The potential of 5-methoxy-N,N-dimethyltryptamine in the treatment of alcohol use disorder: A first look at therapeutic mechanisms of action.

Alcohol use disorder (AUD) remains one of the most prevalent psychiatric disorders worldwide with high economic costs. Current treatment options show modest efficacy and relapse rates are high. Furthermore, there are increases in the treatment gap and few new medications have been approved in the past 20 years. Recently, psychedelic-assisted therapy with psilocybin and lysergic acid diethylamide has garnered significant attention in the treatment of AUD. Yet, they require significant amounts of therapist input due to prolonged subjective effects (~4-12 h) leading to high costs and impeding implementation. Accordingly, there is an increasing interest in the rapid and short-acting psychedelic 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). This paper offers a first look at potential therapeutic mechanisms for AUD by reviewing the current literature on 5-MeO-DMT. Primarily, 5-MeO-DMT is able to induce mystical experiences and ego-dissolution together with increases in psychological flexibility and mindfulness. This could decrease AUD symptoms through the alleviation of psychiatric mood-related comorbidities consistent with the negative reinforcement and self-medication paradigms. In addition, preliminary evidence indicates that 5-MeO-DMT modulates neural oscillations that might subserve ego-dissolution (increases in gamma), psychological flexibility and mindfulness (increases in theta), and the reorganization of executive control networks (increases in coherence across frequencies) that could improve emotion regulation and inhibition. Finally, animal studies show that 5-MeO-DMT is characterized by neuroplasticity, anti-inflammation, 5-HT2A receptor agonism, and downregulation of metabotropic glutamate receptor 5 with clinical implications for AUD and psychiatric mood-related comorbidities. The paper concludes with several recommendations for future research to establish the purported therapeutic mechanisms of action.

The Promise of Therapeutic Psilocybin: An Evaluation of the 134 Clinical Trials, 54 Potential Indications, and 0 Marketing Approvals on ClinicalTrials.gov.

Introduction: Psilocybin, a tryptamine psychedelic, has been touted in the media both historically and recently as a potential game-changing mental health therapeutic. ClinicalTrials.gov has over one hundred and thirty psilocybin clinical trials listed covering the last twenty years. The single most important aspect of any therapeutic is to gain approval for marketing and thus enter the real-world phase of development. A typical new chemical entity progresses from inception to US Food and Drug Administration (FDA) approval in approximately 12 years and seeks approval for a single indication. Methods: An observational study was conducted with the available information on the ClinicalTrials.gov site to observe the extent of progress made demonstrating the clinical utility of psilocybin. Results: The results showed 134 psilocybin trials typically unblinded studies of 10-20 participants, recruited over years at a single site. Additionally, there have been only three advanced trials (1 Phase 2/3 and 2 Phase 3) submitted, and only in the last two years. Discussion: The hundreds of psilocybin clinical trials initiated over the past twenty years comprising a myriad of potential indications may actually be slowing this potential game-changing mental health therapeutic agent's approval and is costing excessive amounts of capital. To fully evaluate the actual potential of psilocybin, purposeful clinical trials need to be designed well, executed efficiently, and analyzed utilizing sequential and statistically valid processes for each potential indication. This will require a change from the current exploratory forays to defined, well-funded, sequential pharmaceutical development practices, including adequate and appropriate blinding of studies, statistical design to determine the number of participants and more importantly, professional expertise in conducting multicenter trials. Unfortunately, these results demonstrate little real progress towards FDA approval of psilocybin and a field with no clear direction forward.

The 'PSILAUT' protocol: an experimental medicine study of autistic differences in the function of brain serotonin targets of psilocybin.

BACKGROUND: The underlying neurobiology of the complex autism phenotype remains obscure, although accumulating evidence implicates the serotonin system and especially the 5HT2A receptor. However, previous research has largely relied upon association or correlation studies to link differences in serotonin targets to autism. To directly establish that serotonergic signalling is involved in a candidate brain function our approach is to change it and observe a shift in that function. We will use psilocybin as a pharmacological probe of the serotonin system in vivo. We will directly test the hypothesis that serotonergic targets of psilocybin - principally, but not exclusively, 5HT2A receptor pathways-function differently in autistic and non-autistic adults. METHODS: The 'PSILAUT' "shiftability" study is a case-control study autistic and non-autistic adults. How neural responses 'shift' in response to low doses (2 mg and 5 mg) of psilocybin compared to placebo will be examined using multimodal techniques including functional MRI and EEG. Each participant will attend on up to three separate visits with drug or placebo administration in a double-blind and randomized order. RESULTS: This study will provide the first direct evidence that the serotonin targets of psilocybin function differently in the autistic and non-autistic brain. We will also examine individual differences in serotonin system function. CONCLUSIONS: This work will inform our understanding of the neurobiology of autism as well as decisions about future clinical trials of psilocybin and/or related compounds including stratification approaches. TRIAL REGISTRATION: NCT05651126.

Bio-Psycho-Spiritual Perspectives on Psychedelics: Clinical and Ethical Implications.

Psychedelics have again become a subject of widespread interest, owing to the reinvigoration of research into their traditional uses, possible medical applications, and social implications. As evidence for psychedelics' clinical potential mounts, the field has increasingly focused on searching for mechanisms to explain the effects of psychedelics and therapeutic efficacy of psychedelic-assisted therapy (PAT). This paper reviews three general frameworks that encompass several prominent models for understanding psychedelics' effects-specifically, neurobiological, psychological, and spiritual frameworks. Following our review, the implications of each framework for ethics and professional competencies in the implementation of psychedelics as medicines are explored. We suggest that interdisciplinary education may be necessary to improve communication between researchers, develop models that effectively incorporate multiple levels of analysis, and facilitate collaboration between professionals with diverse backgrounds in the implementation of psychedelic medicines. We also address pitfalls associated with overemphasis on neuro-mechanisms, risks associated with instigating vulnerable states of consciousness, and hurdles associated with the integration of spiritual frameworks in medicine. Ultimately, as psychedelics push the boundaries of explanatory frameworks focused on one level of analysis, developing new and more useful models to reflect knowledge being produced in this field should be a central aim of psychedelic science going forward.

Are Psychedelic Experiences Transformative? Can We Consent to Them?

Psychedelic substances have great promise for the treatment of many conditions, and they are the subject of intensive research. As with other medical treatments, both research and clinical use of psychedelics depend on our ability to ensure informed consent by patients and research participants. However, some have argued that informed consent for psychedelic use may be impossible, because psychedelic experiences can be transformative in the sense articulated by L. A. Paul (2014). For Paul, transformative experiences involve either the acquisition of knowledge that cannot be obtained in any other way or changes in the self. Either of these characteristics may appear to undermine informed consent. This article argues, however, that there is limited evidence that psychedelic experiences are transformative in Paul's sense, and that they may not differ in their transformative features from other common medical experiences for which informed consent is clearly possible. Further, even if psychedelic experiences can be transformative, informed consent is still possible. Because psychedelic experiences are importantly different in several respects from other medical experiences, this article closes with recommendations for how these differences should be reflected in informed consent processes.

Valuing the Acute Subjective Experience.

Psychedelics, including psilocybin, and other consciousness-altering compounds such as 3,4-methylenedioxymethamphetamine (MDMA), currently are being scientifically investigated for their potential therapeutic uses, with a primary focus on measurable outcomes: for example, alleviation of symptoms or increases in self-reported well-being. Accordingly, much recent discussion about the possible value of these substances has turned on estimates of the magnitude and duration of persisting positive effects in comparison to harms. However, many have described the value of a psychedelic experience with little or no reference to such therapeutic benefits, instead seeming to find the experience valuable in its own right. How can we make sense of such testimony? Could a psychedelic experience be valuable even if there were no persisting beneficial effects? If so, how? Using the concept of psychological richness, combined with insights from the philosophy of aesthetics and the enhancement literature, this essay explores potential sources of value in the acute subjective experience, apart from the value derived from persisting beneficial effects.

Psychedelic Therapy: A Primer for Primary Care Clinicians-Historical Perspective and Overview.

BACKGROUND: Psychedelic drugs have recently emerged as plausibly effective pharmacological agents for the management of depression, anxiety, and other neuropsychiatric conditions, including those that are treatment-resistent. The latter half of the 20th century marked a revolution in the treatment of mental illnesses, exemplified by the introduction of selective serotonin reuptake inhibitors and other pharmacological agents. Nevertheless, mental illness remains a major public health crisis, affecting nearly one billion individuals worldwide. AREAS OF UNCERTAINTY: Because of the decades-long status of several psychedelics as Schedule I drugs, there have not been very many large, double-blind, randomized controlled trials of psychedelics. Owing to small sample sizes, there may be rare yet serious adverse events that have not been reported in the clinical trials thus far. THERAPEUTIC ADVANCES: Esketamine, a dissociative hallucinogen drug, was approved for the management of major depressive disorder by the Food and Drug Administration in 2019. As of January 2024, two Phase III trials of 3,4-methylenedioxymethamphetamine (MDMA), a synthetic drug that inhibits the serotonin transporter, have been completed; the results indicate that MDMA is superior to existing pharmacological treatments for post-traumatic stress disorder. A phase III trial of psilocybin, a naturally occurring serotonin receptor partial agonist, is currently underway. The following series details the current state of research in psychedelic therapeutics, including lysergic acid diethylamide (LSD), N-N-dimethyltryptamine (DMT) and ayahuasca, psilocybin, ibogaine, MDMA, and ketamine. LIMITATIONS: While initial clinical trials of psychedelics for depression were very promising, trials of psilocybin with larger sample sizes (100+ participants) suggest that its remission rate is 25%-29%. This is about the same as the remission rate of antidepressants, which is roughly 30% according to the landmark STAR*D trial. CONCLUSIONS: Psychedelic drugs and structural derivatives offer a great deal of promise for the management of a wide range of psychiatric morbidities. It is imperative that clinicians become familiar with these novel agents and learn how to integrate psychedelic therapy with the rest of their care through open communication and referral.

Psychedelic Therapy: A Primer for Primary Care Clinicians-Lysergic Acid Diethylamide (LSD).

BACKGROUND: Lysergic acid diethylamide (LSD) is a hallucinogenic agent. In the mid-20th century, it was used to augment psychoanalysis and to treat alcohol use disorder. However, LSD was banned in 1970 in part because of concerns that it could bring about or exacerbate mental illness. Its therapeutic potential remains incompletely understood. AREAS OF UNCERTAINTY: While uncontrolled recreational use of LSD can, in rare instances, lead to long-term psychosis, adverse events in clinical trials of LSD, such as anxiety, headache, and nausea, have almost always been mild and transient. Serious adverse events, such as intense panic, suicidal ideation, and psychosis, were reported in either none or very few of the participants. However, patient selection criteria, optimal dosing strategy, and appropriate clinical follow-up guidelines remain to be established. THERAPEUTIC ADVANCES: Preliminary data suggest that LSD may be effective for the management of alcohol use disorder, anxiety, and depression. In trials of LSD for treating anxiety and depression associated with life-threatening illnesses, 77% of participants demonstrate durable relief at 1 year post-treatment. Top-line data from a large-scale phase IIb trial (n = 198) indicate that 50% of participants experience remission from generalized anxiety disorder after a single 100 µg dose of LSD. According to a meta-analysis of RCTs on LSD from the mid-20th century, single-dose regimens of LSD significantly improve alcohol use disorder (P < 0.0003) with an odds ratio (OR) of 1.96. LIMITATIONS: Only one large-scale clinical trial (>50 participants) has been conducted on LSD in the contemporary era of psychedelic research. Further studies with large sample sizes are needed to explore potential clinical applications. CONCLUSIONS: Preliminary data suggest that LSD may be one of the most potent treatments for anxiety in patients both with and without a life-threatening illness. LSD may also be beneficial for treating depression and substance use disorders.

Psychedelic Therapy: A Primer for Primary Care Clinicians-N,N-Dimethyltryptamine and Ayahuasca.

BACKGROUND: N,N-dimethyltryptamine (DMT) is a naturally occurring serotonergic psychedelic found in natural plants around the globe. As the main psychoactive component in ayahuasca, which also contains monoamine oxidase inhibitors, DMT has been consumed as plant-based brew by indigenous peoples for centuries. Further research is required to delineate the therapeutic utility of DMT. AREAS OF UNCERTAINTY: Although previous research has shown that DMT is synthesized endogenously, it may not be produced at physiologically relevant concentrations. Additionally, the phenomenological similarities between the DMT-induced state and near-death experiences led to the popular hypothesis that endogenous DMT is released during the dying process. However, this hypothesis continues to be debated. Generally, DMT and ayahuasca seem to be physiologically and psychiatrically safe, although ayahuasca is known to cause transient vomiting. THERAPEUTIC ADVANCES: A double-blind, randomized controlled trial showed that, within 1 week, ayahuasca causes remission in 36% of patients with treatment-resistant depression. According to top-line results from a recent phase IIa trial, 57% of patients with major depressive disorder experienced remission 12 weeks after receiving a single intravenous dose of DMT. LIMITATIONS: There has only been a single published double-blind randomized controlled trial on ayahuasca and 2 on DMT. All clinical trials have had small sample sizes (≤34 participants). DMT requires further research to understand its therapeutic and clinical potential as a psychedelic. CONCLUSIONS: Preliminary evidence indicates that ayahuasca and DMT may be more effective than existing antidepressants for treating major depressive disorder and treatment-resistant depression.

Psychedelic Therapy: A Primer for Primary Care Clinicians-3,4-Methylenedioxy-methamphetamine (MDMA).

BACKGROUND: After becoming notorious for its use as a party drug in the 1980s, 3,4-methylenedioxy-methampetamine (MDMA), also known by its street names "molly" and "ecstasy," has emerged as a powerful treatment for post-traumatic stress disorder (PTSD). AREAS OF UNCERTAINTY: There are extensive data about the risk profile of MDMA. However, the literature is significantly biased. Animal models demonstrating neurotoxic or adverse effects used doses well beyond the range that would be expected in humans (up to 40 mg/kg in rats compared with roughly 1-2 mg/kg in humans). Furthermore, human samples often comprise recreational users who took other substances in addition to MDMA, in uncontrolled settings. THERAPEUTIC ADVANCES: Phase III clinical trials led by the Multidisciplinary Association for Psychedelic Studies (MAPS) have shown that MDMA-assisted psychotherapy has an effect size of d = 0.7-0.91, up to 2-3 times higher than the effect sizes of existing antidepressant treatments. 67%-71% of patients who undergo MDMA-assisted psychotherapy no longer meet the diagnostic criteria for PTSD within 18 weeks. We also describe other promising applications of MDMA-assisted psychotherapy for treating alcohol use disorder, social anxiety, and other psychiatric conditions. LIMITATIONS: Thus far, almost all clinical trials on MDMA have been sponsored by a single organization, MAPS. More work is needed to determine whether MDMA-assisted therapy is more effective than existing nonpharmacological treatments such as cognitive behavioral therapy. CONCLUSIONS: Phase III trials suggest that MDMA is superior to antidepressant medications for treating PTSD. Now that MAPS has officially requested the Food and Drug Administration to approve MDMA as a treatment for PTSD, legal MDMA-assisted therapy may become available as soon as 2024.

Psychedelic Therapy: A Primer for Primary Care Clinicians-The Strengths, Weaknesses, Opportunities, and Threats of Psychedelic Therapeutics.

The reviews in this special edition have presented a primer on the state of the literature for 7 different psychedelic compounds and their plausible roles in medicine. In a common format underscoring strengths, weakness, opportunities, and threats (SWOT), this article addresses how psychedelic compounds fit into the broader health care landscape for indicated conditions. Historically, psychiatric pathologies have been treated with small-molecule compounds that have limited effect sizes and carry a variety of adverse effect profiles. Psychedelic medicines offer the opportunity to provide more potent and rapidly acting treatments. It is crucial to note that this is an emerging field of medicine, and only one of these compounds (esketamine) is currently Food and Drug Administration-approved for depression. The other compounds discussed are investigational, and this discussion is both imaginative and prospective in nature.

Psychedelic Therapy: A Primer for Primary Care Clinicians-Ketamine.

BACKGROUND: Ketamine, an arylcyclohexylamine dissociative anesthetic agent, has evolved into a versatile therapeutic. It has a rapid-onset, well-understood cardiovascular effects and a favorable safety profile in clinical use. Its enantiomeric compound, esketamine, was approved by the Food and Drug Administration in 2019 for both treatment-resistant depression and major depressive disorder with suicidal ideation. AREAS OF UNCERTAINTY: Research indicates dose-dependent impacts on cognition, particularly affecting episodic and working memory following both acute administration and chronic use, albeit temporarily for the former and potentially persistent for the latter. Alongside acute risks to cardiovascular stability, ketamine use poses potential liver toxicity concerns, especially with prolonged or repeated exposure within short time frames. The drug's association with "ketamine cystitis," characterized by bladder inflammation, adds to its profile of physiological risks. THERAPEUTIC ADVANCES: Data demonstrate a single intravenous infusion of ketamine exhibits antidepressant effects within hours (weighted effect size averages of depression scores (N = 518) following a single 0.5 mg/kg infusion of ketamine is d = 0.96 at 24 hours). Ketamine is also effective at reducing posttraumatic stress disorder (PTSD) symptom severity following repeated infusions (Clinician-Administered PTSD Scale scores: -11.88 points compared with midazolam control). Ketamine also decreased suicidal ideation in emergency settings (Scale for Suicidal Ideation scores: -4.96 compared with midazolam control). Through its opioid-sparing effect, ketamine has revolutionized postoperative pain management by reducing analgesic consumption and enhancing recovery. LIMITATIONS: Many studies indicate that ketamine's therapeutic effects may subside within weeks. Repeated administrations, given multiple times per week, are often required to sustain decreases in suicidality and depressive symptoms. CONCLUSIONS: Ketamine's comprehensive clinical profile, combined with its robust effects on depression, suicidal ideation, PTSD, chronic pain, and other psychiatric conditions, positions it as a substantial contender for transformative therapeutic application.

Effects of psychedelic microdosing versus conventional ADHD medication use on emotion regulation, empathy, and ADHD symptoms in adults with severe ADHD symptoms: A naturalistic prospective comparison study.

Adults with attention-deficit hyperactivity disorder (ADHD) often struggle with emotion regulation (ER), impacting their empathic skills and relationships. ADHD medication might not be as effective for ER issues as for ADHD symptoms. Microdosing (MD) psychedelics has shown promise for ADHD treatment and previous studies reported social-emotional benefits. Two online prospective studies investigated MD effects on ER and empathy in adults with severe ADHD symptoms across three assessments: baseline, two-, and four-week post-initiation. Study 1 examined adults initiating MD on their own (n = 233, n = 64, and n = 44) and found positive effects on ER (cognitive reappraisal and expressive suppression) and aspects of empathy (perspective-taking and personal distress). Study 2, including a control group and an ADHD symptom scale, compared individuals only MD (n = 180, n = 50, and n = 38) to individuals using conventional ADHD medication (n = 37, n = 27, and n = 28). After 4 weeks, ADHD symptoms were lower in the MD group. Only improvements in expressive suppression persisted after adding the control group. This study indicates the positive effects of MD psychedelics on ADHD symptoms and ER in adults with severe ADHD symptoms while lacking evidence for effects on empathy.

Associations between cannabis policies and state-level specialty cannabis use disorder treatment in the United States, 2004-2019.

BACKGROUND: Cannabis use disorder (CUD) treatment prevalence decreased in the US between 2002 and 2019, yet structural mechanisms for this decrease are poorly understood. We tested associations between cannabis laws becoming effective and self-reported CUD treatment. METHODS: Restricted-use 2004-2019 National Surveys on Drug Use and Health included people ages 12+ classified as needing CUD treatment (i.e., past-year DSM-5-proxy CUD or last/current specialty treatment for cannabis). Time-varying indicators of medical cannabis laws (MCL) with/without cannabis dispensary provisions differentiated state-years before/after laws using effective dates. Multi-level logistic regressions with random state intercepts estimated individual- and state-adjusted CUD treatment odds by MCLs and model-based changes in specialty CUD treatment state-level prevalence. Secondary analyses tested associations between CUD treatment and MCL or recreational cannabis laws (RCL). RESULTS: Using a broad treatment need sample definition in 2004-2014, specialty CUD treatment prevalence decreased by 1.35 (95 % CI = -2.51, -0.18) points after MCL without dispensaries and by 2.15 points (95 % CI = -3.29, -1.00) after MCL with dispensaries provisions became effective, compared to before MCL. Among people with CUD in 2004-2014, specialty treatment decreased only in MCL states with dispensary provisions (aPD = -0.91, 95 % CI = -1.68, -0.13). MCL were not associated with CUD treatment use in 2015-2019. RCL were associated with lower CUD treatment among people classified as needing CUD treatment, but not among people with past-year CUD. CONCLUSIONS: Policy-related reductions in specialty CUD treatment were concentrated in states with cannabis dispensary provisions in 2004-2014, but not 2015-2019, and partly driven by reductions among people without past-year CUD. Other mechanisms (e.g., CUD symptom identification, criminal-legal referrals) could contribute to decreasing treatment trends.

Psychedelics for alzheimer's disease-related dementia: Unveiling therapeutic possibilities and pathways.

Psychedelics have traditionally been used for spiritual and recreational purposes, but recent developments in psychotherapy have highlighted their potential as therapeutic agents. These compounds, which act as potent 5-hydroxytryptamine (5HT) agonists, have been recognized for their ability to enhance neural plasticity through the activation of the serotoninergic and glutamatergic systems. However, the implications of these findings for the treatment of neurodegenerative disorders, particularly dementia, have not been fully explored. In recent years, studies have revealed the modulatory and beneficial effects of psychedelics in the context of dementia, specifically Alzheimer's disease (AD)-related dementia, which lacks a definitive cure. Psychedelics such as N,N-dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), and Psilocybin have shown potential in mitigating the effects of this debilitating disease. These compounds not only target neurotransmitter imbalances but also act at the molecular level to modulate signalling pathways in AD, including the brain-derived neurotrophic factor signalling pathway and the subsequent activation of mammalian target of rapamycin and other autophagy regulators. Therefore, the controlled and dose-dependent administration of psychedelics represents a novel therapeutic intervention worth exploring and considering for the development of drugs for the treatment of AD-related dementia. In this article, we critically examined the literature that sheds light on the therapeutic possibilities and pathways of psychedelics for AD-related dementia. While this emerging field of research holds great promise, further studies are necessary to elucidate the long-term safety, efficacy, and optimal treatment protocols. Ultimately, the integration of psychedelics into the current treatment paradigm may provide a transformative approach for addressing the unmet needs of individuals living with AD-related dementia and their caregivers.

Strong Bipartisan Support for Controlled Psilocybin Use as Treatment or Enhancement in a Representative Sample of US Americans: Need for Caution in Public Policy Persists.

The psychedelic psilocybin has shown promise both as treatment for psychiatric conditions and as a means of improving well-being in healthy individuals. In some jurisdictions (e.g., Oregon, USA), psilocybin use for both purposes is or will soon be allowed and yet, public attitudes toward this shift are understudied. We asked a nationally representative sample of 795 US Americans to evaluate the moral status of psilocybin use in an appropriately licensed setting for either treatment of a psychiatric condition or well-being enhancement. Showing strong bipartisan support, participants rated the individual's decision as morally positive in both contexts. These results can inform effective policy-making decisions around supervised psilocybin use, given robust public attitudes as elicited in the context of an innovative regulatory model. We did not explore attitudes to psilocybin use in unsupervised or non-licensed community or social settings.

Psychedelic-assisted therapy for people with gambling disorder?

Gambling disorder is a severe mental health and behavioural problem with harmful consequences, including financial, relationship and mental health problems. The present paper initiates discussion on the use of psychedelics combined with psychotherapeutic support as a potential treatment option for people living with a gambling disorder. Recent studies have shown promising results using psychedelic-assisted therapy (PAT) to treat anxiety, depression, post-traumatic stress disorder, and various substance use disorders. Considering the similarities in the underlying psychosocial and neurobiological mechanisms of gambling disorder and other addictive disorders, the authors suggest that psychedelic-assisted therapy could be effective in treating gambling disorder. The paper also underscores the need for further research into the viability and effectiveness of psychedelic-assisted therapy for gambling disorder.