Motivation and emotion/Book/2022/Psilocybin assisted psychotherapy

Overview
Mental disorders are a cause of widespread human suffering and place a significant burden on the healthcare system and economy and cause approximately one third of disabilities globally (Lake & Turner, 2017; Schenberg, 2018; Vigo et al., 2016). Effective treatment of mental illnesses remains elusive, cognitive behavioural therapies (CBT) psychotherapies represent current gold standard of care yet are ineffective for many patients and often require long term follow-ups to maintain positive effect (Carpenter et al., 2018; Lake & Turner, 2017; Ormel et al., 2019; Van Dis et al., 2020).

Recent systematic reviews and meta-analyses suggest that there is weak and inconclusive evidence supporting the use of anti-depressants and SSRIs for anxiety and depression (Kirsch, 2019; F. Li et al., 2019; Munkholm et al., 2019; Ormel et al., 2019; Penn & Tracy, 2012). While CBT appears to have a large effect size for treating anxiety disorders, it only has small to medium effect sizes in treating treatment resistant depression (J.-M. Li et al., 2018; Ormel et al., 2019).

Psilocybin assisted psychotherapy may offer a paradigm shift in the treatment of mental illnesses (Schenberg, 2018). Preliminary results suggest significant improvements in depressive symptoms have been observed with a single dose of psilocybin (Prouzeau et al., 2022). Positive effects have been observed at 6-12 month follow-ups when combined with psychotherapy (Schenberg, 2018). Psilocybin assisted psychotherapy is a promising new intervention however, more research and replication is required before providing regulatory approval for therapeutic use (Pearson et al., 2022).

Case Study:

Malone et al., (2018) conducted a qualitative study of cancer patients going through treatments of psilocybin assisted psychotherapy. Chrissy is a 50-year-old woman who has stage 4 breast cancer and metastasis in her lungs and had intense generalised anxiety before treatment. On psilocybin she was surrounded by cosmic spirits and light with an intense feeling of comfort. She heard the spirits tell her “We are here all together”. Chrissy then described how she saw a collection of stone faces, which would come into being and then turn to dust and then turn back into faces. She believed this was an insight into the cycles of life. On the psilocybin she felt she could connect with anybody. She experienced her birth and death, stating that she realised that her life would end one day and she accepted it. After her psilocybin therapy, Chrissy had significantly less depression, anxiety, hopelessness and felt like she had renewed purpose in life (Malone et al., 2018).

Focus questions:
 * What are psilocybins?
 * How do psilocybins effect the brain?
 * How effective is psilocybin psychotherapy?
 * What are the risks of psilocybin psychotherapy?
 * How does psilocybin psychotherapy compare with other treatments?

Psilocybins and psychotherapies


Psilocybins are psychedelic hallucinogens found in some mushrooms which have been used by humans for centuries for spiritual and recreational use (Nichols, 2020). Considered a schedule 1 drug and harshly regulated around the world, how can psilocybins be considered useful for psychotherapy? Psilocybins may help the brain break negative systemic processing loops of emotions and cognitions (Pearson et al., 2022). There is also evidence that psilocybins increase the brain's neuroplasticity which could put it into an ideal state to receive psychotherapy (Nichols, 2020).

What are psilocybin assisted psychotherapies?
Psilocybin assisted psychotherapies combine pre-existing evidence based psychological interventions with high doses of the psychedelic psilocybin (Pearson et al., 2022). It is hypothesised that administering certain drugs like psilocybin could put the brain into an adaptive state ideal for receiving psychotherapy (Artin et al., 2021). Psychotherapies are a collection of therapeutic techniques which attempt to treat mental illnesses (Cuijpers, 2019).

Chemical structure of psilocybins and neurological receptors
Psilocybin is a psychedelic hallucinogen which causes vivid sensation of sights, sounds and feelings (Geiger et al., 2018). When ingested, psilocybin is broken down into psilocin by the enzyme alkaline phosphatase (Dinis-Oliveira, 2017; Geiger et al., 2018). Psilocins can cross the blood-brain barrier and bind to neural receptors like a key sliding into a lock (Geiger et al., 2018). Psilocin can strongly and weakly bind to several serotonin receptors (Pearson et al., 2022).

How could psilocybins be used to assist psychotherapy
Psilocybin assisted psychotherapy combines clinically supervised psilocybin trips with psychotherapies most commonly CBT (van Amsterdam & van den Brink, 2022). Ensuring a positive experience while on psychedelics appears to be an important factor in the clinical benefit of psilocybin psychotherapies (Barrett et al., 2018). Psilocybin assisted psychotherapies appear to work through interacting with serotonin receptors and increasing brain neuroplasticity (Prouzeau et al., 2022). Another important mechanism of action appears to be allowing the brain to remodel dysfunctional neural networks (Lowe et al., 2021). Psilocybin assisted psychotherapies appear to show promising preliminary results for treating depressive and anxiety disorders (Pearson et al., 2022).

Techniques
Techniques in psilocybin assisted psychotherapy involve administering high doses of psilocybins in controlled therapeutic settings (Pearson et al., 2022). Psilocybin therapies often involve playing pleasant music help foster a good psychedelic trip (Barrett et al., 2018). A vital component to effective psychedelic therapy involves ensuring a positive experience occurs (Barrett et al., 2018). Currently, there are no regulated standardised techniques for administering psilocybin assisted psychotherapy (Lewis-Healey et al., 2022). However, typically an intervention will last between 6-10 weeks and involve 1-3 psilocybin sessions (Lewis-Healey et al., 2022). The typical structure of an intervention involves a pre-dosing psychotherapy session where therapists will discuss the benefits, risks and process of psilocybin dosing, followed by a dosing session where a clinical therapist is present (Lewis-Healey et al., 2022). Finally, there will then be a debriefing session following the treatment where the therapist will discuss the experiences of the client and investigate insights from the experience (Lewis-Healey et al., 2022). During a dosing session, the client will have a sleep mask on and headphones with music to help guide the psychedelic session towards a positive outcome (Lewis-Healey et al., 2022).

Theoretical model of change for psilocybin assisted psychotherapy


The mechanism of action behind psilocybin assisted psychotherapy is still incompletely understood (N.-X. Li et al., 2022). However, it is hypothesised that beneficial effects of psilocybin assisted psychotherapy may act through several different pathways (Lewis-Healey et al., 2022; N.-X. Li et al., 2022; Pearson et al., 2022). Psilocybin assisted psychotherapies may work through a combined interaction through the pharmacology of psilocybin and the profound experiences caused by psychedelic trips (Lewis-Healey et al., 2022). Individuals who experience more profound personal, spiritual, or mystical feelings during psilocybin administration are more likely to have better improvements in depression and anxiety scores (van Amsterdam & van den Brink, 2022). Individuals who go through these transformative personal experiences become more open and cognitively flexible, both characteristics are crucial to CBT (van Amsterdam & van den Brink, 2022).

Psilocin primarily acts in the brain through binding with the 5-HT2a serotonin receptor and weakly binds to some adrenergic receptors (Pearson et al., 2022; van Amsterdam & van den Brink, 2022). Stimulation of the 5-HT2a serotonin receptors results in increased production of cortical glutamate and activation of AMP and NMDA receptors (Prouzeau et al., 2022). Activity in AMP and NMDA receptors increases expression and production of brain derived neurotrophic factor. Brain derived neurotrophic factor is thought to be a driving factor for increasing neuroplasticity (Prouzeau et al., 2022). Increased neuroplasticity from psilocin's stimulation of 5-HT2a serotonin receptors may be a significant reason psilocybin assisted psychotherapy has large effect sizes in treating anxiety and depression (Prouzeau et al., 2022).

Psilocybin administration also appears to increase functional connectivity and reduce negative hyperactivity between multiple regions of the brain (Lowe et al., 2021; Thomas et al., 2017). This is a potentially very important mechanism. Many mental health disorders including anxiety, depression and post-traumatic stress disorder (PTSD) are hypothesised to be caused by network disruptions in the brain (Lowe et al., 2021). Psilocybins may also significantly improve neuroplasticity, improving the effectiveness of psychotherapies (Prouzeau et al., 2022). CBT may particularly benefit from being combined with psilocybin (van Amsterdam & van den Brink, 2022).

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Effectiveness of psilocybin assisted psychotherapies
Psilocybin assisted psychotherapy has shown practically significant improvements with large effect sizes in treating an array of mental health disorders, including depression, anxiety, addiction, PTSD and extensional anxiety in cancer patients (van Amsterdam & van den Brink, 2022; Varker et al., 2021). Psilocybin assisted psychotherapy does not appear to be effective for any of the psychotic disorders including schizophrenia (Geiger et al., 2018). Future research should explore how psilocybin may interact with people with psychosis. There is some conflicting evidence suggesting that psilocybin may be a treatment for schizophrenia (Geiger et al., 2018; Lowe et al., 2021).

Depression and anxiety


Psilocybin augmented psychotherapy significantly reduces symptoms of major depressive disorder even after a single session (Pearson et al., 2022). Changes in mood are from just 1-3 sessions of psilocybin augmented psychotherapy are still observed at 6-12 month follow-ups (Pearson et al., 2022). Psilocybin psychotherapy provides rapid symptom relief from depression immediately following a single dose compared with SSRIs, which often have a lag time of weeks for any effect to be observed (Penn & Tracy, 2012; van Amsterdam & van den Brink, 2022). How psilocybin assisted psychotherapy improves depressive symptoms is not fully understood (Prouzeau et al., 2022). However, a leading hypothesis is that psilocybin allows for the rapid remodelling of neuronal network connectivity, which is further facilitated by psychotherapy (Corrigan et al., 2021). Psilocybin assisted psychotherapy appears to help the amygdala break out of negative emotional processing biases which are associated with depression (Artin et al., 2021).

Post traumatic stress disorder
Post-traumatic stress response is a complex mental health disorder which is caused by a stressful/traumatic event which triggers associative learning and recurring memories and feelings (Bird et al., 2021). Psilocybin psychotherapy has been moderately effective in treating post-traumatic stress disorder (Bird et al., 2021). Psilocybin psychotherapy is hypothesised to improve PTSD because PTSD has major overlap with depression which appears to be significantly improved with psilocybin therapy (Bird et al., 2021).

Addiction
Psilocybin assisted psychotherapy may be effective in reducing substance abuse in addicts (Johnson & Griffiths, 2017). However, the quality and quantity of this evidence is lower than for other disorders (Johnson & Griffiths, 2017). There is preliminary evidence that psilocybin dosing may reduce alcohol abuse (Johnson & Griffiths, 2017). Replication and more randomised controlled trials could help elucidate this topic further. If psilocybin assisted psychotherapy is effective for addiction, it is hypothesised that a combination of improved neuroplasticity and intense spiritual experiences allow for old bad habits to be broken and new healthy habits to be implemented (Johnson & Griffiths, 2017).

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Risks of psilocybin assisted psychotherapy
Psilocybin has been regulated in many western countries as a schedule 1 drug which implies that it has a high potential for abuse and has no medicinal uses (Lowe et al., 2021). However, psilocybin has a safer risk profile than the current standard anti-depressant medications for anxiety, depression and PTSD (Lowe et al., 2021; van Amsterdam & van den Brink, 2022). Psilocybin, however, does have some potential physical and psychological risks.

Side effects an risks of psilocybins
Between 6-8% of high dose exposures to psilocybin can lead to suicide ideation and self harm, however most adverse events are mild including headache and nausea (van Amsterdam & van den Brink, 2022). Side effects can be mitigated using clinical supervision during trips intervening when a bad trip occurs(van Amsterdam & van den Brink, 2022). There is conflicting evidence that psychedelic drugs like psilocybin may be associated with developing schizophrenia and other psychotic mental disorders (Geiger et al., 2018).

Psychological risks
Psilocybins pose some significant psychological risks. Psychological risks include the potential for negative/bad trips to be just as transformative as positive ones and having long term negative effects (Bogenschutz et al., 2018; Pearson et al., 2022). Environmental cues can mitigate the probability of experiencing an unpleasant trip, like pleasant music, therapeutic environments, and low blood alcohol levels (Barrett et al., 2018; Lowe et al., 2021). From a personality psychology standpoint, going through such a powerful experience which can cause ego dissolution represents an interesting philosophical question of whether you will be the same person as before the psilocybin treatment (Lowe et al., 2021). Many people may want to reduce their experience of depression but may not want their personality to change because of treatment. If psilocybins continue to show such effective treatment results and are approved for clinical use, clinicians should consult each patient with the potential psychological risks of psilocybin psychotherapy.

Why is psilocybin psychotherapy needed?


Psilocybin psychotherapy is needed because current standards of care are insufficiently effective for a large section of people who suffer from mental health disorders (Carpenter et al., 2018; Kirsch, 2019). While CBT and other psychotherapies are effective, they are expensive, time-consuming, and require long-term follow-ups to maintain therapeutic effect (Carpenter et al., 2018). Psilocybin psychotherapy has been observed having large effect sizes with singular doses with a well-tolerated treatment (Pearson et al., 2022; Schenberg, 2018; van Amsterdam & van den Brink, 2022).

Psilocybins effectiveness vs other psychiatric medications
Preliminary evidence suggests that psilocybin assisted psychotherapy may be significantly more effective at treating mental health disorders like depression and anxiety than other psychiatric medications, particularly antidepressants and SSRIs (Kirsch, 2019; Munkholm et al., 2019; Pearson et al., 2022; Schenberg, 2018; van Amsterdam & van den Brink, 2022). Psilocybin has a favourable risk profile compared to anti-depressants (Kirsch, 2019; Pearson et al., 2022). Kirsch (2019) found that when including unpublished data from the Food and Drug Administration (FDA) that antidepressants were no better at treating anxiety or depression than placebo. A recent meta-analysis by Munkholm et al., (2019) found that there is insufficient evidence to support where antidepressants outperform placebo treatments. There is a clear lack of empirical and theoretical support for the use of current anti-depressants to treat anxiety and depression (Kirsch, 2019). There is an obvious need for the development of new pharmaceutical compounds to treat mental illnesses and psilocybin is currently a very promising candidate with effect sizes substantially larger than other treatments (Pearson et al., 2022).

Limitations in psilocybin assisted psychotherapy research
There are several important limitations present in the current psilocybin assisted psychotherapy research literature. These limitations need to be addressed before psilocybins could be medically approved. Perhaps the most important limitation is a large number of seminal studies have small sample sizes (Artin et al., 2021; Pearson et al., 2022; Prouzeau et al., 2022). Small sample sizes can make effect sizes appear larger than they are (Ferguson & Brannick, 2012). So, it is possible that the large therapeutic effect sizes seen in the psilocybin therapy research literature could be considerably smaller than previously observed. If this is the case, it has important implications for policy makers. Psilocybin assisted psychotherapy may be no better than a placebo paired with psychotherapy. Another significant limitation is that it is difficult to create adequate placebos to compare psilocybins with (Pearson et al., 2022). Typically, the most used placebo are low dose psilocybin or other psychedelic drugs, however, the subjective experience of being on high doses of psilocybin actively unbinds the treatment group (Pearson et al., 2022). The limitations in psilocybin research can be improved by replicating previous research studies with much larger sample sizes and with direct comparison groups between psilocybins and other pharmaceutical treatment modalities.

Conclusion
Psilocybin assisted psychotherapies have the potential to be cost-effective treatments for many mental disorders (Nichols, 2020; Pearson et al., 2022; van Amsterdam & van den Brink, 2022). Psilocybins are a well-tolerated drug which has a more favourable risk profile than other psychopharmacological treatments (Kirsch, 2019; Pearson et al., 2022). Psilocybin assisted psychotherapies appear to affect the brain through multiple mechanisms stemming from activation of serotonin receptors causing increased neuroplasticity and restoration of normal neural network activity (Prouzeau et al., 2022). Psilocybin assisted psychotherapies are not without risk. Significant personality changes both positive and negative can be caused by psilocybin therapy (Pearson et al., 2022). The risks of psilocybin therapies can be mitigated through clinical supervision (Pearson et al., 2022). However, considering that currently there are no pharmacological treatments with large effect sizes, policy makers should consider loosening regulations of psilocybins for scientific research. If current preliminary research on psilocybin psychotherapies continues to be replicated, they could rapidly become the gold standard of care for patients with anxiety, depression, and PTSD. Psilocybin psychotherapies should not be used in patients with a history of schizophrenia and other psychosis related mental health disorders until the evidence becomes clearer (Geiger et al., 2018).