Depression affects 322 million people worldwide1 with a lifetime prevalence of 20%2. In the United States, $71 billion is spent treating depression each year by individual patients, government, and insurance programs, and depressive disorders are the sixth most costly health condition overall3. Depression tends to be chronic with high rates of recurrence and remission4.
Depression is widely treated with antidepressants, such as selective serotonin reuptake inhibitors (SSRI’s), but some patients are unresponsive, and many do not achieve full remission5. They are also associated with many side effects. In fact, in a large analysis of 131 randomised, placebo-controlled trials, it was found that while SSRI’s may reduce depressive symptoms, they increase the risk of serious and non-serious adverse events to the extent that the researchers concluded “the potential small beneficial effects seem to be outweighed by harmful effects”6. Safer, more effective treatments are clearly needed to reduce the burden of care and improve quality of life.
Cannabis and Depression
As with anxiety, it is reported that people suffering from depression often self-medicate to treat their depressive symptoms7. Medical cannabis users are also widely using cannabis to treat anxiety, with a recent large review study finding that 34% of medical cannabis users cited depression as a reason for medical cannabis use8. Many users report substituting cannabis for anti-depressant drugs, for reasons such as a belief that cannabis is safer, has fewer side effects, and manages their symptoms better9.
It is possible that cannabis may work as an anti-depressant because of its many targets in the body. Anti-depressant medications tend to only have a single or unimodal mode of action, and usually act on serotoninergic neurotransmission systems. In contrast, cannabinoids (especially CBD) have multimodal activity, affecting multiple systems. One of the systems targeted by cannabinoids is the serotonergic system, which is also the target of SSRI’s. But in addition, cannabinoids also act on other targets associated with mood, such as the opioid system. Many of the targets of cannabinoids are known to be involved in depression and are targeted by anti-depressants10.
Cannabinoids also target the endocannabinoid system, which is found throughout the body and has been implicated in virtually all physiological processes, including emotional processing. The endocannabinoid system is clearly linked to depression, with depressed populations showing low levels of circulating “endocannabinoids”, which are cannabinoids produced by the body11. When people suffering from depression engage in physical exercise, an increase in endocannabinoids may be responsible for improvements in mood12. Plant-based or phytocannabinoids, such as THC and CBD, mimic the actions of endocannabinoids and may have the same effects.
Cannabis and Depression—Research Evidence
Considering the interactions of cannabinoids with mood regulating systems in the body, there is surprisingly little research exploring cannabis and depression. A review study published in 2017 looked at all of the research evidence and found a total of 9 studies that used cannabis for therapeutic purposes, of which 7 noted improvements in depressed mood following the use of cannabis for medical purposes13. In contrast, there are other studies that suggest that cannabis use results in a modestly increased risk of depression. However, these studies looked at the non-medical use of cannabis, and do not show that cannabis use is causing depression. It is possible that people who are already depressed are self-medicating with cannabis, and since there are also non-medical studies that show the opposite pattern, with cannabis use being associated with a lower risk of depression, this is not a well-established relationship13. It is important here to distinguish between the therapeutic or medical use of cannabis, and non-medical use, which may be quite different. The finding that 7 of 9 medical use studies showed a benefit is notable and suggests a potential use for cannabis in the treatment of depression, although many questions remain unanswered, such as effective doses and forms of cannabis.
There has also been little research exploring CBD (the major non-psychoactive cannabinoid in cannabis) and depression, at least in humans. The bulk of the research has been in pre-clinical rodent studies, in which CBD has consistently been found to be very effective in reducing depressive behaviour. CBD has also been found to induce positive changes in rodent brains, such as increasing the growth and development of new brain cells10. Unfortunately, it is unclear whether these findings translate to people, as very few studies have looked at whether CBD can be used to improve mood or treat depression in humans. Subjective reports do suggest that it may be beneficial, with a recent study finding that among 400 patients who reported using CBD to achieve “mood-improving” effects, 250 reported that CBD worked “very well by itself”14. Given the positive effects of CBD in animal models of depression, and its interactions with multiple systems involved in depression, CBD has been proposed as a possible “novel antidepressant”15. At this point, the efficacy and dosing of CBD as an antidepressant remains to be determined. There is currently an ongoing registered clinical trial using CBD to for treatment resistant depression, using a very high dose of up to 1000mg of CBD per day (NCT04732169).
There is subjective evidence that supports the use of both cannabis and CBD to improve mood and reduce depression. However, there is a near total lack of clinical research looking at whether cannabis or cannabinoids can be used to treat depression. Since cannabinoids, especially CBD, interact with critical mood regulating systems in the body, it seems likely that they may have antidepressant action. This idea is supported by pre-clinical animal research and by studies linking the endocannabinoid system to depression. As more clinical evidence becomes available, cannabinoids may emerge as viable antidepressants.
- World Health Organization. (2017) https://apps.who.int/iris/bitstream/handle/10665/254610/WHO-MSD-MER-2017.2-eng.pdf
- Hasin, D. S., Sarvet, A. L., Meyers, J. L., Saha, T. D., Ruan, W. J., Stohl, M., & Grant, B. F. (2018). Epidemiology of Adult DSM-5 Major Depressive Disorder and Its Specifiers in the United States. JAMA psychiatry, 75(4), 336–346. https://doi.org/10.1001/jamapsychiatry.2017.4602
- American Psychological Association, https://www.apa.org/monitor/2017/03/numbers
- Burcusa, S. L., & Iacono, W. G. (2007). Risk for recurrence in depression. Clinical psychology review, 27(8), 959–985. https://doi.org/10.1016/j.cpr.2007.02.005
- Al-Harbi K. S. (2012). Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient preference and adherence, 6, 369–388. https://doi.org/10.2147/PPA.S29716
- Jakobsen, J. C., Katakam, K. K., Schou, A., Hellmuth, S. G., Stallknecht, S. E., Leth-Møller, K., Iversen, M., Banke, M. B., Petersen, I. J., Klingenberg, S. L., Krogh, J., Ebert, S. E., Timm, A., Lindschou, J., & Gluud, C. (2017). Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis. BMC psychiatry, 17(1), 58. https://doi.org/10.1186/s12888-016-1173-2
- Osborn, L. A., Lauritsen, K. J., Cross, N., Davis, A. K., Rosenberg, H., Bonadio, F., & Lang, B. (2015). Self-Medication of Somatic and Psychiatric Conditions Using Botanical Marijuana. Journal of psychoactive drugs, 47(5), 345–350. https://doi.org/10.1080/02791072.2015.109643
- Kosiba, J. D., Maisto, S. A., & Ditre, J. W. (2019). Patient-reported use of medical cannabis for pain, anxiety, and depression symptoms: Systematic review and meta-analysis. Social science & medicine (1982), 233, 181–192. https://doi.org/10.1016/j.socscimed.2019.06.005
- Lucas, P., Baron, E. P., & Jikomes, N. (2019). Medical cannabis patterns of use and substitution for opioids & other pharmaceutical drugs, alcohol, tobacco, and illicit substances; results from a cross-sectional survey of authorized patients. Harm reduction journal, 16(1), 9. https://doi.org/10.1186/s12954-019-0278-6
- Silote, G. P., Sartim, A., Sales, A., Eskelund, A., Guimarães, F. S., Wegener, G., & Joca, S. (2019). Emerging evidence for the antidepressant effect of cannabidiol and the underlying molecular mechanisms. Journal of chemical neuroanatomy, 98, 104–116. https://doi.org/10.1016/j.jchemneu.2019.04.006
- Gorzalka, B. B., & Hill, M. N. (2011). Putative role of endocannabinoid signaling in the etiology of depression and actions of antidepressants. Progress in neuro-psychopharmacology & biological psychiatry, 35(7), 1575–1585. https://doi.org/10.1016/j.pnpbp.2010.11.021
- Meyer, J. D., Crombie, K. M., Cook, D. B., Hillard, C. J., & Koltyn, K. F. (2019). Serum Endocannabinoid and Mood Changes after Exercise in Major Depressive Disorder. Medicine and science in sports and exercise, 51(9), 1909–1917. https://doi.org/10.1249/MSS.0000000000002006
- Walsh, Z., Gonzalez, R., Crosby, K., S Thiessen, M., Carroll, C., & Bonn-Miller, M. O. (2017). Medical cannabis and mental health: A guided systematic review. Clinical psychology review, 51, 15–29. https://doi.org/10.1016/j.cpr.2016.10.002
- Corroon, J., & Phillips, J. A. (2018). A Cross-Sectional Study of Cannabidiol Users. Cannabis and cannabinoid research, 3(1), 152–161. https://doi.org/10.1089/can.2018.0006
- Calapai, G., Mannucci, C., Chinou, I., Cardia, L., Calapai, F., Sorbara, E. E., Firenzuoli, B., Ricca, V., Gensini, G. F., & Firenzuoli, F. (2019). Preclinical and Clinical Evidence Supporting Use of Cannabidiol in Psychiatry. Evidence-based complementary and alternative medicine : eCAM, 2019, 2509129. https://doi.org/10.1155/2019/2509129
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