Know Your Medicine: Tolerance and Reverse Tolerance

The concept of cannabis tolerance is quite interesting. Now that patients are using preparations that contain different prominent cannabinoids, including delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), and cannabinol (CBN), the question of tolerance no longer relates to THC only.

Tolerance is defined as the need to use more of a drug to get the desired effect. Stated another way, less of an effect is achieved with a previously effective amount. It is clear that tolerance to THC develops following repeated exposure. How much exposure is needed to develop tolerance appears to be different for each person. Animal research in the 1990s suggested that tolerance developed due to a reduction of cannabinoid receptors in the brain after they were exposed to chronic THC.

A 2012 study in humans found the same results, namely that chronic, heavy users of THC-rich cannabis had a decreased number of cannabinoid receptors when compared to non-users. The same study also showed that a 4-week abstinence from THC resulted in an increased number of receptors, revealing that tolerance to THC is reversible. Interestingly, the researchers in this study also reported that different parts of the brain became tolerant at different rates. For instance, one may be using THC to treat pain and anxiety and may find with chronic, heavy use that the anxiety is lessened but the effects on pain relief are lost. Tolerance to the effects of THC is easy to reverse with either abstinence or significant reduction of dosing for a few days. The vast majority of THC users do not experience withdrawal symptoms, however, if this does occur, CBD-rich cannabis can counteract most discomfort.

Cannabidiol (CBD) does not cause tolerance as it does not work by binding to the cannabinoid receptor the same way that THC does. On occasion, some of my patients have reported getting beneficial therapeutic results with CBD who then report that they think they have developed tolerance. However, upon further questioning, most had started a new preparation at the time when the effects were lost. What they interpret as tolerance is likely not; it is much more likely, given the lack of standardization in the production of most CBD preparations, that the product was different in potency or strain and was not delivering the same beneficial effect.

Clinically, it appears that THCA and CBDA, the cannabinoids found in the raw (unheated) flower, do not cause tolerance. Similarly, CBN does not appear to cause tolerance although there has been no research focused on this property.

Reverse tolerance, also called drug sensitization, means that less drug is needed to get the desired effect. This is the opposite of tolerance. One example of reverse tolerance is when an alcoholic becomes intoxicated from a smaller amount of alcohol due to liver damage from chronic use. Reverse tolerance has been described for alcohol, stimulants, opiates, nicotine, and antidepressants. Reverse tolerance does not occur in the majority of people using these substances and likely reflects genetic differences in how one absorbs and metabolizes drugs.

In a 1981 study that looked at cannabinoids as potential antiepileptics, animals developed tolerance to THC in all of the seizure models tested. In contrast, CBD showed evidence of reverse tolerance, meaning the seizures were effectively treated with lower doses over the three weeks of treatment. Quite interestingly, there are dozens of reports of reverse tolerance by parents of children with epilepsy who have been using CBD successfully to reduce seizures.

A number of my pediatric patients who were responding positively to CBD oil for a number of months were reported by the parents to have increased frequency of seizures without the presence of a known trigger (such as the reduction of an antiepileptic drug or signs of an illness, both variables known to trigger seizures). Suspecting reverse tolerance, or “CBD saturation” as this phenomenon is known colloquially, I recommended that the patient skip a few doses and restart at a lower dose, which resolved the issue. Not everyone using CBD experiences reverse tolerance.

Research looking at the mechanisms of action for reverse tolerance for substances other than CBD suggests that various non-cannabinoid receptors, including GABA receptors and NMDA receptors, are likely involved. CBD is also known to interact with these receptors. Another hypothesis of the mechanism of action for CBD reverse tolerance is that CBD enhances endocannabinoid function leading to less CBD needed over time. Likely multiple and overlapping mechanisms of action are contributing to this phenomenon.

Although my clinical experience with “CBD reverse tolerance” is mainly in children with epilepsy, some adult patients report that after a few months on CBD with desired results, they find that they don’t need as much and decrease the dose without the loss of beneficial effects.

Tolerance and reverse tolerance are concepts that all cannabis patients should understand. Knowing your medicine and the possibility that you may need to adjust dosing due to these possibilities will help you troubleshoot your medication regimen if you lose the desired effects.


Oviedo, A., et al. Chronic Cannabinoid Administration Alters Cannabinoid Receptor Binding in Rat Brain: A Quantitative Autoradiographic Study. Brain Research (1993) 616: 293-302.

Fan, F., et al. Cannabinoid Down-regulation without Alteration of the Inhibitory Effect of CP 55,940 on Adenyl Cyclase IN the Cerebellum of CP 55,940-tolerant Mice. Brain Research (1996) 706: 13-20 1996.

Hirvonen, Jussi, et al. “Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers.” Molecular psychiatry 17.6 (2012): 642-649.

Vermersch, Patrick. “Sativex® (tetrahydrocannabinol + cannabidiol), an endocannabinoid system modulator: basic features and main clinical data.” Expert review of neurotherapeutics 11.sup4 (2011): 15-19.

Karler, Ralph, and Stuart A. Turkanis. “The cannabinoids as potential antiepileptics.” The Journal of Clinical Pharmacology 21.S1 (1981).

Karler, R., et al. “Blockade of “reverse tolerance” to cocaine and amphetamine by MK-801.” Life sciences 45.7 (1989): 599-606.

Camarini, Rosana, et al. “MK‐801 Blocks the Development of Behavioral Sensitization to Ethanol.” Alcoholism: Clinical and Experimental Research 24.3 (2000): 285-290.

Woo, Sang-Hee, et al. “Inhibition of baclofen on morphine-induced hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity.” Pharmacological research 43.4 (2001): 335-340

Leave a Reply

Your email address will not be published. Required fields are marked *