psychedelic drugs have continued to garner the attention of researchers and clinicians for their promise of unmatched, rapid improvement in a multitude of psychiatric conditions. Classic psychedelic drugs including psilocybin, lysergic acid diethylamide, and ayahuasca, as well as non-classic drugs such as MDMA and ketamine, are currently being investigated for a potential therapeutic role in trauma, depressive disorders, and other psychopathologies. However, psilocybin and MDMA each have a functional profile well-suited for integration with psychotherapy. The present review focuses on psilocybin and MDMA in psychedelic-assisted therapy (PAT), as these studies compose most of the literature pool. In this review, we discuss the current and future uses of psychedelic drugs, with an emphasis on the role of MDMA and psilocybin in PAT in the setting of trauma and related comorbidities on the efficacy of psychedelic drugs across multiple psychiatric disorders. The article concludes with thoughts for future research, such as incorporating wearables and standardization of symptom scales, therapy styles, and assessment of adverse drug reactions.

Objective: The authors provide an evidenced-based summary of the literature on the clinical application of psychedelic drugs in psychiatric disorders.

Methods: Searches of PubMed and PsycINFO via Ovid were conducted for articles in English, in peer-reviewed journals, reporting on "psilocybin," "lysergic acid diethylamide," "LSD," "ayahuasca," "-methylenedioxymethamphetamine," and "MDMA," in human subjects, published between 2007 and July 1, 2019. A total of 1,603 articles were identified and screened. Articles that did not contain the terms "clinical trial," "therapy," or "imaging" in the title or abstract were filtered out. The 161 remaining articles were reviewed by two or more authors. The authors identified 14 articles reporting on well-designed clinical trials investigating the efficacy of lysergic acid diethylamide (LSD), -methylenedioxymethamphetamine (MDMA), psilocybin, and ayahuasca for the treatment of mood and anxiety disorders, trauma and stress-related disorders, and substance-related and addictive disorders as well as in end-of-life care.

Results: The most significant database exists for MDMA and psilocybin, which have been designated by the U.S. Food and Drug Administration (FDA) as "breakthrough therapies" for posttraumatic stress disorder (PTSD) and treatment-resistant depression, respectively. The research on LSD and ayahuasca is observational, but available evidence suggests that these agents may have therapeutic effects in specific psychiatric disorders.

Conclusions: Randomized clinical trials support the efficacy of MDMA in the treatment of PTSD and psilocybin in the treatment of depression and cancer-related anxiety. The research to support the use of LSD and ayahuasca in the treatment of psychiatric disorders is preliminary, although promising. Overall, the database is insufficient for FDA approval of any psychedelic compound for routine clinical use in psychiatric disorders at this time, but continued research on the efficacy of psychedelics for the treatment of psychiatric disorders is warranted.

Scientific interest in serotonergic psychedelics (e.g., psilocybin and LSD; 5-HT receptor agonists) has dramatically increased within the last decade. Clinical studies administering psychedelics with psychotherapy have shown preliminary evidence of robust efficacy in treating anxiety and depression, as well as addiction to tobacco and alcohol. Moreover, recent research has suggested that these compounds have potential efficacy against inflammatory diseases through novel mechanisms, with potential advantages over existing antiinflammatory agents. We propose that psychedelics exert therapeutic effects for psychiatric disorders by acutely destabilizing local brain network hubs and global network connectivity via amplification of neuronal avalanches, providing the occasion for brain network "resetting" after the acute effects have resolved. Antiinflammatory effects may hold promise for efficacy in treatment of inflammation-related nonpsychiatric as well as potentially for psychiatric disorders. Serotonergic psychedelics operate through unique mechanisms that show promising effects for a variety of intractable, debilitating, and lethal disorders, and should be rigorously researched.

The studies of psychedelics, especially psychedelic tryptamines like psilocybin, are rapidly gaining interest in neuroscience research. Much of this interest stems from recent clinical studies demonstrating that they have a unique ability to improve the debilitating symptoms of major depressive disorder (MDD) long-term after only a single treatment. Indeed, the Food and Drug Administration (FDA) has recently designated two Phase III clinical trials studying the ability of psilocybin to treat forms of MDD with "Breakthrough Therapy" status. If successful, the use of psychedelics to treat psychiatric diseases like depression would be revolutionary. As more evidence appears in the scientific literature to support their use in psychiatry to treat MDD on and substance use disorders (SUD), recent studies with rodents revealed that their therapeutic effects might extend beyond treating MDD and SUD. For example, psychedelics may have efficacy in the treatment and prevention of brain injury and neurodegenerative diseases such as Alzheimer's Disease. Preclinical work has highlighted psychedelics' ability to induce neuroplasticity and synaptogenesis, and neural progenitor cell proliferation. Psychedelics may also act as immunomodulators by reducing levels of proinflammatory biomarkers, including IL-1β, IL-6, and tumor necrosis factor-α (TNF-α). Their exact molecular mechanisms, and induction of cellular interactions, especially between neural and glial cells, leading to therapeutic efficacy, remain to be determined. In this review, we discuss recent findings and information on how psychedelics may act therapeutically on cells within the central nervous system (CNS) during brain injuries and neurodegenerative diseases.

4-phosphorloxy-N,N-dimethyltryptamine (psilocybin) and methylenedioxymethamfetamine (MDMA), best known for their illegal use as psychedelic drugs, are showing promise as therapeutics in a resurgence of clinical research during the past 10 years. Psilocybin is being tested for alcoholism, smoking cessation, and in patients with advanced cancer with anxiety. MDMA is showing encouraging results as a treatment for refractory post-traumatic stress disorder, social anxiety in autistic adults, and anxiety associated with a life-threatening illness. Both drugs are studied as adjuncts or catalysts to psychotherapy, rather than as stand-alone drug treatments. This model of drug-assisted psychotherapy is a possible alternative to existing pharmacological and psychological treatments in psychiatry. Further research is needed to fully assess the potential of these compounds in the management of these common disorders that are difficult to treat with existing methods.

Though there was initial interest in the use of psychedelic drugs for psychiatric treatment, bad outcomes and subsequent passage of the Substance Act of 1970, which placed psychedelic drugs in the Schedule I category, significantly limited potential progress. More recently, however, there has been renewal in interest and promise of psychedelic research. The purpose of this review is to highlight contemporary human studies on the use of select psychedelic drugs, such as psilocybin, LSD, MDMA and ayahuasca, in the treatment of various psychiatric illnesses, including but not limited to treatment-resistant depression, post-traumatic stress disorder, end-of-life anxiety, and substance use disorders. The safety and efficacy as reported from human and animal studies will also be discussed. Accumulated research to date has suggested the potential for psychedelics to emerge as breakthrough therapies for psychiatric conditions refractory to conventional treatments. However, given the unique history and high potential for misuse with popular distribution, special care and considerations must be undertaken to safeguard their use as viable medical treatments rather than drugs of abuse.

Background: Research into the therapeutic and naturalistic uses of psychedelics for improving outcomes related to mental health disorders has generated increasing interest in recent years. While controlled clinical trials of psychedelics have signaled benefits for treating substance use disorders, this area has not been well studied in the context of naturalistic psychedelic use. This study sought to investigate the possible relationship between recent naturalistic psychedelic use and subsequent daily illicit opioid use among people who use drugs (PWUD).

Methods: Data (2006-2018) were drawn from three harmonized prospective cohorts of community-recruited PWUD in Vancouver, Canada. We used multivariable generalized linear mixed-effects modeling (GLMM) to estimate the independent association between psychedelic use and subsequent daily illicit opioid use.

Results: Among 3813 PWUD at baseline, 1093 (29%) reported daily use of illicit opioids and 229 (6%) reported psychedelic use in the past six months. Over study follow-up after adjusting for a range of potential confounders, psychedelic use remained independently associated with a significantly reduced odds of subsequent daily opioid use (Adjusted Odds Ratio: 0.45; 95% Confidence Interval: 0.29 to 0.70).

Conclusion: While confirmation in other settings is required, these findings align with growing evidence that psychedelic use may be associated with detectable reductions in subsequent substance use including illicit opioid use.

The mainstay of treatment for opioid use disorder (OUD) is opioid agonist therapy (OAT), which modulates opioid receptors to reduce substance craving and use. OAT maintains dependence on opioids but helps reduce overdose and negative sequelae of substance abuse. Despite increasing availability of OAT, its effectiveness is limited by difficulty in initiating and maintaining patients on treatment. With the worsening opioid epidemic in the United States and rising overdose deaths, a more durable and effective treatment for OUD is necessary. This paper reviews novel treatments being investigated for OUD, including neuromodulatory interventions, psychedelic drugs, and other novel approaches. Neuromodulatory interventions can stimulate the addiction neural circuitry involving the dorsolateral prefrontal cortex and deeper mesolimbic structures to curb craving and reduce use, and multiple clinical trials for interventional treatment for OUD are currently conducted. Similarly, psychedelic agents are being investigated for efficacy in OUD specifically. There is a resurgence of interest in psychedelic agents' therapeutic potential, with evidence of improving mood symptoms and decreased substance use even after just one dose. Exact mechanism of their anti-addictive effect is not fully elucidated, but psychedelic agents do not maintain opioid dependence and some may even be helpful in abating symptoms of withdrawal. Other potential approaches for OUD include targeting different parts of the dopamine-dependent addiction pathway, identifying susceptible genes and modulating gene products, as well as utilizing vaccines as immunotherapy to blunt the addictive effects of substances. Much more clinical data are needed to support efficacy and safety of these therapies in OUD, but these proposed novel treatments look beyond the opioid receptor to offer hope for a more durably effective OUD treatment.

The United States is entering its fourth decade of the opioid epidemic with no clear end in sight. At the center of the epidemic is an increase in opioid use disorder (OUD), a complex condition encompassing physical addiction, psychological comorbidities, and socioeconomic and legal travails associated with the misuse and abuse of opioids. Existing behavioral and medication-assisted therapies show limited efficacy as they are hampered by lack of access, strict regimens, and failure to fully address the non-pharmacological aspects of the disease. A growing body of research has indicated the potential of hallucinogens to efficaciously and expeditiously treat addictions, including OUD, by a novel combination of pharmacology, neuroplasticity, and psychological mechanisms. Nonetheless, research into these compounds has been hindered due to legal, social, and safety concerns. This review will examine the preclinical and clinical evidence that psychoplastogens, such as ibogaine, ketamine, and classic psychedelics, may offer a unique, holistic alternative for the treatment of OUD while acknowledging that further research is needed to establish long-term efficacy along with proper safety and ethical guidelines.

The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals. Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine-like those of other psychedelic compounds-are long-lasting, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling. However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias. Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog-a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step. In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects. This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.