Ask any regular user of cannabis and they’ll tell you that they just don’t get as high as they used to, despite using an ever increasing amount of cannabis. Welcome to the world of cannabis tolerance, where the highs are lower and medicinal effects are blunted.


To help us understand what this phenomenon is and how to combat it, let’s start with the basics. First, let it be known that tolerance develops to many therapeutic compounds, not just cannabis. We see this with all sorts of things, from over-the-counter pain-killers to opioids, and coffee to alcohol. It’s a common response by the body and can be beneficial or detrimental, depending on the substance and the circumstances.


By definition, tolerance, is a state of adaptation in which exposure to the drug causes changes within the body, which result in a diminution of one or more of the drug’s effects over time[i].


Tolerance to many of the effects of cannabis can start to develop only after a few doses[ii], and studies conducted in normal subjects have shown tolerance develops to the effects of cannabis on mood, intra-ocular pressure, sleep, psychomotor performance, nausea, and the cardiovascular system.


There are two distinct ways tolerance develops in individuals: pharmacodynamic tolerance (which occurs at the cellular level), and pharmacokinetic tolerance (which develops at the tissue or organ level). Both these types will develop simultaneously in all individuals, but one will usually dominate.


Pharmacodynamic tolerance


A number of pre-clinical studies suggest that cannabis tolerance of the pharmacodynamic type is mostly linked to changes in the availability of the CB1 cannabinoid receptors to activation. There are two independent (but interrelated) molecular pathways producing these changes. First is receptor desensitization, which is where we see uncoupling of the receptor from the downstream signal events within the cell. Second, is receptor down-regulation, which results from the internalization and/or degradation of the receptor[iii].


To complicate the picture, within the brain, tolerance appears to vary according to different regions, which suggests cellular and tissue-specific mechanisms that regulate desensitization/down-regulation[iv]. This likely occurs in other tissues and organs as well, helping to explain why tolerance develops to some of the effects of cannabis and cannabinoids but not others, and why the clinical presentation of tolerance will vary from person to person.


In situations where cannabis tolerance has developed primarily through the pharmacodynamic pathway, a “tolerance break” is likely needed to help reset the body’s response. When executed properly, a tolerance break lasts two to four weeks, and requires abstinence during that time. This timeframe makes sense as it correlates with the elimination of THC from the body following daily use.


Pharmacokinetic tolerance


Cannabis tolerance of the pharmacokinetic type has also been reported[v]. As mentioned, this occurs at the organ/tissue level and includes changes in absorption (the body up-regulates certain enzymes that prevent absorption), biotransformation (the alteration of cannabinoids by the body, or by microbes in our digestive tract when cannabinoids are ingested), distribution (where within the body cannabinoids are sent to), and excretion (the body up-regulates enzymes related to the breakdown and elimination of cannabinoids).


In many cases, the natural tendency in most cases of tolerance is to use ever-increasing doses. Slowly over time, many users find themselves using greater and greater quantities, or products with stronger potencies. However, this can be a very costly situation for those who don’t grow their own medicine. In a clinical setting, it appears tolerance to the effects of cannabinoids can potentially be minimized by combining lower doses of cannabis or cannabinoids along with one or more additional therapeutic agents[vi]. There are products on the market that specifically target pharmacokinetic tolerance (e.g., Enhanced EffectTM by Cannanda) that work by improving absorption of cannabinoids and help to saturate receptors. Alternatively, a tolerance break would also be very effective in cases of pharmacokinetic tolerance.


Variability of Tolerance


As previously mentioned, the dynamics of tolerance vary with respect to the different effects; tolerance to some of the effects develops more readily and rapidly than to others[vii]. For example, a study of chronic daily cannabis smokers reported regionally-selective down-regulation of brain cannabinoid CB1 receptors[viii]. This finding helps explain the results from another previously published study that showed subjects who were frequent users of cannabis displayed blunted responses to many of the typical effects of THC. While THC can cause—or increase the risk of—cognitive impairments, psychotomimetic tendencies, altered perceptions, anxiety, and increased cortisol levels (compared to controls), frequent cannabis users experienced these to a far lesser degree. Interestingly, however, tolerance did not develop to THC’s euphoric effects[ix]. Similarly, another study reported that tolerance to some of the effects of cannabis, including tolerance to the “high,” but not to the appetite-stimulating effect[x].




So if you’re a regular user of cannabis, you can bet that you’re experiencing some degree of tolerance. Further, your tolerance will develop differently than your friends or family members, and how you each experience tolerance will vary. Whether you decide to overcome tolerance by taking a tolerance break, or by using Enhanced EffectTM, it’s all an individual journey. Experiment with different approaches until you find what works best with your body and physiology, and get back to receiving the full benefits of cannabis once again.




Lee Know is a licensed naturopathic doctor, the recipient of several awards, and the author of Mitochondria and the Future of Medicine (Chelsea Green Publishing, 2018). He has previously held positions as a medical advisor, scientific evaluator, and director of research and development for major organizations, and currently leads Scientific Affairs for Cannanda.


Disclaimer: The information in this article is for educational purposes only, and not to be construed as medical advice. It is not meant to diagnose, or in any way replace qualified medical supervision. For diagnosing or treating any medical condition, consult with your health care provider.


[i] Lynch, M. E. and Watson, C. P. (2006). The pharmacotherapy of chronic pain: a review. Pain Res.Manag. 11: 11-38.

[ii] Institute of Medicine. First, do no harm: consequences of marijuana use and abuse. Marijuana and medicine: Assessing the science base. Joy, J. E., Watson, S. J., and Benson, J. A. Washington, DC: National Academy Press, 1999.

[iii] Wu, D. F., Yang, L. Q., Goschke, A., Stumm, R. and others. (2008). Role of receptor internalization in the agonist-induced desensitization of cannabinoid type 1 receptors. J.Neurochem. 104: 1132-1143.

[iv] Gonzalez, S., Cebeira, M., and Fernandez-Ruiz, J. (2005). Cannabinoid tolerance and dependence: a review of studies in laboratory animals. Pharmacol.Biochem.Behav. 81: 300-318.

[v] Maldonado, R. (2002). Study of cannabinoid dependence in animals. Pharmacol.Ther. 95: 153-164.

[vi] Pertwee, R. G. (2009). Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br.J.Pharmacol. 156: 397-411.

[vii] De Vry, J., Jentzsch, K. R., Kuhl, E., and Eckel, G. (2004). Behavioral effects of cannabinoids show differential sensitivity to cannabinoid receptor blockade and tolerance development. Behav.Pharmacol. 15: 1-12.

[viii] Hirvonen, J., Goodwin, R. S., Li, C. T., Terry, G. E. and others. (2012). Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Mol.Psychiatry. 17: 642-649.

[ix] D’Souza, D. C., Ranganathan, M., Braley, G., Gueorguieva, R. and others. (2008). Blunted psychotomimetic and amnestic effects of delta-9-tetrahydrocannabinol in frequent users of cannabis. Neuropsychopharmacology. 33:2505-2516.

[x] Haney, M., Ward, A. S., Comer, S. D., Foltin, R. W. and others. (1999). Abstinence symptoms following smoked marijuana in humans. Psychopharmacology (Berl). 141: 395-404.

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