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Psilocybin, the active component naturally occurring in ‘magic’ mushrooms, has emerged as a promising therapeutic drug candidate in clinical trials for treatment of depression, anxiety, and post-traumatic stress disorder. While psilocybin is generally regarded as safe and nonaddictive, one side effect remains a concern, a roughly six-hour hallucinogenic experience after consuming the drug. Neuroscientists have recently suggested that hallucinogenic experiences may not be necessary for therapeutic benefit. Here, we leverage our established E. coli-based synthesis approach to produce a larger drug candidate pool with diverse efficacies and psychedelic properties. Three biosynthetic routes were evaluated for the production of non-natural psilocybin derivatives. The first route involves a P450 monooxygenase, with a single-substituted indole, yielding detectable products but limited by the hydroxylase module. The second route circumvents these limitations through a process modification by supplementing a double-substituted indole to produce approximately 30 mg/L 6-fluoropsilocybin. The third route explores multiple halogenases to selectively chlorinate various positions of 4-hydroxytryptophan. This work enhances our understanding of the potential and limitations of derivative psilocybin production using an E. coli-based biosynthetic platform. These findings may help us learn more about this important class of bioactive compounds as a means to develop safe and effective therapeutic modalities.

This study investigated the effects of psychedelics on social connectedness by offering a survey to 455 individuals of various demographics. Given previous research and the importance of this topic in mental health realms, this study aimed to provide a new measure focused on social connectedness referred to as the Aliveness Task. With this measure, we asked participants to rate photorealistic images of people, animals, landscapes, and objects. We analyzed data according to five demographics: (1) age, (2) gender, (3) education level, (4) religious views, and (5) previous psychedelic experience. We hypothesized that this task would yield results that reflect those of more established measures used in previous psychological and psychedelic research. While more statistical measures are needed to validate this new measure, we discovered an association between previous psychedelic experience and stronger feelings of connectedness across most demographics. Participants were recruited using the participant server hosted by the Faculty of Psychology at the University of Zurich and the newsletter of our research group. A self- report questionnaire was used to capture information about participants. This study provides findings that may indicate psychedelics’ significant ability to increase feelings of social connectedness. This study is the first to use this novel measure, adapted by the University of Zurich.

Approximately 300 million people a year suffer from depression worldwide (Olgiati et al., 2013; Davis et al., 2020; Ustün et al., 2004). About 30% of those individuals suffer from treatment-resistant depression (Jaffe et al.,2019). The current treatments for major depressive disorder include transcranial magnetic stimulation (rTMS), electroconvulsive therapy (ECT), psychotherapy, selective serotonin reuptake inhibitors (SSRIs), and most recently ketamine. These treatments have not shown satisfactory remission rates so other forms of treatment need to be considered. Psychedelics have recently resurfaced as an option after the Controlled Substances Act of the Comprehensive Drug Abuse Prevention and Control Act of 1970, passed by President Richard Nixon when he declared the War on Drugs (Reiff et al., 2020), ended the use of psychedelics. Recently, psilocybin has been tested on individuals as psilocybin-assisted psychotherapy for treatment-resistant depression and these studies have shown to be effective. This meta-analysis aims to look at the efficacy for psilocybin-assisted psychotherapy versus other treatments for treatment-resistant depression. Research found that at 95% confidence interval, overall, psilocybin-assisted psychotherapy decreased depression scores by more than two standard deviations. When compared to other treatments, Psilocybin was found to decrease depression scores significantly more than any other treatment. Based on these findings, it is considered that psilocybin be more extensively investigated to understand how effective this treatment can be generalized to the population. This dissertation is available in open access at AURA, https://aura.antioch.edu/ and OhioLINK ETD Center, https://etd.ohiolink.edu

Clinical trials on the use of psilocybin to treat depression are promising but are confounded by the presence of hallucinations which may not be necessary for effectiveness. Preliminary data suggests that when administered to rats, related tryptamines baeocystin, norbaeocystin, and aeruginascin don’t cause hallucination-like acute behavioral responses (i.e., head twitch response) at any dose. This thesis explores whether related tryptamines have similar or better antidepressant efficacy than psilocybin and selective serotonin reuptake inhibitor fluoxetine, through both behavioral and biological markers of depression-associated processes in rats. Therapeutic potential of these tryptamines was assessed by administering baeocystin, norbaeocystin, aeruginascin, psilocybin, vehicle, or fluoxetine via gavage to male Long Evans rats (n=10) and assessed immobility in the forced swim test (FST) to measure antidepressant efficacy. Additionally, Brain Derived Neurotrophic Factor expression was assessed using ELISA and Western Blot. Like fluoxetine, rats given psilocybin and norbaeocystin had significantly decreased immobility time compared to vehicle (p < 0.05). ELISAs showed increased Brain Derived Neurotrophic Factor expression in rat hippocampus after psilocybin treatment, which was not replicated by Western Blot. These results suggest norbaeocystin may have similar antidepressant effects to psilocybin, alternative to traditional antidepressants, warranting further investigation by preclinical and clinical scientists.

Clinical evaluation of psilocybin, a hallucinogen found in “magic mushrooms,” as treatment for severe depression and addiction is ongoing. Our enzymatic pathway to production of psilocybin involves norbaeocystin methyltransferase (PsiM), responsible for the iterative methylation of norbaeocystin, resulting in the production of psilocybin via monomethylated intermediate, baeocystin. Genetic variation between magic mushroom species have motivated this study to evaluate multiple PsiM variants for their ability to produce target compounds. Here, we examine the effect of genetic variability of the PsiM gene and attempt to create a biosynthetic production platform for producing higher titers of psilocybin than previously reported and strains capable of baeocystin-specific production. Screening of genes from Psilocybe cubensis, Psilocybe cyanescens, Panaeolus cyanescens, Gymnopilus dilepis and Gymnopilus junonius yielded production strains capable of exceeding 490 mg/L of psilocybin before optimization. Following fed-batch bioreactor scale-up, production of over 1.46 ± 0.13 g/L psilocybin was observed, surpassing the current benchmark titer of 1.16 g/L. This construct employs a constitutive promoter, enhancing the economic viability by removing the need for inducing chemicals. This work further enhances the viability of industrial batch production of psilocybin using fermentation and provides a basis for development of selective precursor production strains for combined medicinal use.

The visual effects of psychedelic drugs are well-known but not well understood. In this dissertation, I investigate psychedelic visual phenomenology. I provide evidence and analysis to argue that psychedelics selectively impact contextual modulation at multiple levels of mental function. I report preliminary results of two experiments from a pilot study, in which we measured contrast surround suppression in humans under the psychedelic drug psilocybin, using psychophysical and EEG event-related potential (ERP) methods. We found that psilocybin enhanced perceptual surround suppression, and strengthened surround suppression of neural responses, compared with placebo. The results support the hypothesis that psychedelics enhance contextual modulation in visual processes, which has theoretical as well as practical implications for psychedelic therapy, cognitive neuroscience, and philosophy.

Microbial platforms as a means of chemical production present a cost effective, environmentally friendly, and dynamic strategy for the synthesis of biofuels, pharmaceuticals, and food products. Most bacterial chemical production platforms utilize plasmid vectors for gene expression due to the ease of cloning and optimization. However, these vector-based systems necessitate costly antibiotics for genetic stability, making many processes less financially viable and potentially increasing the prevalence of antibiotic resistance in the environment. Therefore, it is desired to utilize gene expression systems integrated into the genomic DNA of the microbe, eliminating the antibiotic selection requirement. Here, we present a system for high efficiency pseudorandom integration of large metabolic pathways using a hyperactive Tn5 transposase coupled with a Cas9/λ-red recombinase-based method for small, site-specific genomic modifications to enable rapid in vivo transcriptional optimization. The norbaeocystin and psilocybin biosynthetic pathways will be utilized as proofs-of-concept. The process presented herein is designed to be agnostic to the pathway of interest and therefore widely applicable to enhance production of microbial products ranging from commodity chemicals to pharmaceuticals. Here, I show a screening, characterization, and validation pipeline which will result in transcriptionally balanced mutants with production comparable to that achieved through plasmid-based optimization approaches.

Psilocybin has come into the spotlight in recent years as a potential therapeutic for long-lasting anxiety and depression relief. Unfortunately, due to its current classification as a schedule I substance research on it has been limited. In order to fill in the gaps in our knowledge and better understand how psilocybin functions, a series of in vivo tests were performed resulting in the first data to show a dose-dependent response in Long-Evans rats. Furthermore, a precursor to psilocybin, norbaeocystin, was also tested separately and in combination. While alone norbaeocystin produced no dose-dependent response, the combination of psilocybin and norbaeocystin produced significantly higher rates of the head twitching behavior (HTRs) than psilocybin alone. To further investigate a possible mechanism of long-lasting anxiety and depression relief, fecal samples were also collected weekly from experimental animals and sequenced to analyze gut microbe composition. The results of which were significant changes across two major groups of bacteria (Bacteroidetes and Firmicutes) at the phylum level. These findings support the idea that psilocybin acts in a dose-dependent manner, its activity can be modulated by its precursors, and produces lasting effects on gut microbe populations

The modern psychiatric crisis has become a global epidemic as the prevalence of psychiatric disorders continues to rise. These numbers have only been exacerbated by the COVID-19 pandemic, and the long-term psychological effects resulting from the social isolation and fear of the disease have yet to be seen. Those already suffering from psychiatric disorders have limited options for treatment, as current therapeutic methods for mood, anxiety, and substance use disorders demonstrate high failure rates with many individuals suffering from treatment resistance. Individuals that do respond to modern therapies typically require treatment for several weeks or months, occasionally even years, before experiencing any reductions in their symptoms. Tryptamine psychedelics have been used for millennia by indigenous cultures through highly ritualized religious ceremonies to purge individuals of disease and offer spiritual guidance, however their application within modern medicine did not begin until Albert Hofmann’s discovery of LSD in 1938. The next several decades saw an explosion in clinical studies involving tryptamine psychedelics showcasing their ability to demonstrate immediate treatment after single doses in individuals suffering from diseases such as depression and PTSD, however research and clinical practices came to a halt after the passing of the Controlled Substances Act of 1970. As renewed interest in psychedelic medicine continues to grow, this review details the therapeutic potential of tryptamine psychedelics while exploring their current status within clinical trials.

n recent years, the study of psychedelic science has reemerged across a variety of fields. Psilocybin and LSD (Lysergic Acid Diethylamide) are two psychedelic substances receiving an influx of attention for their success treating issues such as depression, post-traumatic stress, and addiction. Psilocybin and LSD are still widely used despite their classification as illegal Schedule I substance. This study aims to learn more about current users with the following questions guiding this research: What are barriers limiting psilocybin and LSD consumption? What are the motivations behind use? What impacts are psilocybin and LSD having on users lives? I used Qualitative methods in the form of semi-structured interviews were used to gather information. Seventeen people were interviewed, and the resulting data was analyzed through categorization within excel spreadsheets. The reports of mental healing and positive change confirm that the healing capabilities of LSD and psilocybin are being used among the population. The narrative of psilocybin and LSD provided by users highlight many barrios to psychedelic access and use. This research also examines the social justice issues present in the psychedelic science movement.

Depression is one of the leading causes of disease globally. Over 300 million people globally suffer from depression (World Health Organization Depression Fact Sheet, 2020). The relative risk of all-cause mortality for those with depression is 1.7 times greater than the risk for the general public (Walker, McGee, & Druss, 2015). Recent studies have found promising evidence of the use of psilocybin as a treatment for various modalities of mental disease including depression (Carhart-Harris, et al., 2018) (Carhart-Harris, et al., 2016) (Davis, et al., 2021). The current meta-analysis seeks to find evidence of the effect of psilocybin with psychological support for treatment of depression across studies. Two studies were selected for analysis (n=42). Looking specifically at the Beck’s Depression Index scores it was found that the effects were significantly sustained across studies (Cohen’s d = 2.2936, 95% CI [.2629, 4.3243]) with a high degree of heterogeneity (t2 = 1.8877, 95% CI [.1607,>100], t = 1.3739, 95% CI [.4009,>10], I2 = 87.55%95% CI [37.45,>99. 7323], Q = 8.0318, p = .0046). Adding to the existing promising evidence supporting this current treatment. Both studies did not have any adverse effects and showed large effects of the treatment. The ability to have such an effect in lowering depression with no adverse effects is promising for the future of those who have depression. Current pharmacological treatments have effect sizes far lower than these studies and have many more side effects (Bet, Hugtenburg, Pennix, & Hoogendijk, 2013) (Turner & Rosenthal, 2008). The ability for these treatments to sustain a large reduction in depression shows great opportunity for the reduction of depressive symptoms in the population. Public health advocates and practitioners should pay close attention to this line of research for the use in advocacy campaigns and regulatory changes if future research supports these treatments.