Motivation and emotion/Book/2022/Psilocybin assisted therapy and depression

Psilocybin assisted therapy and depression:
How can psilocybin assisted therapy help to treat depression?

Multimedia presentation (3 min)

Overview

Figure 1. Psilocybe subaeruginosa. Species of psilocybin mushroom.

Depression is a common mental disorder, with an estimated 5% of individuals affected worldwide. Depression has substantial negative effects, including quality of life, high rates of comorbidity and mortality. Current treatment for depression includes psychotherapy and antidepressants. Whilst these methods are effective, they take a significant amount of time for results to be seen. With psychotherapy, results indicate that around 30 to 40% percent of the time, symptoms will reduce (7).  Antidepressants, on the other hand, take around three to six months for symptoms to improve, with research indicating that over 23% of people who took antidepressants for one to two years still relapsed (12). This indicates that there is significant room for improvement in the treatment methods for depression.

Recently, psilocybin has made headway in the psychological field for the treatment of depression, including treatment resistant depression. Through the facilitation of psilocybin assisted therapy, several studies have shown the effectiveness for patients with depressive symptoms and major depressive disorder. The results of these studies demonstrate a rapid and long-lasting effect in the reduction of symptoms (1,4).

Focus questions: Is psilocybin assisted therapy for the treatment of depression effective? Is psilocybin assisted therapy more effective then the current treatment methods? How does psilocybin work? What is the default mode network and how does psilocybin affect it?

What is depression?

Depression can include feelings of sadness and/or hopelessness, outbursts of anger, loss of interest and/or motivation, feelings of worthlessness and/or guilt, loss of appetite, fatigue, erratic sleeping habits and muscle pain and headaches (5). For a clinical diagnosis of depression, the Diagnostic Statistical Manual Fifth Edition identifies that in a two-week period an individual needs to experience five or more symptoms including depressed mood and/or loss of interest or pleasure (6).

What is psilocybin?

Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine), is a naturally occurring psychoactive compound produced by more than 200 species of mushrooms and can lead to a sense of euphoria, reduced negative mood and vivid hallucinations.

How is psilocybin used in therapy?

Figure 3. John Hopkins Psilocybin Session

Psilocybin-assisted therapy is not only the supervised consumption of psilocybin, it also involves a specific environment with psychological support provided by clinically trained therapists. The process is conducted in three stages: preparation, psychedelic active session, and debriefing (9).

Preparation

In the preparation stage, participants undergo psychiatric and drug screening, the therapist develops therapeutic rapport with the participant and gains an understanding of the participants motivation to undertake psilocybin assisted therapy. The therapist also provides psychoeducation about the psychedelic experience including the effects of the drug, the duration and intensity, risks and side effects, the boundaries of the interaction between the therapist and participant, safety measures and the therapeutic approach to be used (9).

In addition, the therapist will aim to manage the participants expectation of the session’s outcome as not every use of a psychedelic substance will endure a positive experience. Some users of psychedelic substances report no effect or negative effects such as panic, anxiety and psychotic like reactions (9). The therapist will work with the participant to identify goals and obstacles for the psychedelic active session and develop a plan for the post-acute effects that may occur. This plan can include different techniques to manage the post-acute effects including grounding techniques, awareness of body sensation exercises, therapeutic touch and rescue mediations. The therapist will also get the participant ready for life after their experience (9).

Psychedelic active session

The room setting is paramount, prior to the participant consuming psilocybin. The therapist needs to ensure the physical space feels warm, inviting and private so the participant can feel safe. This can include decorating the room with plants, flowers, homely furnishings and music. With music preference determined during the preparation stage (9).

Upon arrival, the participant is given standard medical and psychiatric assessment, including blood pressure and pulse, evaluation for suicidality and urine toxicology. Expectations are set, including making the participant aware that the session will take a minimum of 6 hours, they cannot leave the floor, letting them know where the bathroom is located and that there is food and snacks available.  Trip instructions are provided, which encourages curiosity, acceptance and for the participant to lean into experiences, techniques are reviewed on how to deal with distress and their intention is reviewed. When the participant is ready, the psilocybin capsule is offered (9).

The participant is provided headphones, a blindfold and encouraged to lay down on a bed/couch.  During the psychedelic experience, therapists assist the participant emotionally and encourage them to confront troubling ideas, feelings, or memories as they occur. The participant is encouraged to share their experiences, feelings, and reflections on the journey at the end of the session (9).

Prior to departure, the participant is assessed to ensure they are safe to be discharged the clinic including the assessment of vital signs and they are released to their support person. The day after the session, clients undertake a debriefing session (9).

Debriefing

The final phase of the process is the debriefing stage and is arguably the most important. This stage occurs the day after the psychedelic active session and involves the participant and therapist discussing the experience with the aim to integrate meaning. Participants are encouraged to develop their own understanding and thoughts in order to alter any destructive behavioural and emotional patterns. The therapist aids by applying therapeutic techniques so the participant can transform unhelpful patterns into something productive and desirable (9).

Knowledge Check

What is the most important stage of psilocybin assisted psychotherapy?

	Debriefing.
	Preparation.
	Psychedelic active session.

How does psilocybin affect the brain and how does it compare to anti-depressants?

Effects on Neurotransmitters – Serotonin

Psilocybin is inactive until it is consumed, the body metabolises it through the process of dephosphorylation to produce an active drug, Psilocin. Psilocin is a non-selective serotonin 2A receptor agonist, this means it stimulates serotonin receptors including the 5HT2A receptor, due to the molecular structure of psilocin being similar to the neurotransmitter serotonin (5-OH-tryptamine, 5-HT) (14). Serotonin is a neurotransmitter that influences a range of neuropsychological process, including mood regulation, emotional responses such as anger and fear, appetite changes, sleep and sexual activity. The increase in positive emotions and reduction in negative emotions experienced when psilocybin is ingested is due to the effect on the 5HT2A receptor (14).

Default Mode Network

A hallmark of people suffering with depression, is the feeling of being “stuck” in a negative pattern of thoughts about themselves, this feeling/process is called rumination. Patients with increased negative rumination show higher activity in what known as the default mode network, this heightened activity causes individuals to become unresponsive to the world around them (18).

The default mode network (DMN) is the connection between three brain areas: medial prefrontal cortex, posterior cingulate cortex, and angular gyrus (8). This network is active when we are awake, however not paying attention. This includes daydreaming, thinking about the past or future, or thinking about ourselves and others. Through functional MRI brain scanning, studies show that psilocybin reduces activity in the medial prefrontal cortex and the posterior cingulate cortex, these areas are responsible for attention, habits, memory and emotions.

Individuals with depression suffer from hyperactivity activity in the DMN, which leads to is higher negative rumination (10). This hyperactivity causes individuals to form inaccurate or extremely negative forms of self-reflection and can also be an indicator of suicidal behaviour in adolescents (10).

Due to psilocybin reducing the activity of the network, it has been correlated that this reduced activity leads to lower feelings of negative rumination (15) with users of psilocybin have reported increased awareness of the world around them and a feeling of an open mind. It is further hypothesised that psilocybin acts as a reset of the DMN, due to the release of the constraints of the inner self and the experience of ego-dissolution. Ego-dissolution is the loss of a feeling of self that happens during a psychedelic experience, and it makes individuals feel as though the lines separating them from the outside world are vanishing (13).

How does psilocybin compare to anti-depressants?

Pharmacological treatment methods for depression, include a range of different medications. One of the most common anti-depressants used is a selective serotonin reuptake inhibitor (SSRIs). SSRI’s increase the amount of serotonin in the brain and can take up to six weeks for individuals to see a reduction in symptoms (19). Research indicates that 40 to 60% of people who took SSRI’s saw symptom reduction and 23% of people had a relapse in symptoms after one to two years (12). A significant limitation of anti-depressant medication is that it is difficult to predict how a medication will affect an individual, with a lot of trial and error occurring until the right medication is found. In addition, medications can a variety of side effects with over half of people who took SSRI’s having side effects including headaches, dry mouth, sleeping problems and nausea (12).

In comparison, patients treated with psilocybin showed a greater clinical response than those treated with SSRIs (70% versus 48%), with after six weeks 57% of patients were in remission (3). A study conducted by John Hopkins Medicine reported that the severity of depression remained low after one, three, six and twelve months after treatment (4). This is supported by the findings from the Beckley-Imperial Research Program which showed when individuals with treatment resistant depression were treated with psilocybin, 67% had a reduction of symptoms after one week of treatment with 42% in remission for up to three months (6)

Whilst the literature notes there is potential for adverse side effects of psilocybin, such as agitation, confusion, anxiety and paranoia, if experienced during a psychedelic active session they are mitigated through the post-acute effects plan (9).

Knowledge Check

1

Psilocin stimulates the neurotransmitter

2

The Default Mode Network is active when we are not

3

reduces activity in the default mode network.

What are the limitations of psilocybin assisted therapy and how do we address these in future research?

Legal

Research into psychedelics for the treatment of mental disorders, halted in 1970 due to Nixon’s War on Drugs, which caused psychedelics to become prohibited in many countries. In America Psilocybin is classified as a Schedule I substance under the Controlled Substances Act deeming it to have no medical value and in Australia, they are under Schedule 9: Prohibited Substances, which is for substances that are subject to abuse and have no therapeutic use, however drugs under this schedule are available for research purposes (16,17).

Generalisability

In its current state, psilocybin studies have small sample sizes due to the exclusion criteria, this limits the ability for findings to be applied to the larger population. In addition, the dosage amount varies from study to study, which in turn limits the ability for replication.

Suggestions for future research

Research into psilocybin is significantly limited due to the scheduling of the drug. If restrictions were lifted in relation to the administration of psilocybin for treatment by registered physicians only and through sponsorship of a recognised institution, this would significantly improve the accessibility for researchers.

In relation to generalisability, a specific criterion for dosage needs to be created. Whilst taking into account, dosage amount has many variables being gender and weight. Currently the exclusion criteria are holding backing the ability for studies to be applied to the larger population. However, it needs to be taken into consideration that the exclusion criteria is paramount to ensure participants safety. Critiques of psilocybin research need to take this into account.

Conclusion

Depression is a prevalent condition that affects many individuals worldwide. This condition significantly effects a person's life and includes a range of mental and physical symptoms. With current treatment methods of psychotherapy and antidepressants, whilst effective, can take a significant amount of time to work. Due to this, researchers are exploring other treatment methods including the use of psilocybin.

Psilocybin is the psychoactive chemical found naturally occurring in a species of mushroom that is inactive until consumed. Once consumed it metabolises into psilocin which stimulates serotonin receptors. The use of psilocybin for the treatment of depression has proven effective through the facilitation of psilocybin assisted psychotherapy. These sessions consist of three key stage including preparation, psychedelic active session and debriefing, with the final stage being the most important. Researchers theorises that psilocybin not only has an effect on the serotonin receptors, however, also has an effect on the default mode network (DMN). Hyperactivity in the DMN is seen for individuals with depression which leads to higher negative rumination. With psilocybin reducing activity in the DMN, this leads to symptom improvement for individuals with depression. Further, it is theorised that psilocybin acts as a reset, allowing individuals to release any restrictions from the inner self.

Recent studies of psilocybin have proven that they are more effective than antidepressants, with patients in remission after six weeks and levels of depression remaining low up to 12 months after dosage. Whilst there is the potential for adverse effects of psilocybin theses are mitigated through the preparation stage in psilocybin assisted psychotherapy.

There are many limitations of psilocybin assisted psychotherapy, including legality and generalisability. For future research, a development of a dosage schedule would improve the replication of studies. Whilst the small sample size impacts the ability to replicate findings to a larger population, the safety of participants needs to be taken into consideration.

See also

• Psilocybin (Wikipedia)
• Psilocybin and emotion (Book chapter, 2019)
• Psychedelic treatment of addiction (Book chapter, 2020)

Suggestions for this section: Present in alphabetical order. Include the source in parentheses.

References

Carhart-Harris, R. L., Bolstridge, M., Rucker, J., Day, C. M., Erritzoe, D., Kaelen, M., et al. (2016). Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry 3, 619–627. doi: 10.1016/S2215-0366(16)30065-7 (1)

Carhart-Harris, R. L., Roseman, L., Bolstridge, M., Demetriou, L., Pannekoek, J. N., Wall, M. B., ... & Nutt, D. J. (2017). Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Scientific reports, 7(1), 1-11. (2)

Carhart-Harris, R., Giribaldi, B., Watts, R., Baker-Jones, M., Murphy-Beiner, A., Murphy, R., ... & Nutt, D. J. (2021). Trial of psilocybin versus escitalopram for depression. New England Journal of Medicine, 384(15), 1402-1411. (3)

Davis, A. K., Barrett, F. S., May, D. G., Cosimano, M. P., Sepeda, N. D., Johnson, M. W., ... & Griffiths, R. R. (2021). Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA psychiatry, 78(5), 481-489. (4)

Depression (major depressive disorder). Mayo Clinic. https://www.mayoclinic.org/diseases conditions/depression/symptoms-causes/syc-20356007 (5)

Edition, F. (2013). Diagnostic and statistical manual of mental disorders. Am Psychiatric Assoc, 21(21), 591-643. (6)

Elsey, J. W. B. (2017). Psychedelic drug use in healthy individuals: a review of benefits, costs, and implications for drug policy. Drug Sci. Policy Law 3, 1–11. doi:10.1177/2050324517723232 (7)

Greicius, M. D., Krasnow, B., Reiss, A. L., & Menon, V. (2003). Functional connectivity in the resting brain: a network analysis of the default mode hypothesis. Proceedings of the National Academy of Sciences, 100(1), 253-258. (8)

Guss, J., Krause, R., & Sloshower, J. (2020). The Yale manual for psilocybin-assisted therapy of depression (Using acceptance and commitment therapy as a therapeutic frame). (9)

Hamilton, J. P., Farmer, M., Fogelman, P., & Gotlib, I. H. (2015). Depressive rumination, the default-mode network, and the dark matter of clinical neuroscience. Biological psychiatry, 78(4), 224-230. (10)

Institute of Health Metrics and Evaluation. Global Health Data Exchange (GHDx). http://ghdx.healthdata.org/gbd-results-tool?params=gbd-api-2019-permalink/d780dffbe8a381b25e1416884959e88b (Accessed 8 October 2022). (11)

Institute for Quality and Efficiency in Health Care. (2015). Depression: How effective are antidepressants. (12)

Letheby, C., & Gerrans, P. (2017). Self unbound: ego dissolution in psychedelic experience. Neuroscience of Consciousness, 3(13).

Madsen, M. K., Fisher, P. M., Burmester, D., Dyssegaard, A., Stenbæk, D. S., Kristiansen, S., ... & Knudsen, G. M. (2019). Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacology, 44(7), 1328-1334. (14)

Overman, D. (2022). Psilocybin Rewires the Brain for People with Depression. AXIS Imaging News. (15)

Poisons Standard Act 2022 (Cth) (Austrl.). (16)

Schedule of Controlled Substances 2006 s.812 (Americ.) (17)

Sun, H., Tan, Q., Fan, G., & Tsui, Q. (2014). Different effects of rumination on depression: key role ofhope. International journal of mental health systems, 8(1), 1-5. (18)

Taylor MJ, Freemantle N, Geddes JR, Bhagwagar Z. Early onset of selective serotonin reuptake inhibitor antidepressant action: Systematic review and meta-analysis. Arch Gen Psychiatry. 2006;63(11):1217. doi:10.1001/archpsyc.63.11.1217 (19)

External links

• Psychedelic treatment with psilocybin relieves major depression (hopkinsmedicine.org)
• Could psilocybin be as effective as antidepressants? (rollingstone.com)
• The harms of psychedelics need to be put into context (Wired, 2022)