There is still a significant gap in the scientific understanding of psilocybin, particularly when it comes to how and why individuals experience its effects so differently. While the chemical structure and general pharmacological actions of psilocybin are known, researchers have yet to fully uncover what specific factors contribute to the wide variation in subjective experiences among patients. Unlike many traditional pharmaceuticals, psilocybin is highly influenced by personal context, making its effects difficult to predict or standardize. These non-drug variables can either enhance or reduce the therapeutic potential of psilocybin, and they make it challenging to isolate the drug’s true efficacy in a clinical context. Until these variables are better understood and controlled for, fully unlocking psilocybin’s therapeutic potential will remain a complex task. For this study, we are comparing specifically at a patient’s expectation and motivation prior to the psilocybin assisted psychotherapy trial and their treatment outcomes.

This study is a part of a double-blinded randomized clinical trial conducted at the University of Calgary , by the Psychedelics and Cannabinoid Therapeutics lab led by Dr. Leah Mayo. The psilocybin-assisted psychotherapy trial included patients who suffer from moderate or severe Alcohol Use Disorder (AUD). Subjects were enrolled between January 2025 and March 2025. Recruitment was carried out through online advertisement, flyers, and social media. Eligible subjects were patients aged 22-65 who self-reported no current psychotherapy for AUD during trial screening. Three weeks prior to the psilocybin dosing day, patients attended a screening visit. During this visit, they were given a Motivation to Reduce Alcohol Consumption Form (MRAC), which measured how motivated patients were to reduce their alcohol consumption from a scale of 1 to 7. Two weeks prior to the psilocybin dosing day, patients were asked about their expected outcome of the psilocybin-assisted therapy and their motivation for participating in this clinical trial through a baseline survey. This survey assessed  the patient’s current knowledge and perception of psilocybin-assisted therapy, and why they have decided to participate in this clinical trial. The patient’s alcohol consumption amount was measured during this visit through a Timeline Follow Back method (TLFB).  The TLFB is administered by an interviewer and involves asking the patients to estimate their alcohol consumption 30 days prior to the interview date. One day after the dosing visit, the patients participated in their first psychotherapy session. Weekly psychotherapy sessions were conducted for the next 4 weeks following the initial dosing visit. During the last therapy session in the 4th week, the patients completed a follow up survey. This survey collected information of the patient's overall experience during the psilocybin-assisted therapy sessions based on how successful they were in managing their alcohol consumption amount, changes in their relationship with psilocybin throughout the trial, and any realizations they had experienced during the psilocybin dosing session. The patients also received another TLFB, where they disclosed the alcohol use in the past 30 days. Eight days later, patients completed a check up form, which asked about their change in motivations to manage their AUDs, if they have experienced any surprising benefits, and how well this trial has helped them in reducing their alcohol consumption.This study includes data collected on the first seven participants out of 128 total recruited subjects as this is an on-going investigation. The participants’ data were analyzed and plotted in a correlation graph on Prism. The graph compares total motivation scores with the change in alcohol consumption between the second and sixth visits. The statistical significance of the data was determined by a two-sided one sample z-test.

Psychedelics are a class of drugs that are known to cause vision distortions, perception changes, etc.¹ The direct translation from ancient Greek leads to the terms “to reveal” and “manifest”. Many historical events slowed down the process of research in psychedelics, the most profound one being the War on Drugs in the 1970s, a government-led action to stop illegal drug trade by implementing strict regulation around the illegal drugs at the time.¹  After the implementation of these strict regulations, research almost came to a standstill in the late 1980s and 1990s. This was despite the fact that earlier research had suggested potential therapeutic benefits of psychedelics in treating mental health disorders such as alcohol use disorder (AUD).¹

In modern research, psychedelics are sorted into two main classes: classical, and non-classical.² Psilocybin, Lysergic acid diethylamide (LSD), Mescaline, and Dimethyltryptamine (DMT) are all under the class of “classical psychedelics”. These substances primarily affect serotonin receptors, especially the 5-HT2A receptor.² They are known for inducing changes in perception, mood, and cognition, often leading to visual and auditory hallucinations, a sense of ego dissolution, and altered consciousness. Whereas “non-classical” psychedelics like ketamine and phencyclidine (PCP) act as NMDA receptor antagonists, leading to a disconnection between the mind and body, causing users to experience altered perceptions of reality. They are capable of producing more intense alteration in perception, mood, and consciousness compared to “classical” psychedelics.

The current psychedelic research area is largely centered around clinical trials with psilocybin, LSD, and other classical psychedelics, primarily in controlled settings.² These studies have provided initial evidence supporting the safety and efficacy of psychedelics when administered under medically supervised conditions. Pre-modern research suggests that psychedelics can break addiction behaviors, like those associated with alcohol and tobacco, by breaking the patients’  thought process.² When patients battling the aforementioned addictions are having thoughts of consuming alcohol or smoking tobacco, psychedelics can break those thoughts. Evidence also suggests that psychedelics may also be used to treat mental health disorders like depression, post trauma stress disorder, and anxiety.²

Past studies have revealed psilocybin’s effectiveness in treating mental illnesses. A study done by Johns Hopkins Medicine explored the long-term effects of psilocybin-assisted therapy on 27 individuals with major depressive disorder, most of whom were women with an average age of 40.³  Among the participants,  88% had previously tried standard antidepressant treatments with no success. Each participant underwent two psilocybin sessions, spaced two weeks apart, alongside preparatory and follow-up meetings. Depression severity was assessed using the GRID-Hamilton Depression Rating Scale, where scores above 24 indicate severe depression. Before treatment, the average score was  22.8. Following therapy, scores dropped to 8.7 at one week, 8.9 at four weeks, 9.3 at three months, 7 at six months, and 7.7 at 12 months, suggesting a shift from severe to minimal depression levels. These findings indicate that psilocybin, when used in a controlled setting, can lead to significant and lasting reductions in depression symptoms.³ 

Psychedelic experiences are known to be highly subjective, and can be influenced by a number of factors beyond the drug itself.² Studies have shown that up to 50% of the therapeutic outcomes in some psychedelic treatments may be driven by patient’s expectations, making it a key variable in the overall effectiveness of psilocybin-assisted trials.^1,2 Expectations can be shaped by previous experiences with psychedelics, the advice the patients have been receiving from others, and their mood, mental state, etc.⁴ An individual's mindset ('set') and the surrounding environment ('setting') can greatly impact their expectations, and how effective the drug is in inducing long term change. However, much remains unknown about the factors related to expectations and therapeutic outcomes in psychedelic treatments. The unknown areas include:  the long-term impact of expectation-driven therapeutic outcomes, how expectations evolve throughout the treatment process, and how to best design preparatory, integration sessions to effectively manage expectations without creating unrealistic ones.⁴

Limited research has been conducted specifically on how expectation influences the outcomes of psilocybin-assisted treatments. This study aimed at determining how motivations  and expectations for participation in a psilocybin-assisted psychotherapy trial for alcohol use disorder relate to treatment outcomes. The trial assessed the patient's expectations going into these sessions, and compared them to their treatment outcome. The results of this research will allow psychiatrists to tailor psilocybin treatments to maximize the therapeutic effects. Ultimately, this research aims to enhance the efficacy of psilocybin therapy for alcohol use disorder patients, making it a more precise and personalized treatment.

There is a weak negative correlation between total motivation score and change in drinks. However, different types of motivation have little effect on the change in drinks. The 95% confidence interval (-0.88 to 0.54) captures the true correlation, but since it includes 0, the result is not statistically significant. Additionally, the p-value exceeds the significance level, meaning we fail to reject the null hypothesis, indicating no significant correlation between motivation and change in drinks.

This study holds significant potential in enhancing the understanding of how subjective factors affect the effects of psilocybin, and its effectiveness in treating Alcohol Use Disorder. After the clinical trial finishes and more statistically significant data is found, the results could be utilized to improve the preparatory phases of therapy. If the hypothesis is proven to be right, positive expectations will have a positive effect on the effectiveness of psilocybin, vice versa. Psychologists could aim at altering a patient's expectations prior to the psilocybin dosing day. This will maximize the therapeutic effects of psilocybin, making it a better therapeutic tool.
Since the clinical trial is still in its early stages, only data from the first seven participants have been collected and analyzed so far. This limited sample size greatly reduces the reliability and statistical power of any conclusions drawn at this point, as smaller datasets are more prone to variability and may not accurately reflect trends across a broader population. As the study continues and more participants complete the full therapy protocol, I will consistently update and analyze the raw data to identify more robust patterns and correlations. Once a larger dataset is available and the results have undergone thorough statistical validation, the findings will be compiled into a comprehensive report and presented to hospitals and relevant medical institutions for further consideration and potential clinical application.

1. Nichols DE. Psychedelics. Pharmacol Rev. 2016;68(2):264-355. doi:10.1124/pr.115.011478
2. Rucker JJH, Iliff J, Nutt DJ. Psychiatry & the psychedelic drugs. Past, present & future. Neuropharmacology. 2018;142:200-218. doi:10.1016/j.neuropharm.2017.12.040
3. Davis AK, Goldberg SB, Barrett FS, May DG, Cosimano MP, Sepeda ND, Anderson BT, Finan PH, Griffiths RR. Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up. J Psychopharmacol. 2022;36(3):151-158. doi:10.1177/02698811221079871
4. Colloca L, Nikayin S, Sanacora G. The intricate interaction between expectations and therapeutic outcomes of psychedelic agents. JAMA Psychiatry. 2023;80(9):867-868.

This project is supported by the University of Calgary and the Department of Psychiatry. Thank you Dr. Leah Mayo and Mr. Luis Contreras for their mentorship. Thank you Dr. Garcia for making this project possible.