Psychedelic Therapy for Depression, Anxiety, and Posttraumatic Stress Disorder

Educational Objectives

The goal of this program is to improve diagnosis and management of mood disorders. After hearing and assimilating this program, the clinician will be better able to:

1. Design a program for treating posttraumatic stress disorder with methylenedioxymethamphetamine (MDMA).

2. Select appropriate candidates for treatment of depression with psilocybin.

3. Describe the effects of MDMA and psilocybin on brain activity.

Summary

Background: pre-Columbian civilizations and ancient Greeks used psychedelics such as ergotamine, psilocybin, ayahuasca, and peyote; lysergic acid diethylamide (LSD) synthesized in twentieth century by Hofmann (working for Sandoz Laboratories), who discovered its psychedelic effects in 1940s; Sandoz offered it to psychiatrists interested in exploring its possible usefulness, and research on psychedelic-assisted therapy was performed in 1950s and 1960s; in later 1960s, nonscientific, uncontrolled use increased dramatically, and casualties occurred; societal and governmental concerns led to Controlled Substances Act (1970), with LSD being classified as Schedule I drug; further research with psychedelic drugs was suppressed until recently

New avenues of research: psychedelic drugs are of interest partly because other treatments in psychiatry are inadequate to meet needs; many patients go partially treated or untreated; one topic being explored is whether medication may be effective if given once or twice over short duration rather than daily for long term; another is physiology of recovery from depression; in patients with depression, psilocybin and methylenedioxymethamphetamine (MDMA) have long-lasting effects persisting well beyond their half-lives

Administration and setting: psychedelic drugs not useful alone, but must be given in conjunction with therapy; during 6 to 8 hr of preparatory psychotherapy, patient establishes trust with therapist (often 2 therapists); therapist explores history of trauma or depression and provides psychoeducation about effects of drug and what to expect in drug session; tasks of therapy include forming intentions and addressing expectations; drug session lasts 6 to 10 hr; patient wears eye mask and headphones during session; both therapists remain in room while patient encouraged to direct attention inward; music selected to set emotional tone; results optimal when patient able to trust, “let go,” and be open; patient typically spends night; starting in morning, patient attends several integration sessions with objective of making sense of experience (which may be unsettling) and determining how to incorporate insights gained into day-to-day life

Indications: MDMA-assisted therapy is being investigated for treatment-resistant posttraumatic stress disorder (PTSD); psilocybin is being evaluated as treatment for depression (other conditions being studied as well)

Actions of MDMA: drug belongs to same family as amphetamine and mescaline, but unlike these drugs (which primarily release dopamine and norepinephrine), main action of MDMA is release of presynaptic serotonin; MDMA primarily stimulates serotonin 1A and 2A receptors; drug causes elevated mood and prosocial effects and reduces fear; reduction of fear is key for treatment of PTSD; drug also releases oxytocin and prolactin, which may account for enhanced sense of trust with therapist; network effects — functional magnetic resonance imaging (fMRI) shows that drug reduces blood flow and activity in amygdala (especially right amygdala) and increases blood flow and activity in prefrontal cortex; in patients with PTSD, amygdala likely overactive, detecting threat in response to neutral stimuli; prefrontal cortex and hippocampus contextualize incoming information

MDMA and PTSD: psychotherapy difficult in patients with PTSD, who may become overwhelmed quickly, have trouble tolerating therapy, and shut down; MDMA keeps patient in “optimum arousal” zone for 4 to 5 hr in safe, contained environment, permitting patient to process trauma; phase 2 study — in pooled analysis, patients in MDMA group twice as likely to experience improvement; findings also showed that in placebo group, spending hours with therapists also effective, but less effective than MDMA-assisted therapy

Safety and tolerability: side effects include initial restlessness, muscle tension, and sensation of cold; patients often tired at end of session but feel rested on following day; serious adverse effects not observed when drug used in treatment sessions with well-chosen patients; phase 3 study to evaluate 200 to 300 patients; patients to undergo 3 sessions; participants randomized to 1 of 3 groups (80 mg MDMA plus 40 mg booster given 90 min after start of session; larger dose of 120 mg plus 60 mg; or placebo); niacin may be used in placebo group to create flushing and discomfort; primary end point change in score on Clinician-Administered PTSD Scale

Psilocybin: occurs naturally in Psilocybe mushrooms (synthesized psilocybin is used in clinical trials); psilocybin is prodrug for psilocin, which resembles serotonin; blocking serotonin receptor with ketanserin prevents effect of psilocybin; mechanism of action of psilocybin mainly involves serotonin 2A receptor (but also active at other serotonin receptors); recent research on psilocybin has focused on obsessive-compulsive disorder, depression, addiction to tobacco, alcohol use disorder, and anxiety; successful 2016 studies from New York University and Johns Hopkins University of treating psychiatric symptoms in patients with life-threatening illnesses led to approval of phase 3 trials; in 2011 study on healthy normal patients, more than three-fourths of participants described experience with psilocybin as among most important in their lives, akin to birth of children, getting married, or death of parents; patients often reported spiritual experiences; >1 yr later, greater number of patients rated experience as important

Safety of psilocybin: drug has moderate pressor effect; blood pressure should be monitored; patients with unstable heart disease or aneurysm should not be treated; despite reporting that experience important, patients may also describe it as unpleasant; side effects are dose related; psilocybin not appropriate for patients with history or family history of psychosis

Prediction, entropy, and criticality: prediction — brain makes predictions; this activity is adaptive and protects organism from danger; however, patients with adverse life experiences may adopt maladaptive learning model (making negative predictions); entropy — tendency for things to go from state of order to disorder; may be applied to states of consciousness; highly entropic state associated with high level of change and unpredictability; unlike late psychosis (rigid, low-entropy state), early psychosis may be considered entropic state; other low-entropy states include addiction, depression, and possibly PTSD; criticality — refers to phase shift (point at which things begin to change); objective of giving psilocybin is to bring patient into critical state for 4 to 5 hr, resetting brain to less rigid state

fMRI studies: show that some nonadjacent areas of brain work together; for example, default mode network is active, and task-positive network inactive, when patient introspective, depressed, or ruminative; task-positive network is activated when patient not in introspective state; it may be because of these opposing networks that patients with depression have trouble accomplishing tasks; psilocybin may allow patient to “loosen stability”

Effect of psilocybin on brain activity: serotonin 2A receptors richly expressed in cortical layer 5; these glutaminergic neurons project to inhibitory interneurons; resulting net inhibitory effect causes slowing of electrical oscillation in brain; this slowing of activity affects key connective hubs that encompass posterior and anterior cingulate and thalamus; hubs constrain and route information and create predictability in brain; although psilocybin reduces net activity in connective hubs, it also alters connections so that cross-talk occurs between regions of brain that do not normally communicate; this brief rewiring of brain may reset systems into less rigid state that persists after drug cleared

Analogous ideas from cognitive behavioral therapy: erroneous prediction models can hold entire brain hostage; overweighting of previous experiences prevents brain from taking in new information

Studies: psilocybin may permit cortex to handle new information, reset, and become less rigid; in crossover study that randomized patients to low or high dose of psilocybin, changes on Hamilton Anxiety Rating Scale and Hospital and Anxiety and Depression Scale corroborated this finding; in study that employed niacin as active placebo, 80% of patients experienced clinically significant improvements lasting ≥6 mo; in another (open-label) study, single dose of psilocybin reduced depression significantly for weeks to months; drug appears to be as effective as or more effective than ketamine

Safety concerns with psilocybin: drug should be used only in controlled setting; headaches may occur and hypertension must be monitored; physical discomfort common and must be managed; virtually impossible that drug will be approved for home use; Food and Drug Administration likely to require Risk Evaluation and Mitigation Strategy

Summary: in speaker’s view, psychedelic drug therapy changes patient’s experience of misery; using drug to increase openness to their own experience may allow patients to change their “story” about condition sufficiently to reduce experience of suffering

Readings

Bahji A et al: Efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for posttraumatic stress disorder: A systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 2020 Jan 10;96:109735; Carhart-Harris RL et al: Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology (Berl) 2018 Feb;235(2):399-408; Feduccia AA et al: Breakthrough for trauma treatment: safety and efficacy of MDMA-assisted psychotherapy compared to paroxetine and sertraline. Front Psychiatry 2019 Sep 12;10:650; Griffiths RR et al: Psilocybin-occasioned mystical-type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning and in trait measures of prosocial attitudes and behaviors. J Psychopharmacol 2018 Jan;32(1):49-69; Griffiths RR et al: Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol 2016 Dec;30(12):1181-1197; Johnson MW et al: Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. Pharmacol Ther 2019 May;197:83-102; Ross S et al: Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol 2016 Dec;30(12):1165-1180.

Disclosures

For this program, the following has been disclosed: Mr. Penn reported nothing to disclose. The planning committee reported nothing to disclose. Mr. Penn presents information in his lecture related to off-label or investigational use of a therapy, product, or device. 

Acknowledgements

Mr. Penn was recorded at the 18th Annual Psychopharmacology Update, presented by the University of Cincinnati and the Global Academy for Medical Education, and held October 26, 2019, in Cincinnati, OH. For information on the 19th Annual Psychopharmacology Update, scheduled for October 2020 in Cincinnati, OH, please visit globalacademycme.com. The Audio Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

PS490501

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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