How do THC and CBD differ?

By Josh Kaplan, Ph.D.

THC has both recreational and therapeutic benefits but carries risk for short- and long-term health consequences. This risk is lessened by CBD which can block THC’s negative effects. On its own, CBD has a range of therapeutic benefits mediated by a diverse set targets in the brain and body that can be activated at particular doses.   

THC and CBD are just two of many cannabinoids that have recreational and therapeutic benefits. However, they’re the most well-studied and exemplify how you can achieve drastically different brain and body effects through targeted cannabinoid composition and dosing.

Let’s start with THC. THC is a weak activator of CB1 receptors and reduces neurotransmitter release15. These effects are responsible for the high sought by recreational users. Beyond the high, THC can enhance creativity, elevate mood, and have a host of therapeutic benefits such as relieve pain and reduce nausea19-21. But in some people, too much THC can cause adverse side effects like anxiety and paranoia22. This is one of the reasons that many chose to avoid products that only have THC since these negative effects are exacerbated in the absence of other cannabinoids.

Over time, THC consumption can have long-lasting consequences. Repeated THC consumption eventually leads to a weakening of THC’s effects on the brain and body in a process known as tolerance23. Tolerance occurs from repeated activation of CB1 receptors by THC, which leads to a reduction in the number of CB1 receptors present and the strength of their effect on neurotransmitter release. Consequently, numerous psychological problems may develop including impaired sleep24 and learning and memory difficulties25,26. The consistency of these negative effects, however, are debatable and numerous studies have found contradicting evidence. This likely stems from the fact that these effects can be reversed after a short period of abstinence27,28. Furthermore, the degree of tolerance to THC differs as a function of brain and body region, and even cell type. Scientists are working to better understand which of THC’s medicinal benefits can still be achieved despite tolerance to its high-inducing effects.

The challenge then is to find a way to harness THC’s therapeutic benefits on mind and body while minimizing these negative side effects. One approach is to add other cannabinoids to the product being consumed. CBD is an abundant cannabinoid commonly consumed for its therapeutic benefits. CBD blocks many of the adverse effects from THC31 while enabling it to maintain its pain-relieving and anti-oxidant qualities. On its own, CBD has a spectrum of therapeutic effects ranging from anxiety reduction to preventing epileptic seizures17,20,32-35.

CBD’s wide-ranging benefits stem from its many brain and body targets15. These targets can be selectively activated with deliberate dosing strategies. CBD blocks many of THC’s negative side effects by blocking its ability to activate CB1 receptors. But while CBD blocks CB1 receptors, it activates CB2 receptors for powerful anti-inflammatory effects19. Beyond the endogenous cannabinoid system, low to moderate doses of CBD reduce anxiety by activating brain receptors for the neurotransmitter, serotonin16,36. These effects are lost at higher CBD doses when its effects on serotonin receptors are overpowered by its effects on other brain receptors. For instance, high CBD doses block the activity of GPR55 receptors, which may be responsible for its anti-epileptic17 and anti-cancer effects37,38.

An additional benefit of CBD is that it is well-tolerated by both children and adults20,34. While it’s important to note that the long-term consequences of CBD on the developing brain have not been assessed, CBD has minimal side effects at most ages. Even at doses well above what’s normally consumed for therapeutic purposes, CBD at worst led to exhaustion and in some cases diarrhea34. Although because CBD was used as an add-on treatment in these studies, it’s unclear if these side effects resulted from an interaction between drugs, as opposed to CBD’s effects on its own.

So just between two abundant phytocannabinoids, THC and CBD, one can achieve a host of recreational and therapeutic benefits that can be altered by simply shifting dosing. Indeed, this combination has been utilized in the FDA-approved drug, Sativex, which has demonstrated therapeutic benefits across a range of disorders20. However, many believe that the range of these benefits can be expanded, the strength of their abilities enhanced, and side effects minimized through the addition of other cannabis-derived chemicals18. This is the current and future medicinal cannabis state, and it’s substantially improving people’s quality of life.

Summary: THC and CBD are two of many cannabinoids with therapeutic benefits. THC’s therapeutic benefits are limited by adverse side effects and risk of developing tolerance. These negative effects can be mitigated by CBD, which has numerous therapeutic benefits through its actions on a diverse set of brain and body targets. The current and future state of medicinal cannabis involves proper titration of cannabinoid combination, dose, and delivery method.



15        Pertwee, R. G. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol 153, 199-215, doi:10.1038/sj.bjp.0707442 (2008).

16        Resstel, L. B. et al. 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol 156, 181-188, doi:10.1111/j.1476-5381.2008.00046.x (2009).

17        Kaplan, J. S., Stella, N., Catterall, W. A. & Westenbroek, R. E. Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome. Proc Natl Acad Sci U S A 114, 11229-11234, doi:10.1073/pnas.1711351114 (2017).

18        Russo, E. B. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol 163, 1344-1364, doi:10.1111/j.1476-5381.2011.01238.x (2011).

19        Nagarkatti, P., Pandey, R., Rieder, S. A., Hegde, V. L. & Nagarkatti, M. Cannabinoids as novel anti-inflammatory drugs. Future Med Chem 1, 1333-1349, doi:10.4155/fmc.09.93 (2009).

20        Russo, E. B., Guy, G. W. & Robson, P. J. Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine. Chem Biodivers 4, 1729-1743, doi:10.1002/cbdv.200790150 (2007).

21        Mackie, K. Cannabinoid receptors as therapeutic targets. Annu Rev Pharmacol Toxicol 46, 101-122, doi:10.1146/annurev.pharmtox.46.120604.141254 (2006).

22        Freeman, D. et al. How cannabis causes paranoia: using the intravenous administration of ∆9-tetrahydrocannabinol (THC) to identify key cognitive mechanisms leading to paranoia. Schizophr Bull 41, 391-399, doi:10.1093/schbul/sbu098 (2015).

23        Zhuang, S. et al. Effects of long-term exposure to delta9-THC on expression of cannabinoid receptor (CB1) mRNA in different rat brain regions. Brain Res Mol Brain Res 62, 141-149 (1998).

24        Bolla, K. I. et al. Sleep disturbance in heavy marijuana users. Sleep 31, 901-908 (2008).

25        Nestor, L., Roberts, G., Garavan, H. & Hester, R. Deficits in learning and memory: parahippocampal hyperactivity and frontocortical hypoactivity in cannabis users. Neuroimage 40, 1328-1339, doi:10.1016/j.neuroimage.2007.12.059 (2008).

26        Crean, R. D., Crane, N. A. & Mason, B. J. An evidence based review of acute and long-term effects of cannabis use on executive cognitive functions. J Addict Med 5, 1-8, doi:10.1097/ADM.0b013e31820c23fa (2011).

27        Jager, G., Kahn, R. S., Van Den Brink, W., Van Ree, J. M. & Ramsey, N. F. Long-term effects of frequent cannabis use on working memory and attention: an fMRI study. Psychopharmacology (Berl) 185, 358-368, doi:10.1007/s00213-005-0298-7 (2006).

28        Hanson, K. L. et al. Longitudinal study of cognition among adolescent marijuana users over three weeks of abstinence. Addict Behav 35, 970-976, doi:10.1016/j.addbeh.2010.06.012 (2010).

29        French, L. et al. Early Cannabis Use, Polygenic Risk Score for Schizophrenia and Brain Maturation in Adolescence. JAMA Psychiatry 72, 1002-1011, doi:10.1001/jamapsychiatry.2015.1131 (2015).

30        Vaucher, J. et al. Cannabis use and risk of schizophrenia: a Mendelian randomization study. Mol Psychiatry, doi:10.1038/mp.2016.252 (2017).

31        Zuardi, A. W., Shirakawa, I., Finkelfarb, E., & Karniol, I.G. Action of cannabidiol on the anxiety and other effects produced by delta-9-THC in normal subjects. Psychopharmacology 76, 245-250 (1982).

32        Blessing, E. M., Steenkamp, M.M., Manzanares, J., & Marmar, C.R. Cannabidiol as a potential treatment for anxiety disorders. Neurotherapeutics 12, 825-836, doi:10.1007/s13311-015-0387-1 (2015).

33        Devinsky, O. et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 55, 791-802, doi:10.1111/epi.12631 (2014).

34        Devinsky, O. et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med 376, 2011-2020, doi:10.1056/NEJMoa1611618 (2017).

35        Hurd, Y. L. Cannabidiol: Swinging the Marijuana Pendulum From ‘Weed’ to Medication to Treat the Opioid Epidemic. Trends Neurosci 40, 124-127, doi:10.1016/j.tins.2016.12.006 (2017).

36        Bergamaschi, M. M. et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients. Neuropsychopharmacology 36, 1219-1226, doi:10.1038/npp.2011.6 (2011).

37        Piñeiro, R., Maffucci, T. & Falasca, M. The putative cannabinoid receptor GPR55 defines a novel autocrine loop in cancer cell proliferation. Oncogene 30, 142-152, doi:10.1038/onc.2010.417 (2011).

38        Kargl, J. et al. GPR55 promotes migration and adhesion of colon cancer cells indicating a role in metastasis. Br J Pharmacol 173, 142-154, doi:10.1111/bph.13345 (2016).