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-Ibogaine.

BACKGROUND: Ibogaine is a plant-derived alkaloid that has been used for thousands of years in rites of passage and spiritual ceremonies in West-Central Africa. In the West, it has primarily been used and studied for its anti-addictive properties and more recently for other neuropsychiatric indications, including post-traumatic stress disorder, depression, anxiety, and traumatic brain injury. AREAS OF UNCERTAINTY: Ibogaine requires careful patient screening and monitoring because of significant safety issues. There is potential for cardiotoxicity (prolonged QT interval); without rigorous screening, fatal arrhythmias may occur. However, preliminary research suggests that co-administration of ibogaine with magnesium may mitigate cardiotoxicity. Additionally, ibogaine may have dangerous interactions with opiates, so patients who receive ibogaine treatment for opioid use disorder must withdraw from long-acting opioids. Other potential concerning effects of ibogaine include rare incidences of mania or psychosis. Anticipated transient effects during ibogaine treatment can include ataxia, tremors, and gastrointestinal symptoms. THERAPEUTIC ADVANCES: Robust effects after a single treatment with ibogaine have been reported. In open-label and randomized controlled trials (RCTs), ibogaine reduces heroin and opioid cravings by upwards of 50%, up to 24 weeks after the treatment. An observational study of 30 Special Operations Forces veterans with mild traumatic brain injury reported that 86% were in remission from post-traumatic stress disorder, 83% from depression, and 83% from anxiety, one month after a single-dose ibogaine treatment. LIMITATIONS: Although there are several observational and open-label studies, there is only a single double-blind, placebo-controlled RCT on ibogaine. More RCTs with large sample sizes must be conducted to support ibogaine's safety and efficacy. CONCLUSIONS: Given the promising preliminary findings, ibogaine could potentially fill a much-needed gap in treatments for challenging conditions, including opioid dependence. Ibogaine's remarkable effects in traditionally treatment-resistant, combat-exposed individuals hints at its potential in broader populations with physical and psychological trauma.

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.

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

BACKGROUND: The primary psychoactive drug in magic mushrooms, psilocybin, induces profound alterations in consciousness through the 5-HT2A receptor. This review consolidates current research findings to elucidate the pharmacology, safety profile, and clinical applications of psilocybin. AREAS OF UNCERTAINTY: Despite initial concerns that psilocybin could cause psychosis, contemporary research has demonstrated that psilocybin is generally safe. The most common adverse effects are nausea and headache, yet both tend to be transient. Serious adverse events can generally be avoided in controlled settings such as clinical trials. However, in the largest clinical trial to date, there were a total of 7 reported cases of suicidal ideation, up to 12 weeks after receiving a single 25 mg dose of psilocybin. That being said, all 7 cases did not respond to the treatment. Although selective serotonin reuptake inhibitors may blunt the hallucinogenic qualities of psilocybin, preliminary research suggests that they may enhance its antidepressant effects. THERAPEUTIC ADVANCES: In clinical trials, psilocybin has shown promise for treating major depressive disorder and treatment-resistant depression. Initial studies indicated that 42%-57% of patients underwent remission after psilocybin-assisted therapy, which suggests that psilocybin is more effective than existing antidepressant medications. Clinical data have also demonstrated that psilocybin can manage substance use disorders and end-of-life anxiety with clinical outcomes that are sustained for months and sometimes years after 1 or 2 doses. LIMITATIONS: However, larger Phase II trials with more than 100 depressed participants have shown a much smaller remission rate of 25%-29%, though these studies still observed that psilocybin causes a significant reduction in depressive symptoms. CONCLUSIONS: Aside from ketamine, psilocybin is the most clinically well-researched psychedelic drug, with trials that have enrolled hundreds of participants and multiple therapeutic applications. Phase III trials will determine whether psilocybin lives up to the promise that it showed in previous clinical trials.

Magnesium-ibogaine therapy in veterans with traumatic brain injuries.

Traumatic brain injury (TBI) is a leading cause of disability. Sequelae can include functional impairments and psychiatric syndromes such as post-traumatic stress disorder (PTSD), depression and anxiety. Special Operations Forces (SOF) veterans (SOVs) may be at an elevated risk for these complications, leading some to seek underexplored treatment alternatives such as the oneirogen ibogaine, a plant-derived compound known to interact with multiple neurotransmitter systems that has been studied primarily as a treatment for substance use disorders. Ibogaine has been associated with instances of fatal cardiac arrhythmia, but coadministration of magnesium may mitigate this concern. In the present study, we report a prospective observational study of the Magnesium-Ibogaine: the Stanford Traumatic Injury to the CNS protocol (MISTIC), provided together with complementary treatment modalities, in 30 male SOVs with predominantly mild TBI. We assessed changes in the World Health Organization Disability Assessment Schedule from baseline to immediately (primary outcome) and 1 month (secondary outcome) after treatment. Additional secondary outcomes included changes in PTSD (Clinician-Administered PTSD Scale for DSM-5), depression (Montgomery-Åsberg Depression Rating Scale) and anxiety (Hamilton Anxiety Rating Scale). MISTIC resulted in significant improvements in functioning both immediately (Pcorrected < 0.001, Cohen's d = 0.74) and 1 month (Pcorrected < 0.001, d = 2.20) after treatment and in PTSD (Pcorrected < 0.001, d = 2.54), depression (Pcorrected < 0.001, d = 2.80) and anxiety (Pcorrected < 0.001, d = 2.13) at 1 month after treatment. There were no unexpected or serious adverse events. Controlled clinical trials to assess safety and efficacy are needed to validate these initial open-label findings. ClinicalTrials.gov registration: NCT04313712 .

Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial.

OBJECTIVE: Depression is the leading cause of disability worldwide, and half of patients with depression have treatment-resistant depression. Intermittent theta-burst stimulation (iTBS) is approved by the U.S. Food and Drug Administration for the treatment of treatment-resistant depression but is limited by suboptimal efficacy and a 6-week duration. The authors addressed these limitations by developing a neuroscience-informed accelerated iTBS protocol, Stanford neuromodulation therapy (SNT; previously referred to as Stanford accelerated intelligent neuromodulation therapy, or SAINT). This protocol was associated with a remission rate of ∼90% after 5 days of open-label treatment. Here, the authors report the results of a sham-controlled double-blind trial of SNT for treatment-resistant depression. METHODS: Participants with treatment-resistant depression currently experiencing moderate to severe depressive episodes were randomly assigned to receive active or sham SNT. Resting-state functional MRI was used to individually target the region of the left dorsolateral prefrontal cortex most functionally anticorrelated with the subgenual anterior cingulate cortex. The primary outcome was score on the Montgomery-Åsberg Depression Rating Scale (MADRS) 4 weeks after treatment. RESULTS: At the planned interim analysis, 32 participants with treatment-resistant depression had been enrolled, and 29 participants who continued to meet inclusion criteria received either active (N=14) or sham (N=15) SNT. The mean percent reduction from baseline in MADRS score 4 weeks after treatment was 52.5% in the active treatment group and 11.1% in the sham treatment group. CONCLUSIONS: SNT, a high-dose iTBS protocol with functional-connectivity-guided targeting, was more effective than sham stimulation for treatment-resistant depression. Further trials are needed to determine SNT's durability and to compare it with other treatments.

Multiculturalism: A Challenge for Cognitive Screeners in Parkinson's Disease.

BACKGROUND: The Montreal Cognitive Assessment (MoCA) and the Dementia Rating Scale-2 (DRS-2) are recommended screeners for Parkinson's disease mild cognitive impairment (PD-MCI). Cross-cultural studies examining their diagnostic precision have not addressed cultural bias in a multicultural setting. OBJECTIVES: To compare DRS-2 and MoCA performance between patients born in Canada, the USA, and the UK (Anglosphere group) and immigrant patients born elsewhere (International group). To identify sources of cultural bias by comparing group characteristics, and by assessing the relationships between performance and immigration and socio-development variables. To examine the diagnostic precision of both tools in detecting PD-MCI in each group. METHODS: We conducted a clinical chart review of advanced PD patients who completed cognitive screeners (MoCA: n = 288, 30% International group; DRS-2: n = 426, 31% International group). All completed a comprehensive neuropsychological assessment to apply Level II PD-MCI diagnostic criteria. RESULTS: The International group performed worse than the Anglosphere group on the MoCA and DRS-2, and the only variable that accounted for some of the group difference was the Historical Index of Human Development, a societal variable, which fully mediated the group effect on the DRS-2. Diagnostic precision of the MoCA was at chance level in the International group, and was poorer than that of the DRS-II in this group and that of the MoCA in the Anglosphere group, although these were considered poor. CONCLUSIONS: Our results support the recommendation to exert caution in using cognitive screeners to capture PD-MCI in all patients and particularly with first generation immigrants.

Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression.

OBJECTIVE: New antidepressant treatments are needed that are effective, rapid acting, safe, and tolerable. Intermittent theta-burst stimulation (iTBS) is a noninvasive brain stimulation treatment that has been approved by the U.S. Food and Drug Administration for treatment-resistant depression. Recent methodological advances suggest that the current iTBS protocol might be improved through 1) treating patients with multiple sessions per day at optimally spaced intervals, 2) applying a higher overall pulse dose of stimulation, and 3) precision targeting of the left dorsolateral prefrontal cortex (DLPFC) to subgenual anterior cingulate cortex (sgACC) circuit. The authors examined the feasibility, tolerability, and preliminary efficacy of Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), an accelerated, high-dose resting-state functional connectivity MRI (fcMRI)-guided iTBS protocol for treatment-resistant depression. METHODS: Twenty-two participants with treatment-resistant depression received open-label SAINT. fcMRI was used to individually target the region of the left DLPFC most anticorrelated with sgACC in each participant. Fifty iTBS sessions (1,800 pulses per session, 50-minute intersession interval) were delivered as 10 daily sessions over 5 consecutive days at 90% resting motor threshold (adjusted for cortical depth). Neuropsychological testing was conducted before and after SAINT. RESULTS: One participant withdrew, leaving a sample size of 21. Nineteen of 21 participants (90.5%) met remission criteria (defined as a score <11 on the Montgomery-Åsberg Depression Rating Scale). In the intent-to-treat analysis, 19 of 22 participants (86.4%) met remission criteria. Neuropsychological testing demonstrated no negative cognitive side effects. CONCLUSIONS: SAINT, an accelerated, high-dose, iTBS protocol with fcMRI-guided targeting, was well tolerated and safe. Double-blinded sham-controlled trials are needed to confirm the remission rate observed in this initial study.

HPA axis in psychotic major depression and schizophrenia spectrum disorders: Cortisol, clinical symptomatology, and cognition.

The Hypothalamic Pituitary Adrenal (HPA) axis has been implicated in the pathophysiology of a variety of mood and cognitive disorders. Neuroendocrine studies have demonstrated HPA axis overactivity in major depression, a relationship of HPA axis activity to cognitive performance, and a potential role of HPA axis genetic variation in cognition. In schizophrenia differential HPA activity has been found, including higher rates of non-suppression to dexamethasone challenge and higher salivary cortisol levels, which have been a premonitory risk factor for conversion to psychosis in adolescents at risk for developing schizophrenia. The present study investigated the simultaneous roles HPA axis activity and clinical symptomatology play in poor cognitive performance. Patients with major depression with psychosis (PMD) or schizophrenia spectrum disorder (SCZ) and healthy controls (HC) were studied. All participants underwent a diagnostic interview and psychiatric ratings, a comprehensive neuropsychological battery, and overnight hourly blood sampling for cortisol. Cognitive performance did not differ between the clinical groups, though they both performed more poorly than the HC's across a variety of cognitive domains. Across all subjects, cognitive performance was negatively correlated with higher cortisol, and PMD patients had higher evening cortisol levels than did SCZ and HCs. Cortisol and clinical symptoms, as well as age, sex, and antipsychotic use predicted cognitive performance. Diathesis stress models and their links to symptomatology, cognition, and HPA function are discussed.