Psilocybin - What's So Magical About These Mushrooms?

 

 

“Magic” or Therapeutic

    Psilocybin is a substance found in a number of mushroom species that can be ingested to cause psychoactive effects. It is considered a psychedelic or hallucinogenic drug sharing similarities to other psychedelics in terms of effects. Psilocybin is classified as a prodrug, or a substance that is inactive until metabolized into an active drug after ingesting. There has been an increase in research on psychedelics due to their potential in helping with mental health disorders and neuroplasticity. Mood and mental disorders are rapidly increasing and place an enormous burden on the individual and society. Although its research has been controversial, psilocybin (mushrooms) have been found to have positive effects on mental health and neuroplasticity.

Mental Health

    Psilocybin has a long history of use in traditional medicine and spiritual practices, particularly among Indigenous cultures in Central and South America. However, the compound was classified as a Schedule I drug in the United States in the 1970s, which has limited its legal use and research on its therapeutic potential (Zeiss et al., 2021). The Schedule I classification means that the substance is considered to have a high potential for abuse and no accepted medical use. This classification has made it difficult for researchers to conduct clinical trials and for patients to access psilocybin-based therapies. Despite the regulations recent studies have suggested that psilocybin may have therapeutic potential for mental health conditions, including depression.
    A study found that a single dose of psilocybin was associated with significant reductions in depression and anxiety symptoms in patients with life-threatening cancer. It also found that psilocybin-assisted psychotherapy was associated with significant reductions in depression symptoms in patients with treatment-resistant depression. One proposed mechanism is that psilocybin increases neuroplasticity and promotes neurogenesis in the brain, which may help to alleviate symptoms of depression. Psilocybin has also been found to reduce activity in the default mode network, which is hyperactive in patients with depression and may contribute to rumination and negative self-talk (Zeiss et al., 2021).
    Another study found that psilocybin may be effective in reducing symptoms of depression. The study compared both esketamine and psilocybin, and found that they were effective in reducing symptoms of depression, but psilocybin may have longer lasting effects. The study also noted that both esketamine and psilocybin have potential side effects, including dissociation and hallucinations, and that their use should be closely monitored by trained medical professionals (Psiuk et al., 2022).

Addiction

    Psilocybin might not only have use in depression, but also addiction. Traditional addiction treatments, such as behavioral therapy and medication, have limited effectiveness. Psilocybin may offer a new approach to addiction treatment. Psilocybin may also have therapeutic effects on addiction by increasing neuroplasticity and promoting neural connectivity in areas of the brain involved in addiction, such as the prefrontal cortex and the amygdala. Psilocybin has been found to reduce self thinking and negative thoughts. This reduction in activity may help to alleviate symptoms of addiction, such as cravings and negative thought patterns. Furthermore, psilocybin may help to promote positive behavioral changes by increasing feelings of connectedness and empathy. These changes may help individuals to better understand and cope with the underlying causes of their addiction (Principe, n.d.).

    A study explored the potential of psilocybin as a treatment for addiction, particularly for smoking cessation and alcohol dependence. The study found that a single high dose of psilocybin was associated with significant reductions in smoking behavior and cravings, with effects lasting for up to 12 months. They also found that psilocybin-assisted therapy was associated with significant reductions in alcohol dependence, with participants reporting decreased alcohol use and fewer alcohol-related problems after treatment (Principe, n.d.).
    Psilocybin may have potential as a treatment for other types of addiction, including opioid dependence and cocaine addiction. Preclinical studies in animal models have found that psilocybin can reduce self-administration of opioids and cocaine, as well as reduce drug-seeking behavior (Principe, n.d.)

Psilocybin and Neurotransmitters    

     Psilocybin itself is not thought to be psychoactive, until it is ingested and metabolized into a substance called psilocin, which is highly psychoactive. Psilocybin has been found to have an extreme effect on thalamo-cortical neurotransmission as it acts on various molecular targets. Examples are other serotonin receptor subtypes, subtypes of histamine, dopamine, adrenergic receptors, and serotonin transporters (Wojtas et al., 2021).
    Recent research has suggested that psilocin’s activity activates a subtype of serotonin receptor known as the 5-HT2A receptor which is known to cause the drug’s psychedelic effects. The activation of 5-HT2A receptors stimulates dopaminergic VTA cells or serotonergic dorsal raphe neurons which leads to an increase of Dopamine (DA) and 5-HT levels (Wojtas et al., 2021). This is important as the brain's ventral tegmental area (VTA) is responsible for cognitive processes such as learning, memory, regulation of reward, and addictive behaviors through DA release.
    While researchers have some understanding on how psilocin affects the brain, they are still unsure on how this increase in brain activity can lead to the subjective experiences people have while taking psilocybin. Repeated neuronal exposure to psilocybin over multiple days will lead to an increase in tolerance and reduced effectiveness caused by a decrease in 5-HT2A receptors (Wojtas et al., 2021). Overall, psilocybin is not considered to be addictive and is found to be safe in clinical settings.

The “magic” is Neuroplasticity

An unfortunate effect of several neuropsychiatric diseases is a decrease in dendritic spine density in the brain and the ability to promote cortical neuronal growth. Psilocin, the psychoactive compound in psilocybin, has been suggested to promote functional and structural neuroplasticity through activating 5-HT2A. Specifically, the 5-HTP2AR serotonin subtype (Vargas et al., 2023). A research study conducted by Vargas and colleagues used molecular and genetic procedures to demonstrate that intracellular 5-HT2ARs mediate the plasticity-promoting properties of psilocybin. They also demonstrated that the therapeutic effects experienced after the administration are long lasting and sustainable (Vargas et al., 2023).

    A research study conducted by Shao and colleagues found that a single dose of psilocybin led to a 10% increase in spine size and density, caused by an increase in the rate of spine formation (Shao et al., 2021). With structural remodeling happening fast within 24 hours and was persistent 1 month later. Their results suggest that psilocybin mediated synaptic rewiring in the cortex happens fast and provides a structural trace for long term integration of experiences and beneficial actions (Shao et al., 2021). The possibility to disrupt psilocybin’s acute behavioral effects without messing up structural plasticity can have strong implications towards positive treatments, but more research needs to be done on human subjects (Shao et al., 2021; Vargas et al., 2023).

REFERENCES 

Principe. (n.d.). Neuropharmacological analysis of the antiaddictive and therapeutic effects of psilocybin. SURG, 14(1).

Psiuk, Nowak, Dycha, Lopuszanska, Kurzepa, & Samardakiewicz. (2022, September 28). Esketamine and Psilocybin—The Comparison of Two Mind-Altering Agents in Depression Treatment: Systematic Review. International Journal of Molecular Sciences, 23(19). https://doi.org/10.3390/ijms231911450

Shao, L. X., Liao, C., Gregg, I., Davoudian, P. A., Savalia, N. K., Delagarza, K., & Kwan, A. C. (2021). Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron, 109(16), 2535–2544.e4. https://doi.org/10.1016/j.neuron.2021.06.008

Vargas, M. V., Dunlap, L. E., Dong, C., Carter, S. J., Tombari, R. J., Jami, S. A., Cameron, L. P., Patel, S. D., Hennessey, J. J., Saeger, H. N., McCorvy, J. D., Gray, J. A., Tian, L. (2023). Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors. Science (New York, N.Y.), 379(6633), 700–706 https://doi.org/10.1126/science.adf0435

Wojtas, A., Bysiek, A., Wawrzczak-Bargiela, A., Szych, Z., Majcher-Maślanka, I., Herian, M., Maćkowiak, M., & Gołembiowska, K. (2022). Effect of Psilocybin and Ketamine on Brain Neurotransmitters, Glutamate Receptors, DNA and Rat Behavior. International Journal of molecular sciences, 23(12), 6713. https://doi.org/10.3390/ijms23126713

Zeiss, Gahr, & Graf. (2021, September 28). Rediscovering Psilocybin as an Antidepressive Treatment Strategy. Pharmaceuticals, 14(10). https://doi.org/10.3390/ph14100985