Overview of Tolerance
When a stimulus is repeated over time, the body and mind quickly adapt in response, trying to compensate for the change the stimulus caused. This process is ubiquitous in terms of everyday life. In terms of exercising, an individual will adapt to the amount of weight they lift or distance they run making it easier for the body to perform the task without disturbance. This same principle applies to drugs in a process called developing a tolerance. In short, if an individual uses a drug repeatedly over a long period of time they will almost always develop some sort of tolerance. A tolerance can apply to the physical or psychological effects of the drug being used. There are 3 main components of tolerance which are pharmacodynamic, pharmacokinetic, and behavioral. Pharmacodynamic tolerance is the process of high concentrations of a substance constantly binding with a particular receptor, desensitizing it through constant interaction (Bespalov, Müller, Relo & Hudzik, 2016). Once a receptor has been desensitized, further stimulation will lead to internalization which is the removal of the receptor from the cell surface (Daigle, Kearn & Mackie, 2008). Pharmacokinetic tolerance refers to the bodies increased ability to break down a substance after repeated use resulting in faster absorption, metabolism, and excretion. Behavioral tolerance occurs when an individual learns to function despite repeated exposure to a drug. Behavioral tolerance also includes a conditioned tolerance which follows Pavlovian principles. Situational cues are associated with drug administration and the removal of these environmental cues will result in an enhanced pharmacologic effect (Dumas & Pollack, 2008).
Tolerance to Cannabis
Individuals who regularly consume cannabis, whether it be for recreational or medical purposes, will eventually develop both a physical and psychological tolerance to its effects. Research suggests that tolerance to the subjective effects of cannabis develops faster than physical and can occasionally result in a full tolerance which is the complete absence of its cognitive effects. Partial tolerance can occur to the acute intoxicating, psychotomimetic, and cardiac effects following repeated exposure. Each of these aspects plays a critical role in an individuals ability to benefit from cannabis (Colizzi & Bhattacharyya, 2018).
In studies where a single dose of cannabis was administered regular users reported less pronounced and shorter intoxication when compared to non-regular users. Several studies looking at repeated cannabis exposure demonstrate a significant decrease in the intoxicating and subjective effects for regular users and found that partial recovery was achieved after one week of abstinence. Finally, a study comparing different routes of administration indicated that oral consumption elicited intoxicating and subjective effects only in non-regular users, whereas vaporization and smoking had similar effects in regular and non-regular users (Colizzi & Bhattacharyya, 2018).
Several studies have demonstrated that non-regular users perform worse on tasks related to cognitive abilities such as psychomotor ability, divided attention, motor impulsivity, learning, and working memory than regular users. This suggests that tolerance develops to the detrimental cognitive effects of cannabis with regular consumption. More recent studies suggest no significant effects of repeated synthetic cannabinoid, dronabinol, administration on similar cognitive tasks in regular users suggesting complete tolerance (Colizzi & Bhattacharyya, 2018).
Recent studies looking at the psychoactive effects of cannabis found that regular users experience less anxiety, psychotomimetic symptoms, and perceptual changes than non-regular users. Researchers also reported that regular users experience increases in feelings of vigor while non-regular users experience greater sedation. This is further evidence of partial tolerance to the psychoactive effects of cannabis with regular exposure (Colizzi & Bhattacharyya, 2018).
While there is still some debate, studies conducted in larger samples confirmed that after smoking cannabis tachycardia is lower or less prolonged in regular users compared to non-regular users. Several of these studies also demonstrated no measurable difference in blood pressure for regular and non-regular users (Colizzi & Bhattacharyya, 2018).
Physiological and Neurophysiological
Early studies indicated that administration of cannabis-induced several responses in regular users which lessen in magnitude upon repeated exposure including body temperature increase, skin temperature decrease, salivary flow decrease, intraocular pressure decrease, and EEG alpha slowing. These studies also demonstrated that no tolerance developed to the decrease in serum hematocrit, hemoglobin, bilirubin, and plasma testosterone induced by repeated exposure to cannabis. Recent studies indicate that a single intravenous administration of THC induced an increase in cortisol and brain-derived neurotrophic factor which was less pronounced in regular users compared to non-regular users. Lastly, previous cannabis use did not modulate dopamine release following intravenous administration of THC (Colizzi & Bhattacharyya, 2018).
Know Your Dose
Oftentimes as a patient assistant, I encountered individuals who developed complete tolerance to the intoxicating and behavioral effects of cannabis with a partial tolerance to the physiological effects. This can be devastating to a medical patient who is looking for relief from a chronic condition. There are several things that can be done to reduce cannabis tolerance and improve your bodies endocannabinoid system:
- Taking time off cannabis is an easy way to reset your tolerance and endocannabinoid system. A 2011 study published in the Journal of Molecular Psychiatry demonstrated in rodents that approximately 4 weeks cannabis free was enough to restore CB1 density (Hirvonen et al., 2011).
- Using CBD can help increase endocannabinoid signaling and protect against harms caused by chronic use. A 2018 study found that 200mg of CBD restored parts of the hippocampus that were altered by prolonged cannabis use in regular users (Beale et al., 2018).
- Exercise can significantly enhance the sensitivity of CB1 receptors according to a 2009 study published in the Journal of Neuropsychopharmacology (De Chiara et al., 2009). This could help reduce or reverse the desensitization caused by regular consumption of cannabis.
- There is mounting evidence that diet plays a key role in endocannabinoid system health. Secondary compounds in vegetables and spices enhance the activity of CB2 receptors (Gertsch, 2017). Healthy fats from fish, seeds, and nuts up-regulate CB1 receptor gene expression (Lafourcade et al., 2011).
Derek Espinoza, Baked Bros Director of Education
Beale, C., Broyd, S., Chye, Y., Suo, C., Schira, M., & Galettis, P. et al. (2018). Prolonged Cannabidiol Treatment Effects on Hippocampal Subfield Volumes in Current Cannabis Users. Cannabis And Cannabinoid Research, 3(1), 94-107. doi: 10.1089/can.2017.0047
Bespalov, A., Müller, R., Relo, A., & Hudzik, T. (2016). Drug Tolerance: A Known Unknown in Translational Neuroscience. Trends In Pharmacological Sciences, 37(5), 364-378. doi: 10.1016/j.tips.2016.01.008
Colizzi, M., & Bhattacharyya, S. (2018). Cannabis use and the development of tolerance: a systematic review of human evidence. Neuroscience & Biobehavioral Reviews, 93, 1-25. doi: 10.1016/j.neubiorev.2018.07.014
Daigle, T., Kearn, C., & Mackie, K. (2008). Rapid CB1 cannabinoid receptor desensitization defines the time course of ERK1/2 MAP kinase signaling. Neuropharmacology, 54(1), 36-44. doi: 10.1016/j.neuropharm.2007.06.005
De Chiara, V., Errico, F., Musella, A., Rossi, S., Mataluni, G., & Sacchetti, L. et al. (2009). Voluntary Exercise and Sucrose Consumption Enhance Cannabinoid CB1 Receptor Sensitivity in the Striatum. Neuropsychopharmacology, 35(2), 374-387. doi: 10.1038/npp.2009.141
Dumas, E., & Pollack, G. (2008). Opioid Tolerance Development: A Pharmacokinetic/Pharmacodynamic Perspective. The AAPS Journal, 10(4). doi: 10.1208/s12248-008-9056-1
Gertsch, J. (2017). Cannabimimetic phytochemicals in the diet - an evolutionary link to food selection and metabolic stress adaptation?. British Journal Of Pharmacology, 174(11), 1464-1483. doi: 10.1111/bph.13676
Hirvonen, J., Goodwin, R., Li, C., Terry, G., Zoghbi, S., & Morse, C. et al. (2011). Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Molecular Psychiatry, 17(6), 642-649. doi: 10.1038/mp.2011.82
Lafourcade, M., Larrieu, T., Mato, S., Duffaud, A., Sepers, M., & Matias, I. et al. (2011). Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions. Nature Neuroscience, 14(3), 345-350. doi: 10.1038/nn.2736