Therapeutic Psychedelics: An Emerging Frontier in Mental Health by Prime/Magellan Rx

CLINICAL

Insights March 2022

THERAPEUTIC PSYCHEDELICS: AN EMERGING FRONTIER IN MENTAL HEALTH

Contents

3 | INTRODUCTION 4 | A BRIEF HISTORY 4 | RENEWED INTEREST 5 | CURRENT STATE OF INDUSTRY Funding Global Research

6 | INFLUENCERS 7 | SUBSTANCE BRIEF Psilocybin 3,4-Methylenedioxymethamphetamine (MDMA) Lysergic Acid Diethylamide (LSD) Cannabis Ketamine Esketamine (Spravato®)

Contributors Caroline Carney, MD, MSc, FAPM, CPHQ Chief Medical Officer, Magellan Health Maryam Tabatabai, PharmD Vice President, Clinical Information, Magellan Rx Management Chera L. Schweitzer Medical Writer, Magellan Rx Management Vanessa Zeilinger, PharmD, BCPS, CPE, AAHIVP Clinical Specialist Pharmacist, Magellan Health

Special thanks to Astha Chopra, Vice President, Magellan Health for her assistance.

INTRODUCTION An estimated 52.9 million adults suffer from mental illness, according to a 2020 survey by the Substance Abuse and Mental Health Services Administration (SAMHSA). This equates to 1 in 5 American adults. Moreover, United States (US) young adults, ages 18 to 25 years old, were reported to have the highest prevalence of mental health illness.1 Conditions such as major depressive disorder (MDD), bipolar disorder, obsessive-compulsive disorder (OCD), and schizophrenia are some of the top sources of disability in the US and worldwide.2 MDD and other mental health disorders can be debilitating and life threatening, with suicide as the second leading cause of death in ages 10 to 34 years.3 Many MDD sufferers have recurring episodes causing significant interruption and impairment to their occupational and social function. The ongoing COVID-19 pandemic has intensified a global mental health crisis with higher incidence of depression, anxiety, post-traumatic stress disorder (PTSD), and suicidal behavior, escalating the need for more effective treatments.4 One in 4 American adults has reported anxiety or depressive symptoms since the pandemic began.5 Despite the availability of multiple pharmacological and nonpharmacological treatment options, approximately 30% of patients with MDD do not respond adequately to traditional antidepressant medications.6 Further, the global cost of treating mental health conditions is expected to reach $6 trillion by 2030. This climate highlights the need for alternative options to treat mental health conditions. Psychedelics, marijuana, and ket-

amine-based compounds are gaining momentum as possible alternatives.

52.9 MILLION ADULTS = 1 IN 5 ADULTS

suffers from mental illness

YOUNG ADULTS AGES 18-25 YEARS were reported to have the highest prevalence of mental health illness

SUICIDE is the second leading cause of death in

10-34 YEAR OLDS

$ 1 IN 4 ADULTS

~30% OF PATIENTS

has reported anxiety or depressive symptoms since the pandemic began

with MDD do not respond adequately to traditional antidepressant medications

global cost of treating mental health conditions is expected to reach

$6 TRILLION BY 2030

A BRIEF HISTORY Psychedelics – hallucinogenic class of psychoactive drugs that activate non-ordinary states of consciousness - are not new and have been used extensively for medicinal purposes by ancient and indigenous cultures for thousands of years.7 In the 1950’s and ‘60s they were widely researched for psychiatric conditions. However, increased recreational use led to governments banning their use and ultimately leading to classification of lysergic acid diethylamide (LSD) and other hallucinogens, under Schedule I of the 1967 Convention on Drugs.8,9 Although these decisions had little effect on recreational use of the substances, the decision made formal clinical research and treatments illegal and created a field for underground study and research outside of the scientific arena, until a recent resurgence in the last decade.

RENEWED INTEREST Gaining momentum since the 1990’s, worldwide psychedelic research is experiencing a renaissance, exploring the potential for therapeutic benefits and neurobiological effects.10 Two pivotal events in 2006 contributed to a renewed interest in psychedelics. • First, the US Supreme Court decision to allow ayahuasca (a psychoactive tea derived from a plant found in the Amazon rain forest) to be imported into the US for religious ceremonies.11 • Second, the publishing of Roland Griffiths’ paper in Psychopharmacology after conducting a landmark study at Johns Hopkins: “Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance.” This marked the first double-blind, placebo-controlled clinical trial in over 40 years.12 A notable trend supporting the need to look at alternative treatments is the impact of the opioid epidemic. Between 1999 to 2019, nearly 500,000 people have died due to an opioid overdose. Opioid prescriptions for chronic pain began to increase in the 1990’s, leading to an increase in overdoses by the end of the decade. This trend was followed by large increases in heroin overdoses beginning in 2010 and sharp increases in synthetic opioid overdoses beginning in 2013.13 Opioids have traditionally been prescribed for post-operative pain and chronic pain associated with cancer. Studies show opioids’ highly addictive properties. One in 4 patients receiving long-term opioid therapy may become addicted. In addition to the risk of abuse, addiction and overdose, there are a host of adverse effects, as well as potential for tolerance to the drug.14 Psychedelics have been proposed as an alternative treatment and are currently being studied for pain management. Some examples of studies include psilocybin as a treatment for chronic pain associated with fibromyalgia, psilocybin for the treatment of migraine headaches, and efficacy of LSD for the treatment of cluster headaches.15, 16, 17, 18

1950’s 1960’s Psychedelics widely researched for psychiatric conditions

4 MAGELLANRX.COM

1967 Classified under Schedule 1 of the Convention on Drugs

1990’s Research begins experiencing a renaissance Opioid prescriptions began increasing leading to overdoses

CURRENT STATE OF INDUSTRY Funding

Profit and not-for-profit organizations are supporting research to rigorously test the safety and efficacy of hallucinogens for the treatment of multiple mental health illnesses and to further understand the mechanism of action (MOA) of psychedelic substances. A recent National Institute on Drug Abuse (NIDA) grant awarded to Johns Hopkins to study psilocybin for tobacco addiction may mark a sea change in federal funding of psychedelics, which until now had been lacking.19 The bulk of studies are investigating ketamine, psilocybin, 3,4-Methylenedioxymethamphetamine (MDMA), LSD, N,N-Dimethyltryptamine (DMT) (a hallucinogenic tryptamine) and cannabis’s therapeutic effect on PTSD and MDD. In addition to psychedelic-assisted psychotherapy, alternative modes of delivery are under investigation, including micro-dosing or low dose psychedelics as well as different formulations.20, 21, 22 Promising early data have encouraged both private and government donor support for further study. In July 2021, the US House of Representatives passed a bill directing the National Institute of Health (NIH) to allocate funding for psychedelic-assisted therapies.23, 24 The New York University (NYU) Center for Psychedelics has dedicated over $10 million in psychedelic research at the NYU Langone Center for Psychedelic Medicine, and the first psychedelic law and policy initiative, Psychedelics Law and Regulation (POPLAR), was launched at Harvard Law School in June 2021.25, 26 Johns Hopkins was the first in the US to restore psychedelic research, founding The Johns Hopkins Center for Psychedelic and Consciousness in 2019 and publishing over 60 peer-reviewed articles.27 This is one of the leading research centers in the US and is currently recruiting for and conducting multiple clinical trials for diseases such as addiction, PTSD, and Alzheimer’s, including multinational trials in collaboration with Imperial College (London), The University of Zurich (Switzerland), University Hospital Basel (Switzerland), Canada, and Israel.28 Global Research

Interest in research and study has also widened around the globe. The Netherlands, where cannabis and “magic truffles” can be purchased freely, is treating patients with psilocybin, and Canada has issued several exemptions for treatment in patients with end-of-life distress.29, 30 The Canadian biotech company, Mydecine Innovations Group has been given government approval through Health Canada to import/export, cultivate, and extract/ isolate mushroom compounds at their Good Manufacturing Practice (GMP)-certified manufacturing facility. They are currently working with Jamaica to import mushrooms into Canada and are supporting genetic research at a mycology lab in Denver, CO.31

2006 US Supreme Court allows ayahuasca for religious ceremonies Roland Griffiths’ paper published

2019 The Johns Hopkins Center for Psychedelic and Consciousness was founded

2021 US House of Representatives passed bill for funding of psychedelic-assisted therapies Psychedelics Law and Regulation (POPLAR), was launched at Harvard Law School

INFLUENCERS The Multidisciplinary Association for Psychedelic Studies (MAPS), the Heffter Research Institute, Johns Hopkins, NYU, University of California, Los Angeles (UCLA) Health, the University of Zurich and the Usona Institute are just some of the research centers, scientists, clinicians and advocacy and education organizations working collaboratively in a global effort to continue the pursuit of psychedelic-assisted psychotherapy and psychedelic research. As support for psychedelic research in psychiatry has steadily gained momentum in the US and globally, education and advocacy organizations such as MAPS, the Psychedelic Medicine Association (PMA), the Beckley Foundation, and the Heffter Research Institute have been working to encourage and promote the legalization of psychedelics for potential prescription medicine use through rigorous scientific research32. Numerous psychedelic research studies are currently in recruitment or active status for psilocybin, ketamine, MDMA, LSD, DMT, and cannabis.33

MAPS, a nonprofit, is leading psychedelic research and advocacy sponsoring multiple phase 2 and 3 trials, including studies for MDMA-assisted psychotherapy focused on PTSD and life-threatening illness-related distress and anxiety.34 MAPS has completed the first of two phase 3 clinical trials for MDMA-assisted psychotherapy for PTSD. Also, an advocate for special populations, including cancer patients, patients suffering from substance abuse disorders and Alzheimer’s patients, MAPS strives for special populations to have access to the potential benefits of psychedelic medicine. PMA, which includes a society of physicians, therapists and healthcare professionals (HCP) provides practitioners education and informational tools in an effort to properly train therapists.35 The Heffter Research Institute supports publications on classic psychedelics.36 Usona Institute, currently recruiting for trials to study psilocybin’s effect on MDD, is working in association with MAPS and Johns Hopkins to explore the benefits of psychedelic-assisted psychotherapy.37

6 MAGELLANRX.COM

SUBSTANCE BRIEF Psychedelics are a class of natural and synthetic compounds that manifest the mind. Users report feelings of a transcendence of space and time, unity, sacredness, and a dissolution of the ego. Experiences vary widely based on the individual and the type of substance used; some even report mystical experiences cultivating creativity and productivity, while others describe negative feelings or flashbacks in what is coined a “bad trip.”38 Further, use has also been described as an entheogen or spiritual experience. While their MOA is not fully understood, psychedelics’ primary effect and target is that of an agonist or partial agonist at the brain’s serotonin 5-HT2A receptors. They also have actions at other serotonin receptors such as 5-HT1A and 5-HT2C receptors where they have agonist or partial agonist activity. While not designated as classical psychedelics, ketamine and esketamine are postulated to exhibit their antidepressant effects through modulation of the neurotransmitter glutamate and N-methyl-D-aspartate (NMDA) receptor antagonism.39 More research is needed to confirm if the hallucinogenic and dissociative effects seen with these agents are due to the same mechanism. Although selective serotonin reuptake inhibitors (SSRIs) and psychedelics share some similarities, it is hypothesized that psychedelics work differently than SSRIs, activating serotonin receptors in a way that creates an emotional release or “reset” in the brain’s processes and leading to longer lasting remission of depressive symptoms that can last weeks or months after one psychedelic treatment in contrast to taking daily antidepressants.40 While marijuana and NMDA products can be addictive, psychedelics have largely not demonstrated to lead to addiction or dependence as they do not induce cravings or an impulse to re-dose once the desired effects have waned. This may be due to the primarily serotonergic properties without a direct effect on the brain’s dopamine receptors.41 Psilocybin

Psilocybin, known as “magic mushrooms” is a psychoactive prodrug of the Psilocybe genus, dating back thousands of years. When ingested, it converts to the active ingredient psilocin, which causes a psychedelic response similar to LSD and mescaline (a hallucinogen derived from the Peyote cactus primarily used in religious rituals).42, 43, 44 Psilocybin has been granted “Breakthrough Therapy” designation by the FDA for TRD and is currently in phase 2 trials for this use. The current hypothesis is psilocybin is safe and effective when administered in a “controlled setting.”45, 46 • MOA: Psilocybin is actively metabolized to psilocin, a serotonin transporter inhibitor and 5-HT2A receptor partial agonist. Binding sites also include 5-HT2C , 5-HT1A , and 5-HT1B receptors, with binding affinities in descending order. • Addictive properties: Researchers at Johns Hopkins University evaluated the abuse potential of medically administered psilocybin and determined that it would be appropriate for a schedule IV classification.47 MDMA

3,4-Methylenedioxymethamphetamine (MDMA), also known as ecstasy or molly, is a synthetic member of the phenylethtlamine drug class. Phenylethylamines naturally occur in mescaline/ peyote. MDMA has been granted FDA’s Breakthrough Therapy designation and is currently in phase 3 trials to evaluate the efficacy of treatment for PTSD, addiction, anorexia, and autism. • MOA: The effects of MDMA are believed to be mediated by a number of mechanisms, including monoamine release, serotonin and norepinephrine transporter reuptake inhibition, monoamine oxidase inhibition, partial agonism of serotonin receptors (5-HT2A , 5-HT1A , and 5-HT2C receptors).48 • Addictive Properties: In a recent phase 3 clinical trial MDMA was not shown to induce or potentiate abuse potential.

LSD

Lysergic acid diethylamide (LSD) is described as a classical hallucinogen. It is synthetically made from lysergic acid found in a fungus called ergot that grows on grains.49 Its psychosensory effects are primarily mediated by the activation of specific sensors in the brain. LSD is an odorless and colorless substance with a slightly bitter taste.50 • MOA: The mechanism by which LSD works is mainly mediated by activation of serotonin receptors (namely 5-HT2A receptors or 5-HT2AR) with modulation of the 5-HT2C and 5-HT1A receptors. The interactions between the receptor activation and the resulting impairment in cognition and induction of hallucinations are still poorly understood.51 • Addictive Properties: Psychological and physiological tolerance has been reported after repeated daily administration of 3 to 7 days. It has not been observed in studies to produce dependence or reinforcing effects. LSD may be misused but has not demonstrated addictive properties.52, 53, 54, 55

Cannabis

Cannabis is not classified as a psychedelic, yet it does not fit neatly into one category. The cannabis Sativa plant, also known as marijuana, has several chemotypes. Cannabinoids are a group of substances found in cannabis. Over 100 cannabinoid compounds have been found in cannabis. The main cannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD).56 THC is the main psychoactive substance in marijuana, therefore some of cannabis’ effects are psychedelic in nature and relevant to the psychedelic landscape.57 CBD is the active ingredient in oral cannabidiol (Epidiolex®), which is FDA-approved for select seizures. CBD is a marijuana derivative; however, it lacks the psychoactive properties commonly associated with THC. • MOA: Cannabis, commonly known as marijuana, is thought to exert its pharmacologic activity via several mechanisms; the first and most studied is a receptor-mediated MOA.58 • Addictive Properties: Physiological dependence may occur in patients on long-term marijuana treatment.

Ketamine CI NHCH3

Ketamine is a dissociative anesthetic that has some hallucinogenic effects. Since the 1970’s, ketamine has been marketed in the US as an injectable, short-acting anesthetic for use in humans and animals. It is approved by the US Food and Drug Administration (FDA) for general anesthesia and procedural sedation. • MOA: Ketamine’s analgesic and anesthetic effects are a result of N-methyl-D-aspartate (NMDA) receptor antagonism (which blocks the excitatory neurotransmitter glutamate) as well as interaction with opioid and cholinergic transmission. Ketamine selectively interrupts association pathways of the brain before producing somatesthetic sensory blockade; ‘dissociative anesthesia’ is induced through inhibition of thalamoneocortical pathways and limbic stimulation. Functional and electrophysiological dissociation between the cortical and limbic systems prevents higher centers from perceiving visual, auditory, or painful stimuli.59 • Addictive Properties: Abuse and misuse have been reported. Recurrent high doses may be tied to memory and/or attention impairment. Individuals with a history of drug abuse or dependence may be at a greater risk. Physical dependence and tolerance have also been reported with prolonged use. Withdrawal symptoms have been reported after the discontinuation of extended and frequent large doses of ketamine.60

8 MAGELLANRX.COM

Esketamine (Spravato) CI

NHMe

In 2019 the FDA approved the S(+) enantiomer of ketamine (esketamine) nasal spray (Spravato) for treatment-resistant depression (TRD) and subsequently to treat depressive symptoms in adults with MDD with acute suicidal ideation or behavior. It is self-administered under HCP supervision and only available at a certified doctor’s office or clinic. • MOA: Esketamine non-selectively blocks the NMDA receptor, which is an ionotropic glutamate receptor. Esketamine is the S-enantiomer of ketamine, which is primarily used for its anesthetic properties. The mechanism by which esketamine exerts its antidepressant effect is unknown; however, the activity on NMDA receptors may be responsible for both the therapeutic and the adverse psychiatric effects of esketamine, including dissociative symptoms and abuse.61 • Addictive Properties: There is a risk for abuse, misuse, and physiological and psychological dependence. Due to the aforementioned and the risks for sedation and dissociation, esketamine is only available through the FDA Risk Evaluation and Mitigation (REMS) program.62

SITE OF CARE As psychedelic-assisted psychotherapy becomes better supported by scientific research, treatment centers are now available in the US. The majority of off-label ketamine treatments are performed in an office or psychedelic-centered treatment settings. This might serve as a model for clinical therapeutic regulatory requirements if psychedelics are approved. Field Trip Health Centers have treatment programs in the US and overseas offering therapist-guided one-on-one or group ketamine sessions.63 Multiple other treatment centers in different states also provide ketamine-assisted psychotherapy and one even provides treatment in the home setting. Mindbloom is an example of a mental health and wellbeing company that partners with clinicians, technologists, and researchers to increase access to science-backed psychedelic medicine treatments. Their team facilitates ketamine-assisted therapy through an online assessment and video consultation before arriving at the patient’s home for a clinician-guided treatment session.64 Psychedelic-assisted psychotherapy follows a traditional framework adhering to the idea of “set and setting.” Patients are to be properly screened, prepared and monitored during sessions. Sessions include elements such as soft lighting, patient-selected music, comfortable or natural surroundings, and compassionate, skilled guides to help facilitate the journey.65 With the growth of telehealth spurred by the pandemic, the burgeoning development of artificial intelligence and wearables, and as different dosage forms and modes of delivery are investigated, the long-term outlook for psychedelic site of care is evolving.

CLINICAL TRIAL EVIDENCE While there are many clinical trials for psychedelics, currently there is a lack of high-quality published studies in the literature; most are in earlier phases of study, open-label or single-blind design, with small numbers of participants. A limited number of randomized controlled clinical trials have recently been conducted for psychedelics and other psychoactive substances such as cannabis and ketamines. A literature search was performed for the aforementioned psychedelics, cannabis, and ketamines. Studies considered most relevant for the analysis included US, phase 3, randomized, controlled trials, published in English with a behavioral health diagnosis. These high-quality studies are summarized below. This is not an all-inclusive list. A small trial that did not meet inclusion criteria (as it was in an earlier phase [phase 2] study), but warrants men tion, is the widely discussed study, “Trial of psilocybin versus escitalopram for depression,” published in The New England Journal of Medicine.66 While the change in depression scores did not differ significantly between the two groups, this trial is notable because it compared a psychedelic (psilocybin) to a traditional standard of care (escitalopram) in a randomized, controlled trial in patients with moderate to severe MDD.

CLINICAL TRIAL EVIDENCE

AUTHOR

TRIAL DESIGN

OBJECTIVE

NUMBER OF PARTICIPANTS

INTERVENTION, FORMULATION & PRIMARY ENDPOINT

RESULTS

ADVERSE EVENTS & SAFETY

CONCLUSION

MDMA Mitchell JM, et al 2021

Phase 3, randomized, double-blind, placebocontrolled, multicenter

To compare the efficacy and safety of MDMAassisted therapy or placebo with therapy in patients with severe PTSD

Modified intent-totreat randomized & blinded, allocated 1:1 to either the MDMAassisted therapy group or the placebo with therapy group Dosage form: compounded capsules Primary Endpoint ClinicianAdministered PTSD Scale for DSM5(CAPS-5)

MDMA was found to attenuate CAPS5 score compared with placebo (p<0.0001, d=0.91)

No increase in AE related to suicidality was observed in the MDMA group. Five participants in the placebo group & 3 participants in the MDMA group reported AE of suicidal ideation, suicidal behavior or self-harm in the context of suicidal ideation. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation

MDMA-assisted therapy was efficacious in individuals with severe PTSD

Did not reach statistical significance with esketamine 84 mg/antidepressant compared with antidepressant/ placebo (least squares [LS] means difference [95% CI]: -3.2 [-6.88 to 0.45]; 2-sided p=0.088)

Safety was similar between esketamine or antidepressant groups and no new dose-related safety concerns were identified

Esketamine 84 mg/ antidepressant was not statistically significant to placebo; therefore the esketamine 56 mg/ antidepressant arm was not evaluated

Continued treatment with esketamine and antidepressant significantly delayed relapse compared with treatment with antidepressant and placebo (patients who achieved stable remission: HR, 0.49; 95% CI, 0.29 to 0.84; p=0.003)

Most commonly reported; dysgeusia, vertigo, dissociation, somnolence, and dizziness and were transient in nature. No new or unexpected safety concern was observed

Continued treatment with esketamine past the initial treatment phase was clinically and statistically significant in preventing relapse

MMRM analysis of the de jure estimand showed a significant difference in treatment arms (n=89 [MDMA n=46], p<0.0001, between-group difference=11.9, 95% CI=6.3 to 17.4, df=71) MMRM sensitivity analysis of the de facto estimand showed a significant difference in treatment arms (n=90, p<0.0001, df=72)

ESKETAMINE Fedgchin M, et al 2019

Phase 3, randomized, double-blind, multicenter

Efficacy and safety of fixed dose esketamine nasal spray combined with a new oral antidepressant in patients with recurrent MDD

346

Randomized (1:1:1) to double-blind nasal spray treatment with either 1 of 2 fixed doses of esketamine (56 or 84 mg) or placebo Dosage form: nasal spray Primary Endpoint Change from baseline to day 28 in the Montgomery-Asberg Depression Rating Scale total score

Daly EJ, et al 2019

Phase 3, randomized, double-blind, multicenter

Assess the efficacy of esketamine nasal spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in TRD

297

Randomized 1:1 to continue esketamine nasal spray or discontinue esketamine treatment and switch to placebo nasal spray, with oral antidepressant treatment continued Dosage form: nasal spray Primary Endpoint Time to relapse was examined in patients who achieved stable remission

10 MAGELLANRX.COM

CLINICAL TRIAL EVIDENCE continued

AUTHOR

TRIAL DESIGN

OBJECTIVE

NUMBER OF PARTICIPANTS

INTERVENTION, FORMULATION & PRIMARY ENDPOINT

RESULTS

ADVERSE EVENTS & SAFETY

CONCLUSION

ESKETAMINE continued Ochs-Ross R, et al 2020

Dong-Jing Fu, et al 2020

Lonescu DF, et al 2021

Phase 3, randomized, double-blind

Phase 3, randomized, double-blind, multicenter

Phase 3, randomized, double-blind, placebocontrolled, multicenter

In patients with TRD & ≥65 years, assess the efficacy and safety of esketamine nasal spray plus a newly initiated oral antidepressant as compared with a newly initiated oral antidepressant and placebo nasal spray

137

Compare esketamine to placebo, each in addition to standard-of-care treatment, for rapidly reducing MDD symptoms, including suicidal ideation

226

Rapid reduction of depressive symptoms in patients with MDD who have active SI with intent

230

Patients were randomized to a new oral antidepressant and flexibly-dosed esketamine or placebo nasal spray Dosage form: nasal spray Primary Endpoint Change in the MADRS from baseline to day 28

Randomized 1:1 to esketamine 84 mg or placebo nasal spray twice-weekly for 4 weeks Dosage form: nasal spray Primary Endpoint Change from baseline to 24 hours post-first change in MADRS total score Randomized 1:1 to 84 mg esketamine nasal spray or matching placebo. Patients selfadministered intranasal drug twice weekly for 4 weeks Dosage form: nasal spray Primary Endpoint Change from baseline to 24 hours post-first dose in MADRS total score

The median unbiased estimate of the difference (95% CI) between the esketamine/ antidepressant and the antidepressant/ placebo group was −3.6 (−7.20 to 0.07); weighted combination test (based on MMRM analyses) z=1.89, two-sided p=0.059

The most common AE in the esketamine or antidepressant group were dizziness, nausea, elevated blood pressure.

Significantly greater improvement with MADRS total score decreased in both groups with greater improvement in esketamine cohort. (leastsquares mean difference [SE]: -3.8 [1.39]; 95% CI, −6.56 to −1.09; 2-sided p=0.006)

Most common were dizziness, dissociation, nausea, headache, increased blood pressure. One patient, treated with esketamine during the double-blind phase, died by suicide during the follow-up phase

Esketamine nasal spray rapidly reduced depressive symptoms. Statistically and clinically significant results

Greater improvement in MADRS total score was observed with esketamine (mean [SD]: -15.7 [11.56]) versus placebo (-12.4 [10.43]), (leastsquares mean difference [SE]: -3.9 [1.39], 95% CI: -6.60, -1.11; 2-sided p=0.006)

Most common AE were dizziness, dissociation, nausea, dysgeusia, somnolence, headache, and paresthesia. No AE of psychosis were reported during treatment. Patients who reported AE potentially related to suicidality during the double-blind treatment phase were balanced between the treatment groups

Treatment with esketamine plus the standard of care led to significantly and clinically greater improvement

No suicide attempts or suicidal behavior were reported. (11.4%) patients in the esketamine or antidepressant and 9/65 (13.8%) in the antidepressant/ placebo group had post-baseline suicidal ideation; none had suicidal ideation at baseline

The results did not reach statistical significance. Adverse events in those over 65 years was similar to younger patients

CLINICAL TRIAL EVIDENCE continued

AUTHOR

TRIAL DESIGN

OBJECTIVE

NUMBER OF PARTICIPANTS

INTERVENTION, FORMULATION & PRIMARY ENDPOINT

RESULTS

ADVERSE EVENTS & SAFETY

CONCLUSION

ESKETAMINE continued Popova V, et al 2019

Phase 3, randomized, double-blind, activecontrolled, multicenter

Compare the efficacy and safety of switching patients with TRD from an ineffective antidepressant to flexibly dosed esketamine nasal spray plus a newly initiated antidepressant or to a newly initiated antidepressant plus placebo nasal spray

AE = Adverse events CAPS-5 = The Clinician-Administered PTSD Scale for DSM-5 CI = Confidence interval df = Degrees of freedom DSM-5 = The Diagnostic and Statistical Manual of Mental Disorders MADRS = Montgomery-Åsberg Depression Rating Scale MMRM = Mixed-Effect Model Repeated Measure (MMRM) mode SD = Standard deviation

12 MAGELLANRX.COM

223

Confirmed nonresponders were randomly assigned to treatment with esketamine nasal spray (56 or 84 mg twice weekly) and an antidepressant or antidepressant and placebo nasal spray Dosage form: nasal spray Primary Endpoint Change from baseline to day 28 in MADRS score

Greater improvement observed among those in the esketamine plus antidepressant arm as compared with the antidepressant plus placebo arm (difference of least square means=−4, SE=1.69, 95% CI=−7.31 to −0.64; p=0.020)

Most common AE were dizziness, dissociation, dysgeusia, vertigo, and nausea. Nine patients experienced one or more AE leading to discontinuation of intranasal study drug during the treatment phase, 7% in the esketamine plus antidepressant arm (single events of anxiety, depression, depressive

Esketamine was statistically significant at day 28 and demonstrated clinical improvement at earlier time points

PIPELINE The following is a list of psychedelics and other psychoactive substances and corresponding clinical trial indications currently in multiple phases of study. This is not an all-inclusive list.67

LSD

MDD, anxiety

MDMA

PTSD, anxiety, social anxiety in autistic adults, chronic noncancer pain

PSYLOCYBIN

TRD, MDD, MDD in cancer patients, alcohol use disorder, anxiety, smoking cessation

CANNABIS

Acute and chronic pain, cancer-related symptoms, ADHD

KETAMINE

MDD, PTSD, TRD, acute and chronic pain, suicidal ideation, depression in cancer patients, autism

REGULATORY TRENDS Although the increased interest and research into psychedelic-assisted therapies grows, research, advocacy, and education organizations understand that arriving in the clinical setting needs to happen with regulations and oversight to ensure safety and appropriate uptake. The FDA is working closely with MAPS and other organizations in an effort to manage the development and application of potential life-saving psychedelic treatments. MAPS was granted FDA’s “Breakthrough Therapy” designation in 2017 for MDMA-assisted psychotherapy for PTSD.68 A final FDA decision could come in 2023. In 2018 the FDA granted Compass Pathways “Breakthrough Therapy” designation for psilocybin-assisted therapy for the treatment of TRD and they are currently conducting a phase 2 trial in 216 participants with TRD in 22 sites in the US and Europe.69 Usona Institute was also granted “Breakthrough Therapy” designation in 2019 for psilocybin-assisted therapy in the treatment of MDD and has launched a phase 2 trial including 80 participants across 7 sites in the US.70 FDA’s “Breakthrough Therapy” designation as defined by the agency, “is for a drug that treats a serious or life-threatening condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies.”71 This designation will allow sponsors to closely work with the FDA as the products are in development. In December 2019, the FDA agreed to a MAPS Expanded Access program for MDMA-assisted psychotherapy for PTSD.72 This allows treatment-resistant patients with life-threatening conditions early access to treatment outside of the phase 3 clinical trial and will be a multisite, open-label, intermediate-size expanded access study under a treatment Investigational New Drug (IND). Earlier in 2019, Israel became the first government to approve a Compassionate Use program for MDMA-assisted psychotherapy for MDMA.73 Oregon, the first state to legalize psilocybin for clinical use in 2020, tasked the Oregon Health Authority (under Oregon Psilocybin Advisory Board guidance) with developing and implementing clinical psilocybin regulations by the end of 2022.74 75 Oregon might serve as a model as state-by-state legalization expands. Ann Arbor, Michigan, decriminalized psychedelic plants and fungi (ayahuasca, ibogaine, mescaline, peyote, psilocybin mushrooms and other substances with hallucinogenic properties) in September of 2020. Seattle, Washington became the largest US city to decriminalize cultivation and sharing of psychedelics (psilocybin mushrooms, ayahuasca, ibogaine and non-peyote-derived mescaline) in October of 2021.76, 77 In the coming wave of possible legalization and FDA approval, FDA oversight is likely to define appropriate use in the areas of drug control, administration and setting along with federal, state and local laws governing their use.

DRUG SCHEDULING The US Drug Enforcement Agency (DEA) categorizes drugs into 5 distinct schedules (Schedule I to V) depending on the drug’s acceptable medical use and the drug’s abuse or dependency potential.78 Schedule I drugs have no currently accepted medical use, a high potential for abuse, and the potential to create severe psychological and/or physical dependence. As the drug schedule changes, so does the abuse potential, with Schedule V drugs having the least abuse potential. 79 DRUG SCHEDULING MDMA

Schedule I

PSYLOCYBIN

Schedule I

LSD

Schedule I

MESCALINE

Schedule I

DMT

Schedule I

CANNABIS*

Schedule I

KETAMINE

Schedule III

ESKETAMINE

Schedule III

*Cannabis is still a DEA Schedule I drug and currently is not FDA approved for the treatment of any condition or disease. A cannabis-derived drug product, Epidiolex (cannabidiol), is an FDA-approved prescription.80 A number of states allow medical marijuana, but it is illegal under federal law.81 In addition, users are not exempt from criminal prosecution depending on state law since it is prohibited at the federal level. State laws and regulations vary greatly.

DRUG LEGISLATION As phase 3 trials continue for psychedelics, legalization for psychedelic-assisted psychotherapy will continue to be a focus for mental health conditions. Specifically, the possible legalization of MDMA and psilocybin which have both shown promising results in early clinical trial reports. California is considering a bill that would decriminalize the use of psilocybin, MDMA, and multiple other psychedelics in group counseling settings.82 A recent development is the draft Cannabis Administration and Opportunity Act (CAOA).83 If legislation is finalized, it would remove cannabis from the schedule as a controlled substance and legalize it at the federal level, while allowing states to determine their own cannabis policies. The COAO signals a change in the public and political view of cannabis. Federal cannabis reform could be the impetus for increased cannabis medical research, improve the social and economic lives of disproportionately impacted populations suffering from unfair discrimination or legal ramifications, and may indicate a positive outlook for therapeutic psychedelic legalization.

NOTABLE MILESTONES

1986 MAPS is founded by Rick Doblin

1967 The 1967 Convention on Drugs classiﬁes LSD and other hallucinogens, under Schedule I

14 MAGELLANRX.COM

1996 California legalizes medical marijuana

2006 US Supreme Court allows importation of ayahuasca as a religious sacrament Roland Griﬃth’s landmark paper is published in Psychopharmacology

2017 MAPS receives FDA “Breakthrough Therapy” designation for MDMA-assisted psychotherapy for PTSD

QUALITY STANDARDS Since cannabis is not legal at the federal level, there is a lack of quality standards. These public standards are essential for safety and to prevent harm to patients and consumers. The United States Pharmacopeia (USP) is providing parameters to support the quality of cannabis for medicinal use, while policymakers develop the regulatory framework for federal legalization.84, 85 And, regardless of whether a psychedelic is naturally or synthetically derived, quality and purity are key to patient safety, GMP guidelines, and scale.

MAGELLAN’S PERSPECTIVE Magellan Health supports fair and balanced reviews for new therapies to the market. We have four primary tenets of practice, including education, evidence-based, safety, and access. Our overarching perspectives for psychedelics are summarized in these four pillars:

Education & awareness provide forward-facing education, awareness, and thought leadership for all stakeholders (payers, providers, patients, pharmacies, policymakers) on a new frontier while addressing the stigma associated with mental health and psychedelics as treatment options

Evidence-based recommendations & coverage

Patient safety

Responsible & sustainable access

prepare for therapeutic psychedelics before they become mainstream, need highquality evidence of treatment eﬀectiveness, and ensure future recommendations and coverage determinations are grounded in the clinical evidence

advocate for patients by encouraging quality and safety standards and processes, good manufacturing practices, as well as reliable delivery methods for any product on the market for medical use of psychedelics and cannabis

engage in dialogue with inﬂuencers regarding supply entering the market being approached in a manner that is responsible from a regulatory and legislative perspective as well as sustainable from a quality and supply chain angle

2019 2018 Compass Pathways receives FDA “Breakthrough Therapy” designation for psilocybin-assisted therapy in the treatment of TRD

Usona Institute receives FDA “Breakthrough Therapy” designation for psilocybin-assisted therapy in the treatment of MDD

FDA approves esketamine (Spravato®) nasal spray for TRD

The Johns Hopkin’s Center for Psychedelic and Consciousness Research is founded

2021 NIDA funds psilocybin study for tobacco cessation

2020 Oregon legalizes psilocybin-assisted psychotherapy for adults in controlled settings

CAOA to decriminalize cannabis is introduced as draft legislation

SUMMARY Psychedelics have a long history of use in ritual and religious ceremonies, as well as plant-based treatment for a variety of physical and mental conditions in ancient cultures. Since the 1990’s the world has seen a marked increase in the interest of psychedelics and their potential in treating mental health conditions using psychedelic-assisted psychotherapy. As mental health condition statistics progressively rise, healthcare professionals continue to look for effective ways to treat patients, specifically treatment-resistant illness. COVID-19 has significantly increased symptoms of anxiety and depressive disorders, further necessitating the need for more effective, safe and tolerable treatments. Ongoing funding and sponsorship continue to grow as profit and non-profit organizations, including US and international research institutions, advocacy and educational groups, universities and private researchers collaborate in their commitment to investigate the safety and efficacy of psychedelics such as psilocybin and MDMA for their potential use in treating mental illness. The FDA has granted “Breakthrough Therapy” designation for the study of psilocybin and MDMA marking further progress towards possible therapeutic use. Moreover, the recent federal funding to NIDA for psychedelic research, represents an inflection point. Movements to decriminalize and legalize psychedelics, as already seen in states like Oregon and California, will likely only extend to other states and local governments if early studies continue to report promising data. Looking ahead, in 2023 MDMA-assisted psychotherapy for PTSD could reach a milestone if MAPS receives FDA approval. Preliminary clinical trial findings suggest psychedelic-assisted psychotherapy can be efficacious in treating mental health disorders such as PTSD, addiction, and MDD, but more robust studies, as well as comparative trials, are needed to evaluate their safety and efficacy and optimal dosing. For psychedelics to become mainstream, they would need to be validated in large-scale randomized controlled trials.

16 MAGELLANRX.COM

References 1. National Institute of Mental Health. Statistics. Available at: https://www.nimh.nih.gov/health/statistics/mental-illness. Accessed January 20, 2022. 2. Mental health disorder statistics. Johns Hopkins Medicine. Available at: https://www.hopkinsmedicine.org/health/wellness-and-prevention/mental-health-disorder-statistics. Accessed September 26, 2021. 3. Suicide. National Institute of Mental Health. Available at: https://www.nimh.nih.gov/health/statistics/suicide. Accessed September 25, 2021. 4. Hossain M, Tasnim S, Sultana A, et al. Epidemiology of mental health problems in COVID-19: a review. F1000Research. 2020; 9:363. doi: 10.12688/ f1000research.24457.1. eCollection 2020. 5. Melillo G. AJMC: Could psychedelics ease mental health toll from COVID-19, other crises? Available at: https://maps.org/news/media/9540-ajmccould-psychedelics-ease-mental-health-toll-from-covid-19,-other-crises. Accessed September 26, 2021. 6. Lonescu D, Rosenbaum J, Alpert J. Pharmacological approaches to the challenge of treatment-resistant depression. Dialogues in Clinical Neuroscience. 2015; 17(2): 111-126. doi: 10.31887/DCNS.2015.17.2/dionescu. 7. Global history of entheogens. Entheo Society of Washington. Available at: https://entheosocietywa.org/resources/history-entheogens/. Accessed September 10, 2021. 8. 1967/1197 (XLII). LSD and similar substances. United Nations. Office on Drugs and Crime. Available at: https://www.unodc.org/unodc/en/Resolutions/resolution_1967-05-16_3.html. Accessed October 26, 2021. 9. Nutt D. Psychedelic drugs – a new era in psychiatry? Dialogues Clin Neurosci. 2019; 21(2); 139-147. doi: 10.31887/DCNS.2019.21.2/dnutt. 10. A brief history of psychedelic psychiatry. Multidisciplinary Association for Psychedelic Studies (MAPS). 2014. Available at: https://maps.org/news/ media/5289-a-brief-history-of-psychedelic-psychiatry. Accessed September 10, 2021. 11. Greenhouse L. Sect allowed to import its hallucinogenic tea. The New York Times. 2006. Available at: https://www.nytimes.com/2006/02/22/politics/sect-allowed-to-import-its-hallucinogenic-tea.html. Accessed September 10, 2021. 12. Griffiths R, Richards W, McCann U, et al. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology. 2006; 187(3): 268-83. doi: 10.1007/s00213-006-0457-5. 13. Opioid data analysis and resources. Centers for Disease Control and Prevention (CDC). Available at: https://www.cdc.gov/opioids/data/analysis-resources.html. Accesses October 19, 2021. 14. Prescription Opioids. Centers for Disease Control and Prevention (CDC). Available at: https://www.cdc.gov/opioids/basics/prescribed.html. Accessed October 19, 2021. 15. U.S. National Library of Medicine. ClinicalTrials.gov. Psilocybin-facilitated treatment for chronic pain. 2021. Available at: https://clinicaltrials.gov/ct2/ show/NCT05068791?term=psilocybin&draw=4&rank=21. Accessed October 19, 2021. 16. U.S. National Library of Medicine. ClinicalTrials.gov. Repeat dosing of psilocybin in migraine headache. 2021. Available at: https://clinicaltrials.gov/ ct2/show/NCT04218539?term=psilocybin&draw=4&rank=25. Accessed October 19, 2021. 17. Farah T. Can psychedelic drugs treat physical pain? Scientific American. 2021. Available at: https://www.scientificamerican.com/article/can-psychedelic-drugs-treat-physical-pain/. Accessed October 19, 2021. 18. U.S. National Library of Medicine. ClinicalTrials.gov. Lysergic acid diethylamide (LSD) as treatment for cluster headache. (LCH). 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT03781128?term=LSD&draw=2&rank=4. Accessed October 19, 2021. 19. NIDA awards grant for research on potential of psilocybin in treating cigarette addiction. October 4, 2021. Available at: https://www.psychedelicnewswire.com/nida-awards-grant-for-research-on-potential-of-psilocybin-in-treating-cigarette-addiction/. Accessed October 14, 2021. 20. Polito V, Stevenson R, Arnone D. A systematic study of microdosing psychedelics. PLoS One. 2019; 14(2). doi: 10.1371/journal.pone.0211023. 21. Feilding, A. The Beckley Foundation brings microdosing under the microscope. Multidisciplinary Association for Psychedelic Studies. 2018. Available at: https://maps.org/news/bulletin/articles/429-maps-bulletin-spring-2018-vol-28-no-1/7267-the-beckley-foundation-brings-microdosing-underthe-microscope-spring-2018. Accessed October 19, 2021. 22. Psilocybin for psychological and existential distress in palliative care. Clinical Trials.gov. Ottawa Hospital Research Institute. 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT04754061?term=microdosing&draw=7&rank=11. Accessed October 15, 2021. 23. H.R. 4502-Labor, Health and Human Services, Education, Agriculture, Rural Development, Energy and Water Development, Financial Services and General Government, Interior, Environment, Military Construction, Veterans Affairs, Transportation, and Housing and Urban Development Appropriations Act, 2022. Congress.gov. 2021. Available at: https://www.congress.gov/bill/117th-congress/house-bill/4502. Accessed October 19, 2021. 24. U.S. House Appropriations Bill signals sea change in psychedelic, cannabis research. Multidisciplinary Association for Psychedelic Studies (MAPS). 2021. Available at: https://maps.org/news/media/9465-u-s-house-appropriations-bill-signals-sea-change-in-psychedelic-cannabis-research. Accessed October 1, 2021. 25. Announcing the project on psychedelics law and regulation (POPLAR) at the petrie-flom center for health law policy, biotechnology, and bioethics at harvard law school. 2021. Available at: https://petrieflom.law.harvard.edu/resources/article/petrie-flom-center-launches-POPLAR. Accessed September 10, 2021. 26. Siebert A. NYU establishes center for psychedelic medicine with $10 million from mindmed, philanthropists. Forbes. 2021. Available at: https:// www.forbes.com/sites/amandasiebert/2021/02/25/nyu-langone-establishes-center-for-psychedelic-medicine-with-10-million-from-mindmed-philanthropists/?sh=665721d72256. Accessed September 10, 2021. 27. Jones H. Johns Hopkins launches center for psychedelic research. HUB. 2019. Available at: https://hub.jhu.edu/2019/09/04/hopkins-launches-psychedelic-center/. Accessed August 25, 2021. 28. Johns Hopkins center for Psychedelic & Consciousness Research. Available at: https://hopkinspsychedelic.org/index/#research. Accessed September 9, 2021.

29. Lee A. The Canadian government is allowing 4 terminally ill patients to use psychedelic mushrooms to help ease their anxiety. CNN. 2020. Available at: https://www.cnn.com/2020/08/06/world/canada-psychedelic-mushrooms-cancer-therapy-trnd/index.html. Accessed on October 1, 2021. 30. Lewis-Healey E. The legal status of psychedelics around the world. Psychedelic Spotlight. 2021. Available at: https://psychedelicspotlight.com/legalstatus-of-psychedelics-around-the-world/. Accessed October 1, 2021. 31. Health Canada approves expansion of Mydecine’s cultivation capabilities for psilocybin producing mushrooms. 2021. GlobeNewswire. Available at: https://www.globenewswire.com/en/news-release/2021/05/25/2235358/0/en/Health-Canada-Approves-Expansion-of-Mydecine-s-Cultivation-Capabilities-for-Psilocybin-Producing-Mushrooms.html. Accessed September 10, 2021. 32. Beckley Foundation. About the foundation. Available at: https://www.beckleyfoundation.org/about/the-foundation/. Accessed September 10, 2021. 33. U.S. National Library of Medicine. Clinical Trials.gov Available at: https://clinicaltrials.gov/. Accessed September 9, 2021. 34. Mission. Multidisciplinary Association for Psychedelic Studies. Available at: https://maps.org/about-maps/mission/. Accessed August 24, 2021. 35. Psychedelic Medicine Association. Available at: https://psychedelicmedicineassociation.org/. Accessed August 24, 2021. 36. Heffter Research Institute. Mission. Available at: https://www.heffter.org/#mission. Accessed August 31, 2021. 37. Major depressive disorder and psilocybin clinical trial. Usona Institute. Available at: https://usonaclinicaltrials.org/major-depressive-disorder-psilocybin-clinical-trial-psil201. Accessed September 10, 2021. 38. Pollan M. How To Change Your Mind. New York, NY. Penguin Press; 2018; 24; 222. 39. Henter ID, de Sousa RT, Zarate CA Jr. Glutamatergic modulators in depression. Harv Rev Psychiatry. 2018;26(6):307-319. doi: 10.1097/ HRP.0000000000000183. 40. Carhart-Harris R, Goodwin M. The therapeutic potential of psychedelic drugs: past present and future. Neuropsychopharmacology. 2017: 42(11); 2105-2113. doi: 10.1038/npp.2017.84. 41. Nichols DE. Psychedelics [published correction appears in Pharmacol Rev. 2016;68(2):356. Pharmacol Rev. 2016;68(2):264-355. doi:10.1124/ pr.115.011478. 42. Mescaline (Peyote). What is mescaline? Drugs.com Available at: https://www.drugs.com/illicit/mescaline.html. Accessed November 1, 2021. 43. Hallucinogens and dissociative drugs research report. Common hallucinogens and dissociative drugs. Classic hallucinogens. National Institute of Health (NIH). National Institute on Drug Abuse. Available at: https://www.drugabuse.gov/publications/research-reports/hallucinogens-dissociative-drugs/what-are-dissociative-drugs. Accessed November 3, 2021. 44. Psilocybin. Chemistry for Life. Available at: https://www.acs.org/content/acs/en/molecule-of-the-week/archive/p/psilocybin.html. Accessed September 13, 2021. Ketamine. Mechanism of Action. Clinical Pharmacology. Available at: https://www.clinicalkey.com/pharmacology/monograph/333?sec=monmech. Accessed September 14, 2021. 45. Rucker J, Young A. Psilocybin: from serendipity to credibility? Frontiers in Psychiatry. 2021. doi: 10.3389/fpsyt.2021.659044. 46. Fuentes J, Fonseca F, Elices M. Therapeutic use of LSD in psychiatry: a systematic review of randomized-controlled clinical trials. Frontiers in Psychiatry. 2020. doi: 10.3389/fpsyt.2019.00943. 47. Johnson M, Griffiths R, Hendricks P, et al. The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act. Neuropharmacology. 2018; 142: 143-166. doi: 10.1016/j.neuropharm.2018.05.012. 48. Young M, Norrholm S, Khoury L, et al. Inhibition of serotonin transporters disrupts the enhancement of fear memory extinction by 3,4-methylenedioxymethamphetamine (MDMA). Psychopharmacology. 2017; 234(19); 2883-28958. doi: 10.1007/s00213-017-4684-8. 49. What is LSD? Drugs.com Available at: https://www.drugs.com/illicit/lsd.html. Accessed November 1, 2021. 50. Drug Fact Sheet. LSD. Drug Enforcement Administration (DEA). Available at: https://www.dea.gov/sites/default/files/2020-06/LSD-2020_0.pdf. Accessed September 13, 2021. 51. Hwang K, Saadabadi A. Lysergic acid diethylamide (LSD). STATPEARLS. 2021. Available at: https://www.ncbi.nlm.nih.gov/books/NBK482407/. Accessed October 22, 2021. 52. Passe T, Halpern J, Stichtenoth D. The pharmacology of lysergic acid diethylamide: a review. CNS Neuroscience & Therapeutics. 2008: 14(4); 295314. doi: 10.1111/j.1755-5949.2008.00059.x. 53. Liechti M. Modern clinical research on LSD. Neuropsychopharmacology. 2017: 42(11); 2114-2127. doi: 10.1038/npp.2017.86. 54. Fantegrossi W, Murnane K, Reissig C. The behavioral pharmacology of hallucinogens. Biochemical Pharmacology. 2008: 75(1); 17-33. doi: 10.1016/j. bcp.2007.07.018. 55. Nichols D. Hallucinogens. Pharmacology & Therapeutics. 2004: 101(2); 131-81. doi: 10.1016/j.pharmthera.2003.11.002. 56. Dilonardo M. CBD vs. thc: what’s the difference? WebMd. 2021. Available at: https://www.webmd.com/pain-management/cbd-thc-difference. Accessed October 14, 2021. 57. Earleywine M, Ueno L, Mian M. et al. Cannibals-induced oceanic boundlessness. Journal of Psychopharmacology. 2021. doi: 10.1177/0269881121997099. 58. Bonini S, Premoli M, Tambaro S, et al. Cannabis sativa: a comprehensive ethnopharmacological review of a medicinal plant with a long history. Journal of Ethnopharmacology. 2018; 222; 300-315. doi: 10.1016/j.jep.2018.09.004. 59. Ketamine. Mechanism of Action. Clinical Pharmacology. Available at: https://www.clinicalkey.com/pharmacology/monograph/333?sec=monmech. Accessed September 14, 2021. 60. Ketalar [package insert]. Chestnut Ridge, NY; Par; August 2020. 61. Esketamine. Mechanism of Action. Clinical Pharmacology. Available at: https://www.clinicalkey.com/pharmacology/monograph/5130?sec=monmech. Accessed September 14, 2021.

18 MAGELLANRX.COM

62. Spravato [package insert]. Titusville, NJ; Janssen; July 2020. 63. Field Trip. Our treatments. Available at: https://www.fieldtriphealth.com/our-treatments. Accessed August 24, 2021. 64. Mindbloom. How it works. Available at: https://www.mindbloom.com/how-mindbloom-works. Accessed September 10, 2021. 65. Byock, I. Taking psychedelics seriously. Journal of Palliative Medicine. 2018: 21(4); 417-421. doi: 10.1089/jpm.2017.0684. 66. Carhart-Harris R, Giribaldi B, Watts R, et.al. Trial of psilocybin versus escitalopram for depression. New England Journal of Medicine. 2021; 384:14021411. doi: 10.1056/NEJMoa2032994. 67. U.S. National Library of Medicine. ClinicalTrials.gov. Available at: https://clinicaltrials.gov. Accessed September 13, 2021. 68. Press Release: FDA grants breakthrough therapy designation for MDMA-assisted psychotherapy for PTSD, agrees on special protocol assessment for phase 3 trials. 2017. Available at: https://maps.org/news/media/6786-press-release-fda-grants-breakthrough-therapy-designation-for-mdma-assisted-psychotherapy-for-ptsd,-agrees-on-special-protocol-assessment-for-phase-3-trials. Accessed September 9, 2021. 69. Treatment Resistant Depression. Compassion Navigating Mental Health Pathways. Available at: https://compasspathways.com/our-research/psilocybin-therapy/clinical-trials/treatment-resistant-depression/. Accessed October 19, 2021. 70. FDA grants Breakthrough Therapy Designation to Usona Institute’s psilocybin program for major depressive disorder. Businesswire. A Berkshire Hathaway Company. Available at: https://www.businesswire.com/news/home/20191122005452/en/FDA-grants-Breakthrough-Therapy-Designation-Usona-Institutes. Accessed October 19, 2021. 71. Frequently asked questions: breakthrough therapies. US Food & Drug Administration. 2021. Available at: https://www.fda.gov/regulatory-information/food-and-drug-administration-safety-and-innovation-act-fdasia/frequently-asked-questions-breakthrough-therapies. Accessed September 9, 2021. 72. Press Release: FDA agrees to expanded access program for MDMA-assisted psychotherapy for PTSD. Multidisciplinary Association for Psychedelic Studies (MAPS). 2020. Available at: https://maps.org/news/media/8008-press-release-fda-agrees-to-expanded-access-program-for-mdma-assistedpsychotherapy-for-ptsd. Accessed on October 1, 2021. 73. Press Release: Israel embraces research on MDMA-assisted psychotherapy for PTSD. Multidisciplinary Association for Psychedelic Studies (MAPS). 2020. Available at: https://maps.org/news/media/8051-press-release-israel-embraces-research-on-mdma-assisted-psychotherapy-for-ptsd. Accessed October 14, 2021. 74. Oregon Psilocybin Services Overview. Oregon Health Authority. Available at: https://www.oregon.gov/oha/PH/PREVENTIONWELLNESS/Pages/Oregon-Psilocybin-Services.aspx. Accessed August 25, 2021. 75. Pearce K. With Oregon’s ballot measure, a path opens for legal medical mushrooms. HUB. 2020. Available at: https://hub.jhu.edu/2020/12/02/ mushrooms-legalization-johnson/. Accessed October 15, 2021. 76. Ann Arbor decriminalizes magic mushrooms, psychedelic plants. AP News. 2020. Available at: https://apnews.com/article/ann-arbor-plants-featuredca-state-wire-mi-state-wire-b0ce69ca0961c150e0f900e8ea4cf432. Accessed October 25, 2021. 77. Adlin B. Seattle becomes largest U.S. city to decriminalize psychedelics. Marijuana Moment. 2021. Available at: https://www.marijuanamoment.net/ seattle-becomes-largest-u-s-city-to-decriminalize-psychedelics/. Accessed October 26, 2021. 78. Drug Scheduling. United States Drug Enforcement Agency (DEA). Available at: https://www.dea.gov/drug-information/drug-scheduling. Accessed on October 15, 2021. 79. Controlled Substances. United States Drug Enforcement Administration (DEA). Available at: https://www.deadiversion.usdoj.gov/schedules/orangebook/c_cs_alpha.pdf. Accessed September 10, 2021. 80. FDA and cannabis: research and drug approval process. U.S. Food & Drug Administration (FDA). 2020. Available at: https://www.fda.gov/newsevents/public-health-focus/fda-and-cannabis-research-and-drug-approval-process. Accessed September 20, 2021. 81. Hansen C, Alas H. Where is marijuana legal? A guide to marijuana legalization. US News & World Report. 2021. Available at: https://www.usnews. com/news/best-states/articles/where-is-marijuana-legal-a-guide-to-marijuana-legalization. Accessed September 10, 2021. 82. California bill would decriminalize psychedelic drugs like acid and magic mushrooms. New York Post. 2021. Available at: https://nypost. com/2021/02/19/california-bill-would-decriminalize-psychedelic-drugs-like-acid-and-magic-mushrooms/. Accessed September 23, 2021. 83. Cannabis Administration & Opportunity Act. Available at: https://www.democrats.senate.gov/imo/media/doc/CAOA%20Detailed%20Summary%20-.pdf. Accessed October 11, 2021. 84. Atkins P. Everything old is new again: Cannabis returns to USP. Cannabis Science and Technology. 2020; 3(5): 17-22. Available at: https://www.cannabissciencetech.com/view/everything-old-new-again-cannabis-returns-usp. Accessed October 19, 2021. 85. Consistent characterization to help ensure quality, protect patients and promote sound research. USP. Available at: https://www.usp.org/dietary-supplements-herbal-medicines/cannabis. Accessed October 14, 2021.

Disclaimer: The content in this publication is not a substitute for professional medical advice. For questions regarding any medical condition or if you need medical advice, please contact your healthcare provider.

Therapeutic Psychedelics: An Emerging Frontier in Mental Health

Articles inside

SUBSTANCE BRIEF

INTRODUCTION

REFERENCES

SUMMARY

INFLUENCERS

CURRENT STATE OF INDUSTRY