As cannabis use becomes federally legal in many states and more frequently used, researchers have gained interest in the effects of cannabis and its ingredients. There are an estimated 13 million people in the world who have a cannabis dependence (Colizzi et al., 2020), and research has proven that cannabis has substantial benefits in diseases such as Amyotrophic Lateral Sclerosis (ALS), multiple sclerosis, epilepsy, and Crohn’s disease (Mayo Clinic Staff, 2021). The correlation between cannabis use and mental illness, specifically psychosis, is also becoming a popular subject of research.
Delta-9-tetrahydrocannabinol (Delta-9-THC), the critical psychoactive component of THC, has been associated with acute psychosis and a range of effects on schizophrenia (Colizzi et al., 2020). Specifically, research suggests a strong correlation between the use of cannabis and both the exacerbation of schizophrenia symptoms and onset of psychosis (Ganesh et al., 2020). It is critical to understand the neuropharmacological mechanisms behind Delta-9-THC to better study the impact of cannabis on mental illness and psychosis, as this relationship may have major implications on the treatment of mental illness and the public health spectrum as a whole. Specifically, is it a coincidence that both onset of psychosis and prevalence of cannabis use is most common in young ages?
Delta-9-THC plays a significant role in inducing psychological effects, including both positive symptoms (e.g., paranoia, conceptual disorganization, suspicion, delusions, altered perceptions) and negative symptoms (e.g., emotional withdrawal, low spontaneity, blunted affect) of psychosis. Delta-9-THC works as a partial agonist at the CB1 receptor (endocannabinoid receptor type 1), which are located on GABAergic and glutamatergic terminals in regions including the cerebellum, basal ganglia, and frontal cortex. THC, including the Delta-9-THC compound, activates the mesolimbic dopamine system, which is largely understood to have implications on motivated behaviors and reward systems (D'Souza et al., 2004).
A study on striatal glutamate levels in healthy individuals attempted to explore the psychomimetic effects of Delta-9 THC and the correlation between an increase in striatal glutamate and psychotic-like symptoms (Colizzi et al., 2020). Healthy individuals who had not used cannabis in the past 6 months were injected with Delta-9-THC and tested utilizing 1H_MRS Spectra, an imaging technique that allows for the measurement and detection of various brain metabolites, in this case, glutamate levels. Compared to individuals not sensitive to the psychomimetic effects of Delta-9-THC, those who did develop psychotic-like symptoms had lower baseline levels of striatal glutamate and a 2.27x higher increase after Delta-9-THC injection (Colizzi et al., 2020). In other words, those with lower baseline levels of striatal glutamate and increased prior cannabis exposure were more susceptible to the psychomimetic effects of Delta-9-THC and experienced a higher increase in striatal glutamate post-Delta-9-THC injection (Colizzi et al., 2020). These research findings have important implications with regards to the vulnerabilities an individual may have in experiencing Delta-9-THC induced psychosis, as higher striatal glutamate levels may contribute to cannabis-induced psychosis and lower baseline striatal glutamate levels may be a sign of increased sensitivity to psychomimetic effects (Colizzi et al., 2020).
Another possible mechanism of Delta-9-THC is neural oscillations, or fluctuations in synaptic and/or neuronal activity that can be measured using electroencephalography (EEG). Studies have found that 1) Delta-9-THC can implicate psychotic symptoms and 2) neural oscillation frequencies above 20 Hz are correlated with both schizophrenia and psychosis (Nottage et al. 2015). Results show that the increased magnitude of frequencies (reduced low beta and increased high gamma) are correlated along with positive symptoms on the Positive and Negative Syndrome Scale (PANSS), specifically delusion-related symptoms. Researchers hypothesized that it may be possible that the increases in gamma oscillations may be due to the overactivation of the cortex by THC (Nottage et al. 2015).
The mechanistic and pharmacological understanding of Delta-9-THC plays a critical role in understanding the etiology of psychosis and other mental illnesses. Certain individuals may be at a higher vulnerability or have a genetic predisposition that makes them more likely to experience psychosis when exposed to Delta-9-THC. As we better understand predispositions to psychosis through genetic testing, we can be better informed about cannabis as a risk factor in psychosis and take more preventative approaches.
About the Author
Olivia Weber is a sophomore at Harvard College, studying Neuroscience.
References:
Delta-9-tetrahydrocannabinol (Delta-9-THC), the critical psychoactive component of THC, has been associated with acute psychosis and a range of effects on schizophrenia (Colizzi et al., 2020). Specifically, research suggests a strong correlation between the use of cannabis and both the exacerbation of schizophrenia symptoms and onset of psychosis (Ganesh et al., 2020). It is critical to understand the neuropharmacological mechanisms behind Delta-9-THC to better study the impact of cannabis on mental illness and psychosis, as this relationship may have major implications on the treatment of mental illness and the public health spectrum as a whole. Specifically, is it a coincidence that both onset of psychosis and prevalence of cannabis use is most common in young ages?
Delta-9-THC plays a significant role in inducing psychological effects, including both positive symptoms (e.g., paranoia, conceptual disorganization, suspicion, delusions, altered perceptions) and negative symptoms (e.g., emotional withdrawal, low spontaneity, blunted affect) of psychosis. Delta-9-THC works as a partial agonist at the CB1 receptor (endocannabinoid receptor type 1), which are located on GABAergic and glutamatergic terminals in regions including the cerebellum, basal ganglia, and frontal cortex. THC, including the Delta-9-THC compound, activates the mesolimbic dopamine system, which is largely understood to have implications on motivated behaviors and reward systems (D'Souza et al., 2004).
A study on striatal glutamate levels in healthy individuals attempted to explore the psychomimetic effects of Delta-9 THC and the correlation between an increase in striatal glutamate and psychotic-like symptoms (Colizzi et al., 2020). Healthy individuals who had not used cannabis in the past 6 months were injected with Delta-9-THC and tested utilizing 1H_MRS Spectra, an imaging technique that allows for the measurement and detection of various brain metabolites, in this case, glutamate levels. Compared to individuals not sensitive to the psychomimetic effects of Delta-9-THC, those who did develop psychotic-like symptoms had lower baseline levels of striatal glutamate and a 2.27x higher increase after Delta-9-THC injection (Colizzi et al., 2020). In other words, those with lower baseline levels of striatal glutamate and increased prior cannabis exposure were more susceptible to the psychomimetic effects of Delta-9-THC and experienced a higher increase in striatal glutamate post-Delta-9-THC injection (Colizzi et al., 2020). These research findings have important implications with regards to the vulnerabilities an individual may have in experiencing Delta-9-THC induced psychosis, as higher striatal glutamate levels may contribute to cannabis-induced psychosis and lower baseline striatal glutamate levels may be a sign of increased sensitivity to psychomimetic effects (Colizzi et al., 2020).
Another possible mechanism of Delta-9-THC is neural oscillations, or fluctuations in synaptic and/or neuronal activity that can be measured using electroencephalography (EEG). Studies have found that 1) Delta-9-THC can implicate psychotic symptoms and 2) neural oscillation frequencies above 20 Hz are correlated with both schizophrenia and psychosis (Nottage et al. 2015). Results show that the increased magnitude of frequencies (reduced low beta and increased high gamma) are correlated along with positive symptoms on the Positive and Negative Syndrome Scale (PANSS), specifically delusion-related symptoms. Researchers hypothesized that it may be possible that the increases in gamma oscillations may be due to the overactivation of the cortex by THC (Nottage et al. 2015).
The mechanistic and pharmacological understanding of Delta-9-THC plays a critical role in understanding the etiology of psychosis and other mental illnesses. Certain individuals may be at a higher vulnerability or have a genetic predisposition that makes them more likely to experience psychosis when exposed to Delta-9-THC. As we better understand predispositions to psychosis through genetic testing, we can be better informed about cannabis as a risk factor in psychosis and take more preventative approaches.
About the Author
Olivia Weber is a sophomore at Harvard College, studying Neuroscience.
References:
- Colizzi, M., Weltens, N., McGuire, P. et al.(2020) Delta-9-tetrahydrocannabinol increases striatal glutamate levels in healthy individuals: implications for psychosis. Mol Psychiatry 25, 3231–3240 . https://doi.org/10.1038/s41380-019-0374-8
- D'Souza, D., Perry, E., MacDougall, L. et al. (2004). The Psychotomimetic Effects of Intravenous Delta-9-Tetrahydrocannabinol in Healthy Individuals: Implications for Psychosis. Neuropsychopharmacol 29, 1558–1572 . https://doi.org/10.1038/sj.npp.1300496
- Ganesh, S., Cortes-Briones, J., Ranganathan, M., Radhakrishnan, R., Skosnik, P. D., & D'Souza, D. C. (2020). Psychosis-Relevant Effects of Intravenous Delta-9-Tetrahydrocannabinol: A Mega Analysis of Individual Participant-Data from Human Laboratory Studies. The international journal of neuropsychopharmacology, 23(9), 559–570. https://doi.org/10.1093/ijnp/pyaa031
- Mayo Clinic Staff. (2021). Medical marijuana. Mayo Clinic. Retrieved from https://www.mayoclinic.org/healthy-lifestyle/consumer-health/in-depth/medical-marijuana/art-20 137855
- Nottage, J.F., Stone, J., Murray, R.M. et al. (2015). Delta-9-tetrahydrocannabinol, neural oscillations above 20 Hz and induced acute psychosis. Psychopharmacology 232, 519–528 https://doi.org/10.1007/s00213-014-3684-1
