Weed and Fasting: Should I Smoke?

On Friday, we evaluated autophagy as a fundamental cellular process involved in the degradation and recycling of cellular components, and its critical role in maintaining cellular homeostasis. How does the weed at your local dispensary relate to this? Well, recently the intersection of marijuana and autophagy has garnered some interest in the scientific community and I find it particularly intellectually stimulating. Cannabinoids (the active compounds in marijuana) interact with the endocannabinoid system and have been shown to influence autophagy in multiple ways.

THC and Autophagy

Research is indicating that THC, the primary psychoactive in marijuana, can induce autophagy in various cell types, including cancer cells. For Instance, a 2006 study demonstrated that cannabinoid receptors are novel targets for treating melanoma, suggesting that THC triggers autophagy leading to cell death in cancer cells. In 2009 a study found that THC induces autophagy-mediated cell death through stimulation of endoplasmic reticulum (ER) stress in human glioma cells. All of this indicates that THC’s ability to induce autophagy could be harnessed for its potential anti-tumor effects.

CBD and Autophagy

Cannabidiol (CBD), a less-psychoactive component of marijuana, also influences autophagy. A 2011 study reported that CBD induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy. This indicates that CBD can modulate autophagy and apoptosis, providing a potential therapeutic approach for cancer treatment. A 2012 study demonstrated that CBD inhibits angiogenesis (new capillaries forming out of preexisting blood vessels. In people with cancer, it allows for tumor growth) by multiple mechanisms, further underscoring its role in autophagy and its potential anti-cancer properties.

Neuroprotection and Autophagy

Autophagy plays a crucial role in neuroprotection, and cannabinoids have been shown to induce autophagy in neuronal cells. In 2005 researchers found that the endocannabinoid system promotes astroglial differentiation by acting on neural progenitor cells. This suggests that cannabinoids might contribute to neuroprotection indirectly through the enhanced induction of autophagy. In 2014, a study demonstrated that the cannabinoid CB2 receptor agonist, HU-910, reduces neuroinflammation, promotes neurogenesis, and demonstrates potential in assisting the recovery of cognitive deficits. These studies highlight the potential of cannabinoids in treating neurodegenerative diseases through the modulation of autophagy.

Inflammation and Immune Response

Cannabinoids also modulate the immune response and inflammation, partially through the regulation of autophagy. In 2015, Eisenstein and Meissler reviewed the effects of cannabinoids on T-cell function and resistance to infection, indicating that cannabinoids influence immune responses. In 2013, a study reported differential transcriptional profiles mediated by exposure to cannabidiol (CBD) and THC in BV-2 microglial cells, suggesting that cannabinoids can regulate autophagy and inflammation. This is significant for autoimmune and inflammatory diseases, where autophagy plays a critical role.

Mechanisms of Cannabinoid-Induced Autophagy

The mechanisms by which cannabinoids influence autophagy involve various signaling pathways. One key pathway is the PI3K/Akt/mTOR pathway, a major regulator of autophagy. 2006; Maccarrone discussed how endocannabinoids can act as both friends and foes of reproduction, implicating the PI3K/Akt/mTOR pathway in cannabinoid-induced autophagy. 2009; Soroceanu and Aldape highlighted potential targets and rescue strategies for cannabinoids in gliomas, emphasizing the importance of understanding these mechanisms for therapeutic development.

What Does This Mean?

Cannabinoids like THC and CBD have been shown to induce autophagy in various cell types, including cancer and neuronal cells. Cannabinoids also modulate immune responses and inflammation. In Short; if fasting to recover health, marijuana could enhance the hormonal, detoxification, anti-inflammatory, and anti-cancer benefits realized through autophagy. Because of this, Marijuana stands out as a potent assistant in the induction of autophagy. That is, if you can make it past the munchies.

A Caution

While the potential therapeutic benefits of cannabinoids in inducing autophagy are intriguing; recent studies have demonstrated a connection between marijuana use and an increased risk of depression or psychosis. A study published in JAMA Psychiatry in 2019 found that frequent marijuana use, especially during adolescence, is associated with a higher likelihood of developing depression and suicidal behavior in young adulthood. A meta-analysis in The Lancet Psychiatry highlighted a significant correlation between high-potency marijuana use and the onset of psychotic disorders. These studies highlight the importance of a cautious approach to marijuana consumption, and the potential harms of regular consumption.

References: Autophagy

• Blázquez, C., Carracedo, A., Lorente, M., Egia, A., González-Feria, L., Haro, A., … & Guzmán, M. (2006). Cannabinoid receptors as novel targets for the treatment of melanoma. FASEB Journal, 20(1), 2633-2635. doi:10.1096/fj.06-6769com.
• Salazar, M., Carracedo, A., Salanueva, I. J., Hernández-Tiedra, S., Lorente, M., Egia, A., … & Guzmán, M. (2009). Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. Journal of Clinical Investigation, 119(5), 1359-1372. doi:10.1172/JCI37948.
• Shrivastava, A., Kuzontkoski, P. M., Groopman, J. E., & Prasad, A. (2011). Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy. Molecular Cancer Therapeutics, 10(7), 1161-1172. doi:10.1158/1535-7163.MCT-10-1100.
• Solinas, M., Massi, P., Cantelmo, A. R., Cattaneo, M. G., Cammarota, R., Bartolini, D., … & Monti, E. (2012). Cannabidiol inhibits angiogenesis by multiple mechanisms. British Journal of Pharmacology, 167(6), 1218-1231. doi:10.1111/j.1476-5381.2012.02050.x.
• Aguado, T., Monory, K., Palazuelos, J., Stella, N., Cravatt, B., Lutz, B., … & Guzmán, M. (2005). The endocannabinoid system promotes astroglial differentiation by acting on neural progenitor cells. Journal of Neuroscience, 25(29), 6830-6838. doi:10.1523/JNEUROSCI.4147-04.2005.
• Avraham, H. K., Jiang, S., Fu, Y., Rockenstein, E., Makriyannis, A., Zvonok, A., … & Avraham, S. (2014). The cannabinoid CB2 receptor agonist, HU-910, reduces neuroinflammation, promotes neurogenesis, and rescues cognitive deficits in a mouse model of Alzheimer’s disease. Journal of Neuroscience, 34(49), 16152-16162. doi:10.1523/JNEUROSCI.1710-14.2014.
• Eisenstein, T. K., & Meissler, J. J. (2015). Effects of cannabinoids on T-cell function and resistance to infection. Journal of Neuroimmune Pharmacology, 10(2), 204-216. doi:10.1007/s11481-015-9603-3.
• Juknat, A., Pietr, M., Kozela, E., Rimmerman, N., Levy, R., Gao, F., … & Vogel, Z. (2013). Differential transcriptional profiles mediated by exposure to the cannabinoids cannabidiol and Δ9-tetrahydrocannabinol in BV-2 microglial cells. British Journal of Pharmacology, 165(8), 2512-2528. doi:10.1111/j.1476-5381.2011.01453.x.
• Maccarrone, M. (2006). Endocannabinoids: friends and foes of reproduction. Progress in Lipid Research, 45(5), 447-456. doi:10.1016/j.plipres.2006.03.003.
• Soroceanu, L., & Aldape, K. D. (2009). Cannabinoids in gliomas: potential targets and rescue strategies. CNS Oncology, 1(2), 153-163. doi:10.2217/cns.11.10.

References: Mental Health

• Gobbi, G., Atkin, T., Zytynski, T., Wang, S., Askari, S., Boruff, J., … & Mayo, N. (2019). Association of cannabis use in adolescence and risk of depression, anxiety, and suicidality in young adulthood: a systematic review and meta-analysis. JAMA Psychiatry, 76(4), 426-434. doi:10.1001/jamapsychiatry.2018.4500
• Marconi, A., Di Forti, M., Lewis, C. M., Murray, R. M., & Vassos, E. (2016). Meta-analysis of the association between the level of cannabis use and risk of psychosis. Schizophrenia Bulletin, 42(5), 1262-1269. doi:10.1093/schbul/sbw003
• Di Forti, M., Quattrone, D., Freeman, T. P., Tripoli, G., Gayer-Anderson, C., Quigley, H., … & Murray, R. M. (2019). The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI): a multicentre case-control study. The Lancet Psychiatry, 6(5), 427-436.