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Psychiatric issues continued to take center stage as the world stepped out of the depths of the COVID-19 pandemic. Was progress made, or did we stall? 

™ looked at some of the most pressing topics in psychiatry and mental health care as featured on our covers and asked leaders in the field to be the judge.

What is the most important issue in mental health? In an online 

™ poll, 30.7% of respondents felt that social determinants of mental health (SDOMH) were the top issue of 2022. Notably, SDOMH landed on the first cover of the year and were a focus of discussion during the 2022 American Psychiatric Association (APA) Annual Meeting in May. Have things changed?

, the Royal College of Psychiatrists [United Kingdom] has established a funded component to address the need for better education to address the impact of adverse [SDOMH], and in the US both the professional organizations for pediatrics and family medicine have advocated for urgent and concerted action,” Allan Tasman, MD; and Kenneth Thompson, MD, told 

™ in revisiting the subject. “These make it even more difficult to understand the hesitancy of the APA to do anything substantial on this issue.”

Tasman and Thompson shared that the APA eventually supported the formation of a SDOMH caucus, and the APA Assembly separately formed a SDOMH committee. However, the 2 doctors feel that these initiatives, although important, do not have enough meaningful financial support and must rely on the work of volunteer psychiatrists.

“Lack of attention to the role that adverse 

 play in the etiology and subsequent treatment of psychiatric disorders has led to insufficient change in our treatment outcomes in spite of multiple new medications and psychotherapies,” Tasman and Thompson said.

This topic is sure to remain of utmost importance to mental health care for years to come. Research suggests that addressing poverty, food security/nutrition, neighborhood/community impacts, trauma, and racism has significant positive benefits for children and adolescents

; this may be a good place upon which to build.

, psychedelics, the controversial treatment turning heads, took center stage. On the one hand, clinicians are eager for a promising new treatment. On the other, there is some skepticism about a treatment that has its roots in drugs of abuse. Thus, data are essential in determining psychedelics’ potential place in the psychopharmacological armamentarium.

™ also featured psychedelics among the many session topics at the 2022 Annual 

™ World CME Conference in August. Explained John J. Miller, MD, editor in chief of Psychiatric Times™ and cochair of the meeting, “We were honored to have 2 experts update us on the current status of [the pertinent] trials. 

, presented a detailed overview of psilocybin’s history and current research status. Corine de Boer, MD, PhD, provided a well-needed overview on MDMA [3,4-methylenedioxy-methamphetamine] and how it is being studied in patients with severe 

“Both psilocybin and MDMA are steadily moving forward in phase 2 and 3 FDA registration trials to determine their efficacy and safety for various treatments, especially for conditions with unmet needs such as treatment resistant depression and severe PTSD,” Miller added.

Most recently, a randomized, controlled, double-blind phase 2b study showed that a single 25-mg dose of psilocybin could improve symptoms in patients with treatment-resistant depression.

™ will continue to provide timely, accurate, and comprehensive updates as these 2 drugs move forward in the FDA approval process,” Miller said.

Amid the talk of increasing burnout, how do you care for yourself? Research shows that clinician reluctance to seek mental health care may begin as early as college and medical school, with 25% to 56% of medical students reporting depression and anxiety.

Fortunately, there are those taking a stand and fighting the stigma. In the March issue, Jake Goodman, MD, 

“One year ago, I posted about taking medication for my mental health to millions of people online. As a resident doctor, especially one who treats mental illness, this was extremely taboo. I hope my post was able to move the culture in a healthier and more compassionate direction.

“Today, I am still taking medication for my mental health. I still go to therapy for my mental health. I still have some bad days, but overall my mental health is in a really good place. Seeking treatment for depression was one of the best decisions I’ve ever made. Posting about it on social media, and letting others know that they are not alone, is one of my proudest moments. After that post, I received thousands of messages and comments from people around the world thanking me for making them feel seen and less alone.

“One year later, I’m still Dr Jake. I’m still a resident doctor who treats mental illness, and I still take medication for my mental health. By the way, I’m still proud of it.”

Much like Goodman, approximately 25% of practicing physicians in the US have depression.

 But an anonymous survey found less than half those who reported depressive symptoms sought treatment.

 By being open and honest not just with patients, but with colleagues as well, we can make strides to tamp down stigma in the mental health profession.

Like it or not, thanks to COVID-19, telehealth is here to stay, as we reported in the April issue.

“As a field, we have to now accept that new skill sets have to be developed: one skill set for seeing [patients] in person, and one for virtual. The art of psychiatry will have to evolve to include a distinction of who would benefit from which modality and how/when to switch modalities,” said 

™ Editorial Board Member Nidal Moukaddam, MD, PhD.

The highest rates of telehealth visits were among patients with Medicaid (29.3%) and Medicare (27.4%), Black individuals (26.8%), and those earning less than $25,000 a year (26.7%).

 But is telehealth actually helping underserved communities? Moukaddam has doubts.

“I worry this area may be a mixed bag of findings,” she said. “There [are] also data that indicate individuals with broadband connectivity disparities—only a data plan on their phone, no home internet—cannot fully benefit from virtual services because access is not guaranteed.”

On February 24, 2022, Russia invaded Ukraine, causing a worldwide ripple effect of mental health trauma as Ukrainians chose to seek refuge abroad or stay to defend their home. In September, the United Nations Human Rights Monitoring Mission reported that 14,059 civilians had been killed or injured since the invasion, although numbers are predicted to be much higher.

Peter Kowalski, MD, reported to us from the front lines for the 

. Here is the update he shared exclusively with 

“The horror waged by Russia against Ukraine continues. Ukraine pushed the Russians out of Kherson, the gateway to lands that Russia claims. The president of Ukraine asserted ‘this is the beginning of the end’ of the war. But this war is not over. Putin threatens nukes. Winter is here, and the brutal wind slices through the broken plain. Fuel and food are scarce. Refugees may need to leave their homes again.”

Although some volunteers have moved on, they have not forgotten what they saw in Ukraine. War grinds a people down. This should not be happening in the 21st century. Coordinated mental health care is mandatory after the bullets stop flying. As mental health professionals, we can lend expertise and assistance to help put a shattered country together again,” Kowalski said.

“The world continues to engage in multiple armed conflicts with dire consequences in places like Ukraine, Yemen, Syria, Burma, and the Middle East,” Omar Reda, MD, told 

™. “I refuse to preach despair, though; I remain full of hope and I am a strong believer that humans can hurt and also heal each other… We psychiatrists should strive to be the source of light and hope for everyone around us, starting with those we love, and not forgetting to nurse our own wounds in the process of healing others.”

Valeriia Palii, PhD, president of the National Psychological Association of Ukraine,

™: "Not only will we not break down, but we will also become stronger because the enemy shows its true face every time, destroying everything. People die in hospitals without electricity, schools cannot fully function because it is cold, we cannot cook for ourselves because we depend on resources. But we know that by capitulating, we will live even worse than now."

With young athletes admitting mental fatigue (or worse) during the 2022 Winter Olympics, in Beijing, China, all eyes turned to the field of 

In June, new research indicated the type of sport may affect a child’s mental state. The more intense the sport, the bigger the mental health impact. Hoffmann et al published results on the association between sports participation and mental health difficulties among US youth.

 Although they found that those who participated in team sports had fewer mental health problems than those who did not participate, youth involved with individual sports were more likely to have mental health problems such as increased anxiety, depression, withdrawal, social problems, and attentional problems.

“Unlike in team sports, an athlete who competes in individual sport is constantly faced with the realization that they are solely responsible for success or failure. This can take a toll on one’s mental health, particularly at a young age if one has not yet developed the coping skills to deal with this type of pressure or if one is not receiving the necessary support from others to manage the situation,” Matt D. Hoffmann, PhD, told 

Fortunately, the pleas for help have not gone entirely unanswered. Large athletic groups may be taking the first steps to combat this issue. In October, USA Gymnastics unveiled a new program that expands mental health coverage for athletes and coaches alike. Eight annual mental health provider visits will be covered for eligible national team members, and eligible coaches will be covered for 4 visits. Although the previous program provided mental health services during events such as training camps or meets, the new model will reimburse athletes/coaches up to $125 per visit when they return home.

Three digits had the mental health care community talking this year: 

. The new toll-free dialing code, which routes callers to the National Suicide Prevention Lifeline (now known as the 988 Suicide & Crisis Lifeline) has been active since July. Although there was a lot of trepidation at its rollout, how has it worked so far?

According to data from the US Department of Health and Human Services, there was a 45% increase in overall usage volume and 152,000 more calls, chats, and texts answered compared with August 2021. Furthermore, the average answer speed across all contacts decreased from 2.5 minutes to 42 seconds.

 Despite these increases, data also indicate overall contacts are slowing slightly; phone calls fell by 7% the following month.

 Could this be due to a lack of awareness? Results of a recent survey of 2000 US adults found 56% reported they had heard “nothing at all” about 988.

Adding insult to injury, there have been a few viral social media posts warning not to call 988. Why? Posters listed potential police involvement, involuntary treatment in emergency departments/psychiatric hospitals, and the possible emotional and financial toll.

, at least 12 more school shootings have occurred in the US.

 The violence of school shooters persists, as has the media’s erroneous focus on “psychopathological” shooters.

“There is a common misperception that has been perpetuated by the mainstream media that mental illness is the primary, if not sole, factor in 

. It is a very simplistic way of looking at a complex problem,” Alan D. Blotcky, PhD, exclusively told 

™. “The truth is that mass shootings are a complicated, multifactorial problem that is not easily described or researched, much less understood by the citizenry. What is crystal clear is that very few mass shooters have a major mental illness, such as schizophrenia.”

Blotcky does believe, however, that shooters are more likely to have externalizing disorders (ie, antisocial personality, substance use, and other impulsive and aggressive disorders). According to a 2-stage study from 2021, 10.1% to 24.3% of students met criteria for an externalizing disorder.

 “In my opinion, the obsession with mental illness as the culprit in mass shootings is a way of avoiding the harsh reality that firearms are too plentiful and too easily obtained,” Blotcky added.

Perhaps the bigger discussion should fall on prevention, and some progress has been made. In June 2022, President Joe Biden signed into law the first major gun safety legislation passed in decades, which includes funding for school safety. California, New York, and other states also have passed new laws to regulate untraceable ghost guns and strengthen background checks.

 According to an early 2022 study, such legislation might reduce gun deaths, as states with weaker gun laws had higher rates of homicides, suicides, and accidental killings using a gun.

Overall, the experts seem to agree that psychiatry has made steps toward dealing with the issues in 2022, but more needs to be done. 

™ readers seem to agree, according to results of a recent online survey (

In addition, there are ongoing factors, such as prior authorization and managed care struggles, the debate over how to address incomplete recovery and residual symptoms, and the need for additional resources and clinicians.

We want to hear from you! Was progress made in psychiatry in 2022? What story was most impactful to you?
What are some lingering issues you want to see addressed? Write to us at 

The key social determinants of mental health: their effects among children globally and strategies to address them: a narrative review.

2. Kuntz L. A single dose of psilocybin for treatment-resistant depression. 

https://www.psychiatrictimes.com/view/a-single-dose-of-psilocybin-for-treatment-resistant-depression

A conceptual model of medical student well-being: promoting resilience and preventing burnout.

Professional stigma of mental health issues: physicians are both the cause and solution.

5. Karimi M, Lee EC, Couture SJ, et al. National survey trends in telehealth use in 2021: disparities in utilization and audio vs. video services. Assistant Secretary for Planning and Evaluation; Office of Health Policy. February 1, 2022. Accessed November 8, 2022. 

https://aspe.hhs.gov/sites/default/files/documents/4e1853c0b4885112b2994680a58af9ed/telehealth-hps-ib.pdf

6. Ukraine: more than 14,000 casualties to date but ‘actual numbers are likely considerably higher.’ United Nations. September 9, 2022. Accessed November 8, 2022. 

https://news.un.org/en/story/2022/09/1126391

7. Hoffmann MD, Barnes JD, Tremblay MS, Guerrero MD. 

Associations between organized sport participation and mental health difficulties: data from over 11,000 US children and adolescents.

8. USA Gymnastics expands mental health services for athletes. AP News. October 10, 2022. Accessed November 8, 2022. 

https://apnews.com/article/sports-health-mental-gymnastics-57baecee03219f54c3726e91866cb30c

9. HHS Secretary: 988 transition moves us closer to better serving the crisis care needs of people across America. Substance Abuse and Mental Health Services Administration. September 9, 2022. Accessed November 8, 2022. 

https://www.samhsa.gov/newsroom/press-announcements/20220909/hhs-secretary-988-transition-moves-closer-to-better-serving-crisis-care-needs

10. 988 Lifeline performance metrics. Substance Abuse and Mental Health Services Administration. Updated October 31, 2022. Accessed November 8, 2022. 

https://www.samhsa.gov/find-help/988/performance-metrics

11. Lopes L, Kirzinger A, Sparks G, et al. KFF/CNN Mental Health in America Survey. KFF. October 5, 2022. Accessed November 8, 2022. 

https://www.kff.org/report-section/kff-cnn-mental-health-in-america-survey-findings/

12. Social media posts warn people not to call 988. Here’s what you need to know. NPR. August 25, 2022. Accessed November 8, 2022. 

https://www.npr.org/sections/health-shots/2022/08/11/1116769071/social-media-posts-warn-people-not-to-call-988-heres-what-you-need-to-know

13. School shootings this year: how many and where. EducationWeek. Updated October 31, 2022. Accessed November 8, 2022. 

https://www.edweek.org/leadership/school-shootings-this-year-how-many-and-where/2022/01

14. Norrholm SD, Blotcky AD. Most mass shooters are terrorists, not mentally ill. 

https://www.psychiatrictimes.com/view/most-mass-shooters-are-terrorists-not-mentally-ill

15. Danielson ML, Bitsko RH, Holbrook JR, et al. 

Community-based prevalence of externalizing and internalizing disorders among school-aged children and adolescents in four geographically dispersed school districts in the United States. 

16. Tucker E. These are the gun control laws passed in 2022 so far. CNN. July 30, 2022. Accessed November 8, 2022. 

https://www.cnn.com/2022/07/30/us/gun-control-laws-2022/index.html

17. Gun safety policies save lives. Everytown. Updated January 19, 2022. Accessed November 8, 2022. 

Assessing 2022: What’s the Prognosis in Psychiatry?

 covered a wide variety of psychiatric issues and industry updates, from the unique challenges of treating physician-patients to updates on MDMA and psilocybin research and access. Here are some highlights from the week.

Concurrent Treatment With SRIs and Anticoagulants: Minimizing the Hemorrhagic Hazard

Serotonergic antidepressants (SRIs) are among the most commonly prescribed medications and play important roles in treating depression, anxiety, agitation, and other behavioral syndromes. Data from 2015 to 2018 published by the National Center for Health Statistics show that during those years, 13.2% of adults aged 18 years and over reported using an antidepressant medication within the preceding 30 days. Women aged 60 years and older reported a rate of 24.3%.

The SRIs include selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). Although the SRIs’ adverse effect profiles are milder than those of the earlier tricyclic antidepressants and monoamine oxidase inhibitors, SRI treatment is nonetheless associated with several potentially problematic adverse reactions including effects on sexual function, sleep, appetite, and sodium regulation. Another important adverse effect of SRIs is their association with increased bleeding. Their serotonin reuptake blocking effect not only improves depression through its activity in the brain, but also interferes with normal hemostasis by diminishing platelets’ accumulation of serotonin, which cannot be synthesized by a platelet. 

Senators Introduce New Bill to Promote Research and Access to MDMA, Psilocybin

Senators Cory Booker (D-NJ) and Rand Paul (R-KY) introduced a new bill, the Breakthrough Therapies Act, that would allow the Drug Enforcement Administration to make findings to reclassify MDMA and psilocybin as schedule II drugs. MDMA and psilocybin are currently schedule I substances and have “no currently accepted medical use and a high potential for abuse,” according to the Controlled Substances Act.

“Recent studies suggest that some schedule I substances such as MDMA and psilocybin could represent an enormous advancement for the treatment of severe post-traumatic stress disorder, depression and addiction,” Booker said. “Unfortunately, regulatory red tape and a series of bureaucratic hurdles involved in studying schedule I substances impedes critical research on these and other promising schedule I compounds.” 

“Oh No, My Patient is a Physician!” Hurdles When Treating Physician-Patients

Control is a powerful tool and can affect every aspect of daily life. Within the medical field the term control has its own implications, especially when treating patients. There is an unspoken bond that control is relinquished by the patient and given to the physician in hopes of recovering from the illness. What happens when the physician is the one in need of treatment? What happens when the physician perceives themself as ill and weak?

Physician-patients can be very reluctant to give control of their medical health to another person. The general public is taught from a young age that “the illness belongs to the patient” and that physicians are supposed to be invulnerable. When they are sick, they can be in a world of denial and feel forced to bear the torment of their illness alone. Therefore, physicians may delay seeking medical help; when they do, they may also project their own feelings onto the treating physician, or transference. On the other hand, it is very easy for the treating physicians to project their own feelings onto the physician-patient, or countertransference. 

The Benefits and Limitations of Resilience

After the tragic mass shooting in a LGBTQ+ club in Colorado Springs over the weekend, Nietzsche’s well-known statement takes on tragic proportions. Five were killed, and many more wounded. There will be inevitable traumatic ripples into the wider LGBTQ+ communities, and those who love them.

The goal of trauma recovery will include resilience. Resilience is the ability to bounce back stronger after trauma with the supportive help of community and a vision for the future. That vision, which we have discussed in the last 2 columns, must include less violence and hate toward LGBTQ+ individuals. Generally, resilience is thought to be a positive characteristic, even a panacea for getting through trauma stronger. Yet, like most good things in life, too much resilience may be problematic at times. Why? How could increased psychological strength be a problem? 

. And be sure to stay up-to-date by subscribing to the 

Do you have a comment on any of these or other articles? Have a good idea for an article and want to write? Interested in sharing your perspectives? Write to us at 

From the unique challenges of treating physician-patients to updates on MDMA and psilocybin research and access, here are highlights from the week in Psychiatric Times.

The Week in Review: November 21-25

“Recent studies suggest that some schedule I substances such as MDMA and psilocybin could represent an enormous advancement for the treatment of severe post-traumatic stress disorder, depression and addiction,” Booker said. “Unfortunately, regulatory red tape and a series of bureaucratic hurdles involved in studying schedule I substances impedes critical research on these and other promising schedule I compounds.”

The passage of this legislation could help facilitate a phased roll-out of MDMA and psilocybin via FDA-approved Expanded Access pilot programs. Additionally, it would lessen federal regulations that impede research and development of drugs listed in schedule I.

“I’m proud to co-lead this legislation with Sen. Booker that would streamline the registration process for breakthrough therapies currently restricted by outdated drug classifications,” said Paul. “This bill will make it easier for researchers to conduct studies that can lead to breakthrough therapies to treat patients battling serious and life-threatening conditions.”

Martin R. Steele, a retired Lieutenant General in the United States Marine Corps, Chief Executive Officer of Reason for Hope, and head of the recently formed Veteran Mental Health Leadership Coalition is strongly in favor of the bill’s passage: "We urge Congress to swiftly pass the Breakthrough Therapies Act, which responsibly reduces the barriers to research and limited access of potentially life-saving treatments like MDMA- and psilocybin-assisted therapy,” said Steele. “Veterans should not be forced (nor should anyone else) to leave the country—at great expense—to access breakthrough therapies that can be safely provided and further studied in real-world settings here at home."

1. Booker, Paul introduce bipartisan legislation to promote research and access to potential life saving drugs. Cory Booker. News release. November 17, 2022. Accessed November 22, 2022. 

https://www.booker.senate.gov/news/press/booker-paul-introduce-bipartisan-legislation-to-promote-research-and-access-to-potential-life-saving-drugs

A new bill, the Breakthrough Therapies Act, would encourage the reclassification of MDMA and psilocybin from schedule I to schedule II drugs. 

Senators Introduce New Bill to Promote Research and Access to MDMA, Psilocybin 

The final participant visit is complete in MAPP2, a multi-site phase 3 study of MDMA-assisted therapy (“MDMA-AT”) for posttraumatic stress disorder (PTSD), according to reports.

“The completion of our confirmatory phase 3 study brings us closer to potentially achieving our goal of delivering MDMA-assisted therapy to the millions of Americans with PTSD who are grossly underserved by existing treatment options,” said Amy Emerson, chief executive officer at MAPS Public Benefit Corporation. “This has been a decades-long journey born out of a desire to explore the potential of MDMA-assisted therapy to treat various mental health conditions. Our progress to date would not be possible without the tireless commitment of the investigators, therapists, clinical trial participants and of course MAPS and the thousands of donors who have funded our research to date.”

MAPP2 is the second of 2 phase 3 trials studying MDMA-AT. The study’s protocol was essentially the same as MAPP1 with 2 primary differences: (1) MAPP2 enrolled participants with moderate and severe PTSD, while participants in MAPP1 had severe PTSD, (2) people of color enrolled at double the rate in MAPP2 with the total participants of color representing more than 50% of the total in the study. MAPP2 will be the groundwork for the New Drug Application expected to be submitted to the US Food and Drug Administration (FDA) midway through 2023. The FDA has already granted MDMA-AT Breakthrough Therapy Designation.

MAPP1 examined the safety and efficacy of MDMA-AT versus placebo control in treating individuals with severe PTSD. The results showed that 88% of the participants treated with MDMA-AT had a clinically significant improvement in their PTSD symptoms and 67% no longer qualified for a PTSD diagnosis. Common adverse events included muscle tightness, decreased appetite, nausea, sweating, pupil dilation, and feeling cold. No serious adverse events were reported.

1. MAPS PBC completes second phase 3 “MAPP2” trial of MDMA-assisted therapy for treatment of PTSD. MAPS Public Benefit Corporation. News release. November 17, 2022. Accessed November 18, 2022. 

https://mapspublicbenefit.com/press-releases/mapp2-completion-announcement/

The second of a phase 3 study examining MDMA-AT just completed its final participant visit. 

MDMA-Assisted Therapy for PTSD: Completion of Phase 3 Study 

According to the results of a phase 2b trial of COMP360 psilocybin therapy for treatment-resistant depression (TRD), the largest study of its kind, patients with TRD could see symptom relief after a single dose of psilocybin.

Investigators gathered 233 participants with TRD and gave them either 1 mg, 10 mg, or 25 mg COMP360 psilocybin, in conjunction with psychological support from specially trained therapists. Approximately 30% of participants with TRD in the randomized, controlled, double-blind phase 2b study were in remission at week 3 after a single 25 mg dose of COMP360 psilocybin therapy. The difference between the 25 mg group and 1 mg group was -6.6 on the MADRS depression scale at week 3 (p<0.001).

“Over 100 million people around the world suffer with [TRD], and haven’t found relief from existing therapies. With every new treatment, the chance of responding decreases significantly, and patients become even more hopeless. Yet in this study, a substantial number of patients in the 25mg group experienced improvement in their symptoms of depression, with the effects lasting for up to 3 months,” said Scott Aaronson, MD, Chief Science Officer of the Institute for Advanced Diagnostics and Therapeutics, Sheppard Pratt Health System, and a principal investigator on the trial.

Participants who received a 25 mg dose also had double the sustained response at week 12 (20.3%), as compared with those who received 1 mg (10.1%). COMP360 psilocybin was generally well-tolerated; on the day of administration, common adverse events included headache, nausea, and dizziness.

“We saw positive results in a particularly difficult to treat group of patients, and the highest dose of COMP360 psilocybin had the greatest impact on people’s depression. This suggests that COMP360 psilocybin has a true pharmacological effect, a finding that is critical for it to be recognized as a new treatment option in the future,” said Guy Goodwin, MD, DPhil, Chief Medical Officer at COMPASS Pathways. “We look forward to starting our phase 3 program later this year, moving us closer to providing COMP360 psilocybin with psychological support for patients who desperately need it.”

1. Goodwin GM, Aaronson ST, Alvarez O, et al. 

Single-dose psilocybin for a treatment-resistant episode of major depression.

2. COMPASS Pathways announces publication of phase 2b study of COMP360 psilocybin therapy for treatment-resistant depression in The New England Journal of Medicine. News release. November 3, 2022. Accessed November 4, 2022. 

https://compasspathways.com/compass-pathways-announces-publication-of-phase-2b-study-of-comp360-psilocybin-therapy-for-treatment-resistant-depression-in-the-new-england-journal-of-medicine/

A single dose of psilocybin could help patients with treatment-resistant depression, according to a new study. 

A Single Dose of Psilocybin for Treatment-Resistant Depression

There is a buzz surrounding the potential use of psychedelic drugs as novel treatments in mental health—both for the public and within the scientific community. Although this buzz may be akin to a similar, less regulated boom that occurred in the 1950s and 1960s, 

 have been used for spiritual and folk healing rituals for thousands of years. In particular, the use of naturally occurring compounds such as N,N-dimethyltryptamine (DMT), ibogaine, 

 (“magic mushrooms”), and mescaline have dated to 10,500 BP or earlier, in various locations throughout the world.

 These compounds share similarities in their pharmacologic and psychotropic properties, namely due to their agonistic effects on postsynaptic serotoninergic (5-HT) receptors and consequent hallucinogenic properties. Evidence suggests that the 5-HT2A receptor mediates drug effects, as there is a very strong correlation between receptor affinity and human hallucinogenic potency.

 Together with other synthetically manufactured drugs such as lysergic acid diethylamide (LSD), these substances make up a family of compounds known as classic psychedelics.

Classic psychedelics induce altered states of consciousness that are experienced through visual effects, changes in perception, and distortions in sense of time and space. They can produce a sense of awe and connectedness, as well as personal insights and strong emotions. Research into classic serotonergic psychedelics began in the late 1930s when Albert Hofmann synthesized LSD for use as a cardiorespiratory stimulant only to accidentally ingest it and realize its psychotropic properties.

 This event, coupled with an article by R. Gordon Wasson in Life in 1957 entitled “Seeking the Magic Mushroom,” catapulted 

 into public and scientific awareness. Numerous research studies were carried out over a decade in various patient cohorts including alcohol use disorder, schizophrenia, and depression before the work was abruptly halted. Growing concerns over the mainstream use of psychedelics, their impact on individuals’ health, and the enactment of the Controlled Substances Act in the United States led to an embargo on research.

Although this initial wave of psychedelic research would not hold up to the rigorous scientific methods and ethical policies of today, it has helped inform the development of present-day trials, both positively and negatively. Current protocols involve intensive screening procedures followed by several hours of psychological support provided before, during, and after the dosing session(s). Psychedelic research has increased exponentially over the past 10 years (

), with the market value projected to grow from $2 billion in 2020 to $10.75 billion by 2027.

 Besides 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), classic psychedelics—especially psilocybin—are at the forefront of this growth with increasing interest in their therapeutic potential as fast-acting antidepressants.

 is one of the most common psychiatric illnesses throughout the world, affecting more than 290 million individuals.

 In 2010, it was reported that depressive disorders alone were the second-leading cause of years lived with disability,6 and the rates of diagnosis are expected to increase as the repercussions from the COVID-19 pandemic become more apparent.

 and/or second-generation antipsychotics along with structured psychotherapy. Unfortunately, for some individuals, these options are sometimes ineffective; current medication options can come with undesirable adverse effects (AEs) and high rates of relapse, in addition to delays in therapeutic effects.

More recently, several clinical trials have demonstrated positive response and remission rates for intravenous and intranasal 

, which are thought to produce their antidepressant effects through NMDA receptor antagonism.

 Larger-scale studies with longer follow-up periods and larger, representative sample sizes are needed before any concrete conclusions can be made.

 Finally, neurostimulation treatments including repetitive transcranial magnetic stimulation have emerged with promising results; however, optimal treatment parameters have yet to be determined and accessibility remains a barrier. Thus, psychedelic drugs have experienced a resurgence in interest as a potential treatment for mood disorders.

Depression is characterized by negativity bias, rigid thought patterns, rumination, and cognitive inflexibility. The brain’s default mode network (DMN)—made up of the ventromedial prefrontal cortex, the perigenual anterior cingulate cortex, and the posterior cingulate cortex—is involved in introspection and self-referential thinking. Altered activity, specifically overactivity, of the DMN has been demonstrated in depression

 in addition to hypoconnectivity with other higher- order cognitive networks such as the executive network and the salience network.

Although there is some debate in the field, it is believed that classic psychedelics may exert their effects—at least in part—by disrupting activity in these networks.

 Evidence from ayahuasca and psilocybin imaging studies has demonstrated decreases in activity in key regions of the DMN.

 Connectivity alterations may also be strengthened by the promotion of structural and functional neuronal plasticity.

 Taken together, it is theorized that classic psychedelics exert their effects through differential changes in connectivity, which can result in increased cognitive flexibility and disruptions to maladaptive patterns of thoughts and behavior.

Several trials investigating the use of psilocybin for major depression have been conducted using open-label or wait-list controlled designs.

Results were promising, with rapid and significant antidepressant effects 1 week

 post treatment that were largely sustained at follow-up periods of 3,

; a study found that 58% of participants maintained remission at 12 months.

 Likewise, trials have been conducted in patients in end-of-life care who are experiencing 

 Most AEs reported in the trials were mild and transient, with the most common being a headache following the dosing session.

More recently, a phase 2, double-blind, randomized, controlled trial of escitalopram vs psilocybin-assisted therapy for major depressive disorder (MDD) was conducted.

 Participants randomized to the psilocybin group had 2 dosing sessions separated by 3 weeks, where they received 1 dose of 25 mg of psilocybin at each session and were given placebo pills to take between treatments. Participants in the escitalopram group received 10 to 20 mg of escitalopram administered over 6 weeks. All participants had moderate to severe depression at baseline (mean scores of 14.5 in the psilocybin group and 16.4 in the escitalopram group, as determined by the Quick Inventory of Depressive Symptomatology Self-Report [QIDS-SR-16]).

At the 6-week follow-up, participants in both groups had lower QIDS-SR scores compared with baseline, but the scores did not significantly differ between the escitalopram and 

 groups (difference, –2.0; 95% CI, –5.0 to 0.9; P = .17). Similar results between the groups were seen for response (decrease in score of ≥ 50% from baseline) and remission (score of 0-5 using the QIDS-SR-16) rates. Secondary measures of depression (Beck Depression Inventory, Hamilton Depression Rating Scale, Montgomery-Asberg Depression Rating Scale [MADRS]) favored psilocybin over escitalopram. However, the authors did not correct for multiple comparisons, so these results must be interpreted with caution.

Psilocybin is not the only serotonergic psychedelic being investigated as a potential treatment for depression. The “vine of the souls” plant traditionally found in South America and commonly known as ayahuasca has also demonstrated antidepressant properties in clinical and nonclinical trials.

 In one randomized, controlled trial, patients with treatment-resistant depression who were given a single dose of ayahuasca had significantly lower MADRS scores compared with the placebo group at day 1 (P = .04), day 2 (P = .004), and day 7 (P = .0001) post dose.

 Likewise, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a potent, short-acting psychedelic, and LSD, a serotonergic and dopaminergic partial agonist, have ongoing or completed clinical trials investigating their therapeutic benefits for depression (

Although this evidence demonstrates positive results, the data on efficacy and safety of psychedelics in the treatment of MDD are preliminary and should be considered in the context of several challenges facing the field.

It appears that research into the therapeutic effects of serotonergic psychedelics will grow in the coming years. As more data become available, establishing clear guidelines for psychedelic-assisted psychotherapy (PAP) will be important. Discussions regarding therapist training, burden of cost, accessibility, and participant safety are needed. Psychedelic therapy is resource intensive and necessitates several hours of specialized therapy. Innovative study protocols aimed at reducing cost and resource burdens will be important in facilitating this research into clinical practice, especially in underresourced communities.

Recent studies have found serious AEs to be rare if proper screening, monitoring, and safety protocols are in place. However, increasing attention to these drugs suggests that investigators need to be cautiously aware of how results of clinical trials are communicated to the public. Transparency regarding AEs, rigorous reviews of study data, and critiques from the scientific community should not be overshadowed by positive results.

Expectancy effects also require consideration—previous experience using psychedelics and enthusiasm in the media may predispose study participants to expect positive 

. This issue is further confounded by difficulties in blinding for both participants and therapists. Blinding helps prevent bias and ensures an equal distribution of placebo effects. Current protocols have tried to mitigate these challenges through active placebos or drug comparisons using standard-of-care treatment, but more work is required.

Investigators should also pay special attention to informed consent. It can be difficult to fully prepare someone for a psychedelic experience; it necessitates a thorough consent and preparatory process in which participant boundaries (eg, hand-holding when feeling distressed during the dosing sessions) are established in advance of treatment.

Finally, more research needs to be conducted in participants with diverse ethnic and socioeconomic backgrounds. To date, most studies investigating PAP have been conducted in North America and western Europe with patient cohorts being predominantly white.

 Study samples more representative of the general population need to be a focus in future work.

Psychedelic research is expanding into other areas of psychiatry including 

 (OCD), body dysmorphic disorder, substance use disorders, posttraumatic stress disorder, anorexia nervosa, and binge eating disorder (

). Two exploratory studies have conducted thematic analyses on the psychological effects of and participant perspectives regarding use of ayahuasca for 

 Both studies reported reductions in ED symptoms along with increased self-love and acceptance. There are now several registered trials investigating the use of psilocybin for various EDs (Table). In addition, a preliminary open-label trial assessed the use of psilocybin for the treatment of OCD.

 Although the sample size was small (n = 9), there were marked decreases in OCD symptom severity for all participants. To date, there are 4 registered trials investigating psilocybin for the treatment of OCD (

There has also been a large expansion into addictions research (eg, cocaine, alcohol, opioids). Although psilocybin remains the most-studied agent in substance use disorders, ibogaine is also receiving attention. Ibogaine is an indole alkaloid with dissociative properties that may exert therapeutic benefit for substance use disorders by reducing drug cravings, improving mood, and preventing withdrawal symptoms. Promising case reports and open-label trials in opioid addiction have demonstrated elimination of withdrawal symptoms and anticraving capacities following ibogaine administration.

 There are 3 ongoing trials registered in Spain, Brazil, and the United States to investigate ibogaine treatment in methadone detoxification, opioid withdrawal, and 

Classic psychedelic research is rapidly expanding, and preliminary evidence demonstrates therapeutic potential especially for the treatment of major depression and end-of-life distress. However, the field is facing several ethical and methodological challenges that need to be addressed. Larger, well-designed prospective trials are needed to confirm preliminary evidence for the therapeutic actions of psychedelics in individuals with mood and anxiety disorders, including depression and OCD.

is research coordinator for psychedelic studies in the Centre for Complex Interventions (CCI) at the Centre for Addiction and Mental Health (CAMH) in Canada

is a clinician scientist and lead of the Mood Disorders Service at CAMH, and associate professor of psychiatry at the University of Toronto in Canada.

Classic psychedelic research is rapidly expanding...

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