Motivation and emotion/Book/2023/Psychedelic treatment of anxiety

Overview
 Josh is a 30 year old living with his partner, Charlie in Canberra, Australia. Three months ago, Josh was diagnosed with Stage 3 breast cancer and was told that they could not operate and remove the cancer until the tumour was treated to shrink. Josh did not take the initial diagnosis well and has been incredibly anxious about the possibility of an early death. This anxiety is heavily impacting Josh's day-to-day life as he actively avoids activities he used to enjoy due to the regular panic attacks he experiences. Josh misses going out with his friends and partner, however he feels trapped in the same mental cycles (Figure 1). Two months ago, Josh saw a psychiatrist and was diagnosed with adjustment disorder with anxiety. Despite regular therapy and anti-anxiety medications, Josh is not seeing any improvements in his symptoms, however he has run out of treatment options.

Anxiety is one of the most common mental health disorders (Nikolaidis et al., 2023) with a global lifetime prevelency of 13% (Davis et al., 2020). Finding effective treatment methods for anxiety is vital for maintaining the individuals quality of life, not just psychologically but also in the social and financial aspects of ones life (Weston et al., 2020). The current approach for treating anxiety commonly involves a combination of therapeutic interventions and medications, however on average, the medications used today only produce a 50% decrease in anxious symptoms (Nikolaidis et al., 2023). Furthermore, these commonly-prescribed medications produce short-lived results and many individuals quickly build a tolerance to them (Davis et al., 2020).

One promising alternative to the current method is psychedelic treatment. Initially researched as a potential western medicine in the 1950s, studies on psychedelic treatment potential were delayed as issues surrounding recreational use began to surge and new legal restrictions were implemented (Doblin et al., 2019). However, in the last 20 years, there has been more research into psychedelic treatment than ever before, with researchers naming this period a "renaissance" of psychedelic research (George et al., 2019). In this chapter, the potential for psychedelics to reduce symptoms of anxiety is explored. First, an outline of psychedelics and the theories underpinning their therapeutic potential are outlined. Next, an analysis on how accessible psychedelic treatment is for patients with anxiety is conducted, before recently answered research questions are addressed. Finally, this chapter outlines what a patient can expect when undergoing psychedelic therapy, including the benefits and risks associated with this treatment method.

Our case study, Josh is an example of somebody who could benefit from psychedelic treatment, as he is resistant to the medications that he has been offered thus far. Throughout this chapter we will revisit Josh's story to examine whether psychedelic treatment is a solution for him. Focus questions


 * Can psychedelic treatment improve symptoms of anxiety?
 * What are the underpinning theories to support psychedelic treatment for anxiety?
 * What are the benefits and risks associated with psychedelic treatment for anxiety?
 * How are psychedelics used in the treatment of anxiety today?

A quick guide to psychedelics
The word "Psychedelic" originates from the Greek words "psyche" (mind) and "delos" (clear/brough to life), essentially translating to "mind manifesting" (Moreton et a;., 2019). In scientific terms, psychedelics are "compounds that alter consciousness by acting on serotonin receptors in the brain" (Kelmendi et al., 2022, p. 63). These substances can alter various elements of the user's mood, cognition and/or perception including hallucinations, feelings of connectedness to the universe/others, ecstasy and a sense of transcending time and space (Vollenweider & Kometer, 2010).

Many psychedelics are derived from natural recourses such as psilocybin (Figure 2) and lysergic acid diethylamide (LSD). These substances are referred to as classical psychedelics, in contrast to a-typical psychedelics such as ketamine and MDMA which are synthesised (Schimmel et al., 2022). Whilst the therapeutic potential of most psychedelic substances is not significantly different, psilocybin is utilised for the majority of experimental trials (Kelmendi et al., 2022).

Psychedelics are commonly known for their recreational use in Western culture from the 1960s into the present day (Schenberg, 2018), however they have been used for medicinal and spiritual purposes by Indigenous Nations for over a millennia (Vollenweider & Kometer, 2010).

Psychedelic theory
There is still much to learn about how psychedelics affect the brain, and whilst psychedelics have been shown to have a strong relationship with the reduction of anxious symptoms (Davis et al., 2020; de la Salle et al., 2022; Leger & Unterwald, 2022; Schimmel et al., 2021), the exact mechanisms of these effects are not entirely known. Currently, there are three main hypotheses, all of which are not mutually exclusive:

Serotonin hypothesis
The serotonin hypothesis is the basis of many mood and anxiety medications used today, declaring the root of anxiety to be a deficit in serotonin production in the brain (Lowe et al., 2022; Romeo et al., 2021). Classical psychedelics have been shown to have an affinity with a variety of 5-HT serotonin receptors which are densely located in the prefrontal cortex where anxiety disorders are mediated (Kelmendi et al., 2022; Lowe et al., 2022). When an individual takes a psychedelic substance, it will act as an agonist on the 5-HT receptors, which triggers brain development, explaining the intense learning revelations that psychedelic users have described (Romeo et al., 2021).

Neuroplasticity hypothesis
The neuroplasticity hypothesis explores the lasting effects of psychedelics on anxious symptoms in comparison to other medications. This hypothesis proposes that classical and atypical psychedelics encourage open-mindedness through a regression of learning that is caused by altered brain connectivity (Carhart-Harris et al., 2012). This regression causes psychedelic flexibility to increase and new cognitive pathways to form (Romeo et al., 2021). Davis et al., (2020) found that a person's neuroplasticity was a key mediator for the relationship between the mystical effects of psychedelics and a reduction in anxiety, further supporting this hypothesis.

Anti-inflammatory hypothesis
Psychedelics such as psilocybin have been used to treat pain due to their anti-inflammatory properties (Lowe et al., 2022). The anti-inflammatory hypothesis supports the lasting effects of psychedelic treatment for anxiety, speculating that the anti-inflammatory properties of psychedelics can return the brain to its ideal state of homeostasis and prevent the brain from reverting back to its pre-treatment state (Flanagan & Nichols, 2018).

Accessibility of psychedelic treatment for anxiety
Psychedelic treatment has been explored by scientists since the 1950s, however this was brought to an abrupt halt between the 70s and 90s as Richard Nixon's 'War on Drugs' triggered the criminalisation of psychedelic drugs in several countries (Hall, 2022). Whilst a renaissance of psychedelic treatment is well under way (Doblin et al., 2019), there are various limitations, barriers and accessibility issues still to be addressed.

Research limitations
Due to the controversial stigma and criminalisation surrounding psychedelic substances, anonymous survey-based studies are popular in order to gain a substantial sample group (Davis et al., 2020; Nikolaidis et al., 2023). These studies could exclude members of the population who are not confident in using technology, or are not interested in or engaged with online forums that advertise these studies (Davis et al., 2020; de la Salle et al., 2022). Additionally, a survey design depends on each participant's recollection of their experiences, which will typically only give the researchers data on significant and memorable psychedelic experiences (de la Salle et al., 2022). Finally, anonymous surveys also depend on the honesty of participants, as there is no way to confirm responses as factual (Raison et al., 2022).

The recent surge in psychedelic findings has brought about a wave of optimism for academics studying psychiatric solutions (Kelmendi et al., 2022). Whilst this can be positive, researchers and readers are cautioned to maintain an awareness of their own positivity bias (Leger & Unterwald, 2022). A dismissal of these potential biases could result in misinterpretations of data and existing research due to favourable and selective attention.

The controversies surrounding psychedelics in the medical sector still serve as a significant barrier to ongoing research advancements (Nikolaidis et al., 2023). This stigma could be combatted with further education on psychedelics as well as an increase in empirical support obtained from experimental research designs (Lowe et al., 2022).

 Josh's anxiety is continuing to worsen and his partner Charlie is concerned that without the proper treatment Josh may lose his quality of life all together. After conducting some research on alternative treatment methods, Charlie learns about psychedelic treatment and is excited to share their findings with Josh. Josh is willing to give the treatment a try, however they soon discover that there are no therapists trained in psychedelic integration within the ACT. On top of this, there a still significant legal restrictions in place and seeking treatment is not only out of budget but also potentially illegal. Josh gives up his search for treatment and returns to his state of perceived helplessness.



Indigenous considerations
Whilst western advancements into psychedelic treatment began in the 1950s (Hall, 2022), classical psychedelics have been used for over a millennia by Indigenous populations across the world (Vollenweider & Kometer, 2010). Mayan, Aztec and South American (Figure 3.) Cultures, to name a few, hold rich and vast understandings of the spiritual, emotional and medicinal benefits of psychedelics (Kelmendi et al., 2022). With the new surge in western psychedelic research, there is concern from some Indigenous communities surrounding the lack of acknowledgement surrounding Indigenous medicinal wisdom, and a possibility of cultural appropriation should researchers fail to learn about the traditional customs and uses of the substances they are studying (Celidwen et al., 2023). Furthermore, there are growing concerns surrounding the inequitable accessibility of psychedelic treatment, with legal and financial restrictions favouring wealthy, typically Caucasian patients and dismissing traditional psychedelic healing in Indigenous communities (George et al., 2019).

Recent research questions
With so much enthusiasm being channelled into psychedelic research, it can be difficult to sift through all of the literature. Through clinical trials, psychedelics have proven to cause a significant decrease in anxiety (Nikolaidis et al., 2023; Raison et al., 2022; Schimmel., 2022), but there is still much to learn surrounding these findings. Below are some of the questions that are beginning to be answered through the literature published in the last three years (as of 2023).

Does psychedelic treatment reduce anxiety outside of western sample groups?
As mentioned above, psychedelics have been used by non-western groups long before clinical research began, however the participant samples in western research tend to lack cultural diversity (Celidwen et al., (2023). de la Salle et al., (2022) sought to address the lack of research on Indigenous Communities by conducting a survey across North America and Canada that asked Indigenous-identifying individuals to share their naturalistic psychedelic experiences. Along with other benefits, the study found that participants noticed a decrease in anxious symptoms that lasted up to 30 days after using a psychedelic substance. These finings could be further fortified with experimental studies that do not rely on memory recall.

Is there are difference in anxiety levels between clinical and naturalistic psychedelic use?
According to self-reported data, individuals who have used psychedelics in a naturalistic setting have experienced purposeful or unintentional prolonged positive effects including a reduction in anxiety levels (de la Salle et al., 2022; George et al., 2019; Raison et al., 2022). However, psychedelic therapy minimises some of the risks associated with substance use by creating a safe space in which the client is supported by a trained professional (Raison et al., 2022)

Do patients need to be physically healthy to receive treatment?
Much of the current literature has explored the benefits of psychedelic treatment for death anxiety in terminally ill patients (Schimmel et al., 2021) and has shown extremely promising results. Aside from eliminating death anxiety, psychedelics are also proving to work as pain medication (Lowe et al., 2022), opening the possibility of psychedelics acting as a multi-solution substance for patients suffering from physical and mental conditions.

What is the ideal treatment model to decrease anxiety?
Researchers are still learning about how to best prescribe psychedelics, however there are some key factors that have been shown to influence results (Table 1). Research has shown clients who undergo multiple sessions yield more significant reductions in anxiety (Leger & Unterwald, 2022). There are limits to this however, with positive results plateauing after 15-20 uses within one's lifetime (Raison et al., 2022). The client's psychedelic experience also influences the treatment results, as a more intense mystical experience predicts higher levels of psychological flexibility (Davis et al., 2020; Romeo et al., 2021).

Table 1. Influential and non-influential factors of psychedelic treatment for anxiety, according to the current literature (Leger & Unterwald, 2022; Raison et al., 2022; Romeo et al., 2021).

Psychedelic assisted psychotherapy (PAP) - what to expect
In order to most effectively treat anxiety with psychedelics, a combination of simultaneous psychotherapy and psychedelic use has shown greater results (Weston et al., 2020). Whilst there is some variation in the treatment methods that have been trialled, the following is the most common practice as per systematic literature reviews conducted by Cavarra et al., (2022); Schenberg, (2018) and Weston et al., (2020):

Treatment rooms are generally made to feel homely and comfortable (Figure 4) as opposed to clinical to assist in setting the patient at ease. Music is played throughout the treatment and the client is asked to wear a blindfold to encourage introspection without distractions.

In most cases, treatment begins with a set-up phase in which the client is informed of the overall process and what they can expect during and after their sessions. During this time, the psychotherapist sets clear goals and intentions, setting their client up for an optimistic and productive session. This phase is important for creating a therapeutic alliance so that a basis of trust can be formed before the patient is under the influence of psychedelics.

Next, psychedelic-assisted session begins. These sessions can range from two-eight hours in duration depending on the substance being used. The client is given a clinically prepared substance to control for strength and quantity, regardless of whether the psychedelic is classical or a-typical. During the time that it takes for the substance to take effect, the therapist may re-iterate the goals and strategies of the session, or they may encourage the client to begin practicing introspection in silence.

Once the substance has begun to take effect, we begin to see more variety in how treatment is carried out. In some trials, therapists play a reasonably inactive role, acting as a support person through affirmations and physical touch during distressing moments but ultimately facilitating a client-lead experience. The other method that is commonly used is more intentionally directed by the psychotherapist, however this method risks an overstep in how much influence a therapist should have on their client.

Finally, as the psychedelic effects begin to wear off, the patient is asked to reflect on their experiences and learnings, in order to integrate their take aways from the experience into their every day lives. Much like the previous phase, there is little consistency across the literature regarding how involved the psychotherapist is in leading this reflection, nor is there consistency in the frequency of treatments following the initial appointment. In some models, psychedelics are used in every session, in others, a mix of traditional psychotherapy and PAP are utilised.  Several months later, Josh has successfully had his tumour removed and is in remission for breast cancer, however his debilitating anxiety continues to persist. Josh is invited to participate in a study observing the effects of psilocybin assisted therapy on anxiety. The invitation outlines the time commitments surrounding the study, with sessions lasting eight hours each. Josh accepts the offer with the support of his partner and workplace.

Josh arrives for his first session and is greeted by a trained therapist who will be assisting him with his treatment. The therapist shows him into the clinic room which has been outfitted to look like a cosy living room (Figure 4). The therapist explains the process in detail before getting to know Josh and his reasons for seeking therapy, including what has and hasn't worked for him in the past. He is given a small capsule containing psilocybin that has been extracted from its original source in a lab and is asked to lie down comfortably and don a pair of light-blocking shades while he waits for the capsule to take effect. The therapist reminds him that they are expecting him to experience a reduction in anxious symptoms following the session.

Josh notices that his perception of the shapes and colours behind his closed eyelids begin to brighten and change. Josh begins to panic and worries that he is dying, until he feels the therapists hand gently press on his arm, as they reassure him he is okay. The therapist reminds Josh of some of the de-escalation techniques he has learned in previous therapy sessions. Once he is calm, Josh begins to look inward and feels as though he is making one life-changing revelation after another.

After many hours, the effects of the psilocybin begin to dissipate. Josh is given a notebook and told to reflect upon his experience. He is able to take the notebook home to revisit the messages he has written for himself.

Benefits
Arguably, the largest benefit of psychedelic treatment is it's ability to promote psychological flexibility in the patient. Not only do psychedelics produce immediate effects, these changes are longer lasting in comparison to current mainstream medications (Leger & Unterwald, 2022; Moreton et al., 2020). If a client is compatible with psychedelic therapy, they should only have to attend 10 sessions at most across their lifetime (Raison et al., 2022). This could be life-changing for individuals affected by anxiety, freeing up time and mental energy for other pursuits and eliminating the need for daily medication and frequent therapy sessions.

Another key benefit to treating anxiety with psychedelics is the lack of side effects in comparison to other anti-anxiety medications when administered correctly (Kelmendi et al., 2022). The side effects associated with current commonly prescribed anxiety medication can be distressing and off-putting for patients eg: weight changes, nausea and issues with sleep (Schendberg, 2018). Psychedelics are unlikely to produce an addictive effect and do not pose high levels of toxicity, especially considering the small number of doses necessary for positive change (Lowe et al., 2022). Additionally, many medications used today aim to reduce the patient's emotionality in order to make the anxiety more manageable, whereas psychedelics allow the patient to feel and process their emotions in full (Romeo et al., 2021). This reduction in potential side effects could encourage more individuals to pursue treatment, as the side effects of commonly prescribed medications to not always outweigh the difference they make on the client's anxiety.

Psychedelic treatment is also beneficial for patients who are experiencing comorbid issues such as anxiety and depression, as the treatment can simultaneously reduce multiple mental and physical ailments in the same session (Leger & Unterwald, 2022; Vollenweider & Kometer, 2010). With one substance and therapeutic intervention model, treating comorbid mental health disorders could become a far more simplified experience for practitioners and clients.

Risks
Although the current research proposes a lot of exciting benefits supporting psychedelic treatment, it is important to acknowledge the potential risks that have been identified in recent studies. Firstly, practitioners need to be especially mindful of their choice of wording and vocal tone whilst undergoing psychedelic therapy. While the client begins to re-write their cognitive pathways with the assistance of therapeutic prompts, they become extremely succeptable to influence, making it is vital that the practitioner avoids leading questions or any changes in language or tone that could persuade the client to take on the therapist's personal beliefs (Cavarra et al., 2022). Training in psychedelic integration should strive ensure that the importance of non-biased therapeutic guidance is reinforced to minimise the risk of clients taking on attitudes and beliefs that do not align with them.

Whilst psychedelic experiences are generally non-harmful (Kelmendi et al., 2022), there are some cases in which these substances can have adverse effects. Patients who already suffer from anxiety are at greater risk of experiencing a "bad trip" in which anxious symptoms elevate during treatment due to the new sensations and/or lack of perceived control (Butlen-Ducuing et al., 2023). Additionally, in some rare cases, patients have experiences prolonged psychedelic effects throughout the day of treatment (Weston et al., 2020). Clients with a personal or family history of psychosis may also not be eligible for psychedelic treatment as they could potentially develop Hallucinogen Persisting Perceptual Disorder or experience ongoing psychotic episodes (Raison et al., 2022).

Although they do not carry the same addictive characteristics as other substances, it should be acknowledged that there is still potential for psychedelic treatment to lead to excessive substance use. Pleasure-seeking individuals who enjoy their controlled, therapeutic psychedelic experience may choose to seek psychedelics out illegally for recreational use (Hall, 2022). Furthermore, positive experiences with psychedelics could act as a gateway into the use of more harmful substances, putting patients at physical and mental risk to themselves (Raison et al., 2022). Whilst all of these risk factors have not been found to occur often, further research is necessary to identify at-risk groups and long-term effects of treatment.  After two sessions of psilocybin-assisted psychotherapy, Josh is experiencing little to no death anxiety in his life. He is confident in attending social events once more, as he is no longer concerned about potential panic attacks. Reflecting on his experience with psychedelic therapy, Josh recalls many hours of fear and discomfort during sessions, however he is grateful for the end result and is yet to experience any signs of relapse.

Test your knowledge
{The neuroplasticity hypothesis proposes that psychedelics: - Are toxic to brain tissue + Allow cognitive pathways to be re-written - Refortify pre-existing positive cognitions making them resistant to change
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{Psychedelic treatment is effective on anxious symptoms, as long as the patient is not experiencing depression: - True + False
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Conclusion
So, can psychedelics be used to reduce symptoms of anxiety? According to the current literature, there is a lot of evidence to support this method. Whilst the "hows" and "whys" of psychedelic mechanisms are yet to be determined, research suggests that psychedelics can alter anxiety levels through acting on serotonin receptors, increasing neuroplasticity and openness to new ideas, whilst also managing inflammation in order to produce immediate and lasting reductions in anxiety. In rare cases and in some specific groups, psychedelics can prove to produce detrimental effects on the user, however with the correct background assessments and empirically-based administration, psychedelic assisted therapy could be the answer many humans suffering from anxiety have been waiting for. As of now, further experimental research is necessary to gain a thorough understanding of the ongoing risks and benefits of psychedelic use in medicine, however the ongoing findings paired with a rich Indigenous history point towards a hopeful future in psychedelic research.