Nearly 15 years after experts at Johns Hopkins University School of Medicine helped to reinvigorate research on the potential therapeutic effects of psychedelic substances, experts have launched the Center for Psychedelic and Consciousness Research, the first of its kind in the United States and the largest in the world.1 The center is fully funded by private donors, including The Steven and Alexandra Cohen Foundation and 4 philanthropists, who altogether contributed $17 million to cover operational expenses for the first 5 years.1  

Initial research on psychedelics that began in the 1950s and 1960s “abruptly ended in the early 1970s in response to unfavorable media coverage, resulting in misperceptions of risk and highly restrictive regulations,” according to the new Center’s website.2 Additionally, psilocybin — the key compound found in “magic mushrooms” and a main area of focus in psychedelics studies — was classified as a schedule I drug during the Nixon administration. However, researchers have subsequently demonstrated relatively low abuse potential and toxicity associated with the agent.1

After obtaining regulatory approval in 2000 to reinitiate psychedelics studies, Johns Hopkins researchers published a landmark double-blind study in Psychopharmacology in 2006 showing positive, sustained effects of psilocybin on the attitudes and behavior of healthy volunteers.1,3 The study also demonstrated the safety of the substance when administered under well-controlled conditions.3 This “sparked a renewal of psychedelic research worldwide,” according to a press release announcing the new center.1 In the aftermath, a sizable body of research has demonstrated therapeutic benefits of psilocybin and other psychedelic substances, including ketamine, lysergic acid diethylamide (LSD), 3,4-methylenedioxy-methamphetamine (MDMA), ayahuasca, and ibogaine, some of which have long been used by indigenous cultures in medicine and spiritual practices.4,5

Overall, results thus far support the efficacy of psychedelics in a wide range of conditions and populations, typically in combination with psychotherapy. For example, an open-label trial published in 2018 in Psychopharmacology examined the effects of psilocybin on treatment-resistant depression in 20 patients (6 female). Patients received 2 doses (10 and 25 mg) of the drug 7 days apart, along with psychological support at each session.6

At weeks 1 and 5, significant reductions in depressive symptoms were noted (Cohen d = 2.2 and 2.3, respectively; both P <.001). Many patients met criteria for response (n = 9) or remission (n = 4) at 5 weeks. In addition, results were sustained for months after the intervention (Cohen d = 1.5 and 1.4 at 3 and 6 months, respectively; both P <.001). No serious adverse events were observed. Several other trials have also found improvements in depressive symptoms following psilocybin-assisted psychotherapy.6

In a randomized, double-blind crossover trial published in 2016 in the Journal of Psychopharmacology, 51 patients with life-threatening cancer were treated with high-dose psilocybin (22 or 30 mg/70 kg) and had substantial reductions in self- and clinician-rated depressed mood, anxiety, and death anxiety, as well as increased quality of life, optimism, and life meaning.7 At 6 months, clinically significant improvement in depressed mood and anxiety were sustained in approximately 80% of patients.

Numerous other studies have demonstrated the efficacy of psilocybin in combination with cognitive behavioral therapy for smoking cessation, psilocybin and LSD for alcohol use disorder, ayahuasca for treatment-resistant depression, ibogaine for opioid dependence, ketamine (alone and as a part of ketamine-assisted psychotherapy) for treatment-resistant depression, and MDMA-assisted psychotherapy for posttraumatic stress disorder and other conditions.8-13

Limitations of psychedelics research include the inability to conduct blinded studies with these agents for both ethical and practical reasons. Thus, participants are aware of whether they have ingested a drug or not.14 Additionally, research is limited by the lack of objective measures of improvement.

“The investigation of hallucinogens as treatments may be endangered by grandiose descriptions of their effects and unquestioning acceptance of their value,” wrote Guy Goodwin, MD, senior research fellow at the University of Oxford, in a 2016 paper.15 He also cautions that the legalization of psychedelics for medical purposes, such as marijuana in many American states, could potentially lead to widespread recreational drug use.

To learn more about the use of psychedelics in psychiatric treatment, Psychiatry Advisor interviewed Matthew W. Johnson, PhD, associate professor of psychiatry and behavioral science at Johns Hopkins, associate director of the new center, and author of nearly 50 scientific manuscripts pertaining to psychedelics.

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Psychiatry Advisor: According to research findings thus far, what are some of the psychiatric disorders for which psychedelics appear to be a promising treatment approach?

Dr Johnson: The most rigorous, advanced-stage evidence is for depression and anxiety treatment in cancer patients. But very promising lower-level initial evidence has been published for other disorders including depression outside of cancer and multiple forms of addiction. The largest modern work on addiction is the work I’ve led using psilocybin for treating tobacco addiction.8

Psychiatry Advisor: What are believed to be the underlying mechanisms in these cases?

Dr Johnson: There are many likely mechanisms and different levels of analysis. Psychologically, several of our studies show that long-term positive outcomes (more likely to quit smoking, less depression, better well-being in healthy people) a half-year or year later are related to the nature of the subjective experience during the psychedelic session, with greater “mystical” content being associated with these better outcomes. Mystical sounds a bit “woo” but is actually a well-validated psychological construct not necessarily related to anything religious or supernatural. One key feature is experiencing a sense of unity — for example, feeling at one with the universe or with the rest of humankind.

At the biological level, we know a lot is happening during drug effects (receptor level and brain network effects), but the real unanswered question which I am currently studying in my randomized smoking study using functional magnetic resonance imaging brain scans is what biological changes, including in brain network dynamics, might mediate long-term response. Changes in connectivity might mediate those longer-term responses. Other candidates — not mutually exclusive — are decreases in neuroinflammation and epigenetic effects.   

Psychiatry Advisor: What are the initial research priorities at the new center?

Dr Johnson: New studies will focus on treating opioid addiction, posttraumatic stress disorder, mood issues in early Alzheimer’s disease, anorexia, mood issues in posttreatment Lyme disease syndrome, dual alcoholism and depression, effects in healthy people in terms of high-dose effects on creativity, and the effects of so-called “microdosing.”

Psychiatry Advisor: What else do you want clinicians to know about the state of this research?

Dr Johnson: It is important to know that we are following the data, that there are risks that are well mitigated in clinical research and in potential nonresearch clinical use if approved, and that it is not ready for approval yet. However, the data are very promising and call for major investments in further research, including by the National Institutes of Health. More information can be found on our website at https://hopkinspsychedelic.org

***

Natalie Gukasyan, MD, psychiatrist and postdoctoral research fellow at Johns Hopkins, and medical director of the new center, added the following clinical considerations and key challenges involved in providing psilocybin-based interventions. She has worked on an ongoing study of psilocybin for depression at Johns Hopkins, as well as their recently launched study of psilocybin for anorexia nervosa.

  • Clinicians should be aware that most ongoing and planned clinical trials of psilocybin for depression and other conditions have strict exclusion criteria surrounding co-occurring disorders as well as family history. There may be a risk of inducing mania or psychosis — though the exact magnitude of this risk is not well-understood — so bipolar or schizophrenia spectrum disorders are typically grounds for exclusion. Having a first-degree relative with bipolar 1 disorder or any psychotic disorder is also a common exclusion criterion. Personality disorders, specifically cluster B personality disorders, may also be incompatible with participation. 
  • Another point to understand is that participants in these studies have, for the most part, not been on any serotonergic drugs while receiving the intervention. We know little about the interactions between commonly used serotonergic medications and psychedelics. There is a theoretical risk of serotonin syndrome, though anecdotal evidence and the small body of published work about this suggests that concurrent drugs like selective serotonin reuptake inhibitors and tricyclic antidepressants may actually dampen the response to the drug.
  • A lesser-discussed aspect of this intervention is the psychotherapy that occurs around preparation and follow-up after psilocybin administration. Thus far it has been understood that “set and setting,” (ie, patient assumptions, expectations, environmental factors, and other aspects) play a substantial role in shaping response to the drug. This is obviously a complex and difficult-to-study facet of psychedelic-assisted treatment, but in any case, it seems that at least some aspect of psychotherapy is helpful for longer-term benefits.
  • On a systems level, if psilocybin or other psychedelics become approved for wider use, there may be challenges in delivering this type of treatment within the existing mental health infrastructure. Though benefits from just 1 or 2 doses may have long-lasting effects and could ultimately cut healthcare spending, the intervention could actually have a rather high upfront cost for patients or insurers. For example, participants in our studies work with 2 clinicians who are both present for preparation, dosing days, and follow-up. Meetings can last up to 8 hours, as on dosing days. Additionally, our treatment rooms more closely resemble a comfortable home environment than a medical office or research laboratory, so existing facilities may be inadequate for delivery of care.

References

1. Johns Hopkins Medicine. Johns Hopkins Launches Center for Psychedelic Research [press release]. https://www.hopkinsmedicine.org/news/newsroom/news-releases/johns-hopkins-launches-center-for-psychedelic-research. September 4, 2019. Accessed September 25, 2019.

2. Johns Hopkins Center for Psychedelic & Consciousness Research. About. https://hopkinspsychedelic.org/. Accessed October 21, 2019.

3. Griffiths RR, Richards WA, McCann U, Jesse R. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology (Berl). 2006;187(3):268-283.

4. Schenberg EE. Psychedelic-assisted psychotherapy: a paradigm shift in psychiatric research and development. Front Pharmacol. 2018;9:733.

5. Nichols DE. Psychedelics. Pharmacol Rev. 2016;68(2):264-355.

6. Carhart-Harris RL, Bolstridge M, Day CMJ, et al. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology (Berl). 2018;235(2):399-408.

7. Griffiths RR, Johnson MW, Carducci MA, 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;30(12):1181-1197.

8. Johnson MW, Garcia-Romeu A, Griffiths RR. Long-term follow-up of psilocybin-facilitated smoking cessation. Am J Drug Alcohol Abuse. 2017;43(1):55-60.

9. Garcia-Romeu A, Davis AK, Erowid F, Erowid E, Griffiths RR, Johnson MW. Cessation and reduction in alcohol consumption and misuse after psychedelic use [published online May 14, 2019] J Psychopharmacol. doi:10.1177/0269881119845793

10. Palhano-Fontes F, Barreto D, Onias H, et al. Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychol Med. 2019;49(4):655-663.

11. Noller GE, Frampton CM, Yazar-Klosinski B. Ibogaine treatment outcomes for opioid dependence from a twelve-month follow-up observational study. Am J Drug Alcohol Abuse. 2018;44(1):37-46.

12. Dore J, Turnipseed B, Dwyer S, et al. Ketamine assisted psychotherapy (KAP): patient demographics, clinical data and outcomes in three large practices administering ketamine with psychotherapy. J Psychoactive Drugs. 2019;51(2):189-198.

13. Multidisciplinary Association for Psychedelic Studies (MAPS). MDMA-Assisted Psychotherapy Study Protocols. https://maps.org/research/mdma. Accessed September 25, 2019.

14. Carey B. Johns Hopkins Opens New Center for Psychedelic Research. The New York Times. https://www.nytimes.com/2019/09/04/science/psychedelic-drugs-hopkins-depression.html. September 4, 2019. Accessed October 21, 2019.

15. Goodwin GM. Psilocybin: psychotherapy or drug? J Psychopharmacol. 2016;30(12):1201-1202.