PSYCHEDELICS IN TODAY’S MEDICINE

Psychedelic therapies

PSYCHEDELICS

What are psychedelics

“LSD gave me an inner joy an open mindedness, a gratefulness, open eyes and an internal sensitivity for the miracles of creation.” (Albert Hofmann)

“[It’s difficult] trying to find words to describe it… You really need to be a poet!” (Study participant)

These quotes are from LSD discoverer Albert Hofmann and from a person who took the classic psychedelic psilocybin in an  Imperial College study (1). They both describe some of the extraordinary effects of psychedelic experiences. Patients who had used psychedelic substances often describe a fundamental positive change of their attitudes after one or two guided therapy sessions. Therapies involving these substances are said to be a real disruption in the psychiatric field as potentially effective treatments for several mental disorders.

DEFINITION

Classic psychedelics

“Classic” psychedelics are substances that target the same serotonin receptors in the brain. The most known psychedelics are: psilocybin – a psychoactive compound found in ‘magic mushrooms’ and more than 200 other mushroom species, lysergic acid diethylamide [LSD] – the first psychedelic to be approved as medicine in 1949 , mescaline and dimethyltryptamine [DMT], which is also an active compound in ayahuasca – a plant-based brew used in traditional healing ceremonies in some Amazonian tribes.

Psychedelic is a neologism coined in 1953 by psychiatrist Humphrey Osmond from the Greek psyche (mind) and delos (reveal/manifest). Back then, it has primarily referred to the effects of lysergic acid diethylamide (LSD), but today the term is used to describe a range of pharmacologically diverse substances.

(Photo: Albert Hofmann, discoverer of LSD)

MODE OF ACTION

What do psychedelics do in the brain?

Psilocybin and other psychedelics operate by modifying human consciousness in the sense of altered perception of the self and the world. They stimulate neuronal growth, leading to increased psychological flexibility, openness, and the rise of new perspectives. A psychedelic-activated brain becomes more interconnected. Under psychedelics, communication between different neural regions was shown to be intensified (2). In addition, they also inhibit the activity of the Default Mode Network (DMN) a neural network that is activated during rest and passive/mind-wondering activity, and implicated in the perception of the self and the ego. A brain under psychedelic substances tends to be more playful and imaginative, thus readier to face challenging experiences or memories, reacting with more resilience and creativity.

All these effects seem to be essential for psychedelics’ therapeutic action, contributing to psychological and emotional ‘breakthroughs’, especially when administered within a context of psychotherapy (3). Several brain regions are affected by the action of psychedelics and the effects contribute to the emergence of altered states of consciousness, neurological and biological modifications, and a wide range of psychological, cognitive and emotional effects. These can be of spiritual, mystical and even transpersonal nature (4). However, although the research on psychedelics is rapidly growing, the exact therapeutic mechanisms are not yet entirely understood. It is safe so say though that psychedelics need to be administered in a safe therapeutic context which makes it essential to see them as a tool within a psychotherapeutic process – and not as a ‘magic pill’.

PSYCHEDELICS-ASSISTED THERAPY

Treatment of mental disorders

Multiple types of scientific studies report psychedelics-augmented (or assisted) psychotherapy to be a promising treatment for several mental disorders. Yet only psilocybin and MDMA are currently (in 2021) being investigated in ongoing so-called phase III studies which means that the evidence for the following indications is still to be seen as preliminary. Phase III studies lead to an approval of the substances in the health systems if they succeed.

For instance, psychedelic-assisted psychotherapy was found to be effective in phase II studies for anxiety and depression secondary to a life-threatening illness (5), treatment-resistant depression (6, 7, 8) and substance use disorders (SUDs) (9), including alcohol (10) and tobacco (11).

Concerning therapy for opioid-related disorders also the atypical psychedelic ibogaine seems to represent an interesting therapeutic tool (12). These substances showed promising results also in the treatment of obsessive–compulsive disorder (OCD) (13), even suggesting applicability for psychosomatic disorders like functional blindness, aphonia/dysphonia, sensory changes and weakness (14).

MDMA, that is known as ecstasy in recreational users, is not a ‘classic’ psychedelic but an entactogen known for its anxiety-relieving and “heart opening” properties. The effects of MDMA are also promising in the treatment of post-traumatic stress disorder (PTSD) (15) and have shown first results in treating social anxiety in autistic adults (16). Ketamine is also a compound having psychedelic-like properties but is primarily a dissociative anaesthetic. It has shown potential in treating depression, pain, anxiety and OCD, and also reducing suicidal tendencies (17). In the OVID Clinic, we provide ketamine-augmented psychotherapy.

About ketamine

PSYCHEDEDLIC PSYCHOTHERAPY

What is psychedelic-augmented psychotherapy like?

You will come back/ and relate your journey/ and we shall know together/ of where you have gone/ and how you have returned/ taking this journey.” – Phil Wolfson (28)

Psychedelic-assisted psychotherapy includes preparatory psychological screening and motivational preparation with a trained therapist, the dosing session(s), and post-dosing integrative psychotherapy. During the dosing sessions, participants usually lie comfortably on a couch, wearing eyeshades, listening to preselected music, and directing their thoughts toward their internal experience. Given the growing evidence for the unity of body and mind, these substances’ neuro-biological effects are closely interrelated with the psychotherapeutic work and with setting preparation.

A widely-referenced model for the common factors is the contextual model, which posits three primary mechanisms of psychotherapy: the real relationship, the creation of expectations through explanation of disorders and treatments, and the enactment of health promoting actions (29). For some people, psychedelic-assisted psychotherapy seems to enhance the already cited openness to new experience and more complex social emotions like forgiveness and self-compassion. They can increase insights into the self and for many, involve so-called peak or mystical experiences. Besides, even if these experiences trigger challenging phases, these have been shown to be essential for many patients in the transformation of emotional self-regulation and the construction of meaning (30). Indeed, several studies noted correlations between symptom reduction and the appraisals of the psilocybin experiences as personally meaningful (31). This therapeutic meaning enhancement can lead to disidentification from one’s old way of living, promoting a creative restructuring and growing freedom from the symptom’s prison.

STUDIES

What is the current research situation?

Psychedelics are being investigated in several universities in the world  in the treatment of mental disorders. If finally successful in phase III studies, psychedelic-assisted therapy could offer a cost-effective alternative to the treatments with mainstream antidepressants for many patients. Several world-renowned institutions like John Hopkins University Baltimore, Imperial College London, University of Zürich and the Central Institute of Mental Health Mannheim are now participating in the struggle to increase the understanding of psychedelics’ action. The legal status of these substances however often creates an obstacle in manufacturing and administering them to patients.

Nonetheless, the interest in clinical research on psilocybin for the treatment of depression keeps growing. Research on ClinicalTrials.gov (on March 21) revealed that more than 30 psychedelic drug trials for depression with psychedelics are registered (mostly with psilocybin, although a few are with LSD, ayahuasca, DMT and ketamine).

Amongst others, two prominent studies started in 2019. In the US, the non-profit organization Usona Institute started a phase II study with psilocybin for major depressive disorder (MDD),[1] while the company COMPASS Pathways sponsored a phase II study about the’ Safety and Efficacy of Psilocybin in Participants With Treatment Resistant Depression (P-TRD).’ Several other prominent research and clinical institutions have started to develop activities in the field of psychedelic research and therapy. The Massachusetts General Hospital, which is the largest teaching hospital of the Harvard Medical School, established the Center for Neuroscience of Psychedelics and collaborates with the German biotech company ATAI Life Sciences (19). Likewise, New York University established the Langone Center for Psychedelic Medicine, which engages in the research of psychedelic medicine and training for research in the field (20).

In Europe, the Center for Psychedelic Studies of the Imperial College London is running a study comparing psilocybin with Escitalopram, a common antidepressant, for Major Depressive Disorder (MDD) (21). At the University of Basel, several trials are in progress, e.g., psilocybin-assisted treatment of major depression (22); LSD-assisted treatment of anxiety (23); and a trial investigating the efficacity of psilocybin for alcohol use disorder (24), as well as as a study about the safety of psilocybin in concomitance with an antidepressant (25).

In March 2021 an important study has started in Germany. The EPIsoDE study will research psilocybin as a treatment for depression. The study is led by Prof. Dr. Gerhard Gründer and will take place at the ZI Mannheim and the Charité Universitätsmedizin in Berlin (26). This project also involves members of the OVID Clinic team, including Dr. med. Andrea Jungaberle and Dr. rer. soc. Max Wolff and the non-profit MIND Foundation.

The completion of the studies above will shed more light on the therapeutic properties of psychedelics. The collected data will provide an important contribution to improving mental health practices and the policies around them. It is possible, that in the near future psychedelics, such as psilocybin, may become approved drugs for treating various mental disorders when used in responsible treatment settings (27).

CURRENT SITUATION

Do such therapies exist today?

Outside of clinical studies, therapies with the mentioned substances, such as psilocybin, are not possible today. Abridging the current state of psychedelic-assisted psychotherapy evolution, it’s evident that the interest is growing both in renowned academic institutions (university and hospitals) and private institutions or companies. Undoubtedly, the argument is getting into mainstream discourse, which is also based on the growing number of informative articles and books.

Today, it is not possible to provide broader access to psychedelic therapies outside of clinical studies. One exception is off-label with the atypical psychedelic ketamine. Ketamine can create valuable altered states of consciousness that are used in psychotherapy. In the OVID clinic, we integrate ketamine infusions into a holistic and evidence-based therapeutical concept to augment psychotherapy.

Ketamin-augmented psychotherapy

Published on 21. April 2021

1) Turton, S., Nutt, D. J., & Carhart-Harris, R. L. (2014). A qualitative report on the subjective experience of intravenous psilocybin administered in an FMRI environment. Current drug abuse reviews, 7(2), 117–127. https://doi.org/10.2174/1874473708666150107120930

2) Carhart-Harris, R. L., Leech, R., Hellyer, P. J., Shanahan, M., Feilding, A., Tagliazucchi, E., Chialvo, D. R., & Nutt, D. (2014). The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs. Frontiers in human neuroscience, 8, 20. https://doi.org/10.3389/fnhum.2014.00020

3) Nichols D. E. (2016). Psychedelics. Pharmacological reviews, 68(2), 264–355. https://doi.org/10.1124/pr.115.011478

4) Johnson, M. W., Hendricks, P. S., Barrett, F. S., & Griffiths, R. R. (2019). Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. Pharmacology & therapeutics, 197, 83–102. https://doi.org/10.1016/j.pharmthera.2018.11.010

5) Griffiths, R. R., Johnson, M. W., Carducci, M. A., Umbricht, A., Richards, W. A., Richards, B. D., Cosimano, M. P., & Klinedinst, M. A. (2016). Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. Journal of psychopharmacology (Oxford, England), 30(12), 1181–1197. https://doi.org/10.1177/0269881116675513

6) Carhart-Harris, R. L., Bolstridge, M., Rucker, J., Day, C. M., Erritzoe, D., Kaelen, M., Bloomfield, M., Rickard, J. A., Forbes, B., Feilding, A., Taylor, D., Pilling, S., Curran, V. H., & Nutt, D. J. (2016). Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The lancet. Psychiatry, 3(7), 619–627. https://doi.org/10.1016/S2215-0366(16)30065-7

7) Goldberg, S. B., Pace, B. T., Nicholas, C. R., Raison, C. L., & Hutson, P. R. (2020). The experimental effects of psilocybin on symptoms of anxiety and depression: A meta-analysis. Psychiatry research, 284, 112749.

8) Carhart-Harris, R. L., Bolstridge, M., Day, C., Rucker, J., Watts, R., Erritzoe, D. E., Kaelen, M., Giribaldi, B., Bloomfield, M., Pilling, S., Rickard, J. A., Forbes, B., Feilding, A., Taylor, D., Curran, H. V., & Nutt, D. J. (2018). Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology, 235(2), 399–408. https://doi.org/10.1007/s00213-017-4771-x

9) Rafael G. dos Santos, José Carlos Bouso, Miguel Ángel Alcázar-Córcoles & Jaime E. C. Hallak (2018) Efficacy, tolerability, and safety of serotonergic psychedelics for the management of mood, anxiety, and substance-use disorders: a systematic review of systematic reviews, Expert Review of Clinical Pharmacology, 11:9, 889-902, DOI: 10.1080/17512433.2018.1511424

10) Bogenschutz, M. P., Forcehimes, A. A., Pommy, J. A., Wilcox, C. E., Barbosa, P. C., & Strassman, R. J. (2015). Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. Journal of psychopharmacology (Oxford, England), 29(3), 289–299.

11) Rucker, J., Iliff, J., & Nutt, D. J. (2018). Psychiatry & the psychedelic drugs. Past, present & future. Neuropharmacology, 142, 200–218. https://doi.org/10.1016/j.neuropharm.2017.12.040

12) Thomas Kingsley Brown & Kenneth Alper (2018) Treatment of opioid use disorder with ibogaine: detoxification and drug use outcomes, The American Journal of Drug and Alcohol Abuse, 44:1, 24-36, DOI: 10.1080/00952990.2017.1320802

13) Moreno, F. A., Wiegand, C. B., Taitano, E. K., & Delgado, P. L. (2006). Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder. The Journal of clinical psychiatry, 67(11), 1735–1740. https://doi.org/10.4088/jcp.v67n1110

14) Stewart, B, Dean, JG, Koek, A, et al. (2020) Psychedelic‐assisted therapy for functional neurological disorders: A theoretical framework and review of prior reports. Pharmacol Res Perspect. ; 8:e00688. https://doi.org/10.1002/prp2.688

15) Mithoefer, M. C., Mithoefer, A. T., Feduccia, A. A., Jerome, L., Wagner, M., Wymer, J., Holland, J., Hamilton, S., Yazar-Klosinski, B., Emerson, A., & Doblin, R. (2018). 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. The lancet. Psychiatry, 5(6), 486–497. https://doi.org/10.1016/S2215-0366(18)30135-4

16) Danforth, A. L., Grob, C. S., Struble, C., Feduccia, A. A., Walker, N., Jerome, L., Yazar-Klosinski, B., & Emerson, A. (2018). Reduction in social anxiety after MDMA-assisted psychotherapy with autistic adults: a randomized, double-blind, placebo-controlled pilot study. Psychopharmacology, 235(11), 3137–3148. https://doi.org/10.1007/s00213-018-5010-9

17) Wilkinson, S. T., Katz, R. B., Toprak, M., Webler, R., Ostroff, R. B., & Sanacora, G. (2018). Acute and Longer-Term Outcomes Using Ketamine as a Clinical Treatment at the Yale Psychiatric Hospital. The Journal of clinical psychiatry, 79(4), 17m11731. https://doi.org/10.4088/JCP.17m11731

18) ClinicalTrials.gov. (2020) A study of psilocybin for major depressive disorder (MDD). Start Date October 15, Extimated End Date february 2021, Accessed March 20 2021. https://clinicaltrials. gov/ct2/show/NCT03866174 8. ClinicalTrials.gov.

19) https://www.prnewswire.com/news-releases/atai-life-sciences-to-collaborate-with-massachusetts-general-hospital-to-accelerate-discovery-of-mechanisms-underlying-therapeutic-effects-of-psychedelic-agents-301214781.html

20) https://www.prnewswire.com/news-releases/center-for-psychedelic-medicine-established-at-nyu-langone-health-301234761.html

21) ClinicalTrials.gov. (2018) Psilocybin vs escitalopram for major depressive disorder: comparative mechanisms (Psilodep-RCT). Published February 12,  Accessed July 1, 2020. https:// clinicaltrials.gov/ct2/show/NCT03429075

22) ClinicalTrials.gov. (2018) Phase II, Randomized, Double Blind, Placebo Controlled, Parallel Group, Single Center Study of Psilocybin Efficacy in Major Depression.  Start Date March 11, 2019, Extimated End Date October 2021, Acessed March 21 2021. https://clinicaltrials.gov/ct2/show/NCT03866174

23) ClinicalTrials.gov. (2020) LSD Treatment in Persons Suffering From Anxiety Symptoms in Severe Somatic Diseases or in Psychiatric Anxiety Disorders: a Randomized, Double-blind, Placebo-controlled Phase II Study  Start Date May 31, 2017, Extimated Completion Date May, 1 2021, Accessed March 21 2021 https://clinicaltrials.gov/ct2/show/NCT03153579

24) ClinicalTrials.gov. (2020) Phase II, Randomized, Double Blind, Placebo Controlled, Parallel Group, Single Center Study of Psilocybin Efficacy and Mechanism in Alcohol Use Disorder, Sart Date June 8 2020, Extimated End Date January 31 2023, Accessed  March 21 2021. https://clinicaltrials.gov/ct2/show/NCT04141501

25) ClinicalTrials.gov. Effects of SERT Inhibition on the Subjective Response to Psilocybin in Healthy Subjects. Published November 26, 2020. Accessed March 3, 2021. https://clinicaltrials.gov/ct2/show/NCT03912974?term=psilocybin+randomized+clinical+trial&draw=3&rank=12

26) ClinicalTrials.gov. (2021) Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression (EPIsoDE). Published December 2020,  Accessed March 19, 2021. §

27) Nutt D, Carhart-Harris R. The Current Status of Psychedelics in Psychiatry. JAMA Psychiatry. 2021;78(2):121–122. doi:10.1001/jamapsychiatry.2020.2171

28) Wolfson, P. E. (2014). The transformative power of ketamine: Psychedelic states and a personal history of transformation. International Journal of Transpersonal Studies, 33(2), 193–202.. International Journal of Transpersonal Studies, 33 (2). http://dx.doi.org/10.24972/ijts.2014.33.2.193

29)Kyle T. Greenway, Nicolas Garel, Lisa Jerome & Allison A. Feduccia (2020) Integrating psychotherapy and psychopharmacology: psychedelic-assisted psychotherapy and other combined treatments, Expert Review of Clinical Pharmacology, 13:6, 655-670, DOI: 10.1080/17512433.2020.1772054

30) Miceli McMillan R. (2020) Prescribing meaning: hedonistic perspectives on the therapeutic use of psychedelic-assisted meaning enhancementJournal of Medical Ethics . doi: 10.1136/medethics-2020-106619

31) Reiff, C. M., Richman, E. E., Nemeroff, C. B., Carpenter, L. L., Widge, A. S., … Rodriguez, C. I. (2020). Psychedelics and Psychedelic-Assisted Psychotherapy. American Journal of Psychiatry, appi.ajp.2019.1. doi:10.1176/appi.ajp.2019.19010035

32) Petranker, R., Anderson, T., & Farb, N. (2020). Psychedelic Research and the Need for Transparency: Polishing Alice’s Looking Glass. Frontiers in psychology, 11, 1681. https://doi.org/10.3389/fpsyg.2020.01681

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