The endocannabinoid system (ECS) plays a crucial role in regulating various physiological processes, including pain, inflammation, sleep and immune function (1). The ECS consists of endogenous cannabinoids (endocannabinoids), cannabinoid receptors, and enzymes responsible for synthesizing and degrading endocannabinoids (2). CB1 receptors are one of the two types of main cannabinoid receptors and are primarily found in the brain, where they modulate neurotransmitter release from (3). Medical cannabis, which contains various phytocannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), has been shown to have potential therapeutic benefits for a variety of conditions, including chronic pain, epilepsy, and multiple sclerosis (4). Understanding the mechanisms of action of medical cannabis, including how it affects CB1 receptor signaling, is critical for healthcare professionals who prescribe it to patients.
The ECS is a complex system that regulates a multitude of physiological processes. The discovery of endocannabinoids and their receptors has led to a better understanding of the mechanisms underlying their effects on the body (1). The CB1 receptor, one of the two primary cannabinoid receptors, is widely expressed in the brain, and its activation modulates neurotransmitter release (3). Medical cannabis, which contains various phytocannabinoids, has been shown to have potential therapeutic benefits for a variety of conditions (4). However, the effects of chronic high THC cannabis use on CB1 receptor signaling are not as well researched and understood (5). It has been observed that patients on stable larger doses of medical cannabis may experience downregulation of CB1 receptors, which could potentially lead to reduced efficacy of medical cannabis and increased risk of adverse effects (2). On the other hand, downregulation of CB1 receptors may also have potential benefits, such as reducing the risk of cannabis use disorder, decreasing the intoxicating effects of THC, and improving metabolic health (6, 7). Understanding the mechanisms underlying CB1 receptor downregulation and its potential implications is critical for healthcare professionals who prescribe medical cannabis to patients.
II. CB1 Receptor Downregulation
CB1 receptor downregulation is a phenomenon that occurs after prolonged exposure to cannabis and is characterized by a decrease in the density of CB1 receptors in the brain (8). Chronic cannabis use has been shown to lead to downregulation of CB1 receptors, which may have both potential benefits and harms (9). The downregulation of CB1 receptors may result in reduced cannabis tolerance, decreased psychotropic effects, improved cardiometabolic health, and a lower risk of developing cannabis use disorder (10). On the other hand, downregulation of CB1 receptors may also potentially lead to unwanted adverse effects such as impairments in cognitive function, motivation, and reward processing (11).
Research has demonstrated that the extent of CB1 receptor downregulation is related to the dosage and frequency of cannabis use. For example, studies have found that individuals who use cannabis frequently or at higher doses have a greater degree of CB1 receptor downregulation compared to those who use cannabis less frequently or at lower doses (12). Moreover, the degree of CB1 receptor downregulation can be influenced by individual differences, such as genetic factors (13).
The mechanisms underlying CB1 receptor downregulation are not fully understood but involve alterations in CB1 receptor membrane trafficking and degradation (14). Specifically, chronic activation of CB1 receptors by THC leads to the internalization of receptors, reducing their availability on the cell surface (15). This process is thought to be mediated by the upregulation of regulatory proteins, such as β-arrestin, which facilitates the internalization and recycling of CB1 receptors (16).
In addition to the potential benefits and harms associated with CB1 receptor downregulation, research has also suggested that the phenomenon may have implications for medical use of cannabis (17). For example, downregulation of CB1 receptors may be a result from the development of tolerance to the therapeutic effects of THC, which may limit the long-term efficacy as a treatment option (18).
In summary, CB1 receptor downregulation is a complex phenomenon that can have both potential benefits and harms. While downregulation may reduce the risk of cannabis use disorder and decrease the psychotropic effects of THC, it may also impair cognitive function and motivation. The extent of CB1 receptor downregulation is influenced by various factors, such as the frequency and dosage of cannabis use and individual differences. Further research is needed to fully understand the mechanisms and implications of CB1 receptor downregulation for both recreational and medical cannabis use.
III. Potential Benefits of CB1 Receptor Downregulation
CB1 receptor downregulation, although generally seen as a negative consequence of chronic cannabis use, may have some potential benefits in diseases like diabetes, obesity, substance use disorder, anxiety, and chronic pain (19, 20, 21, 22). These benefits include a reduction in the rewarding effects of THC, which may help to decrease the risk of addiction or dependence (12). Additionally, CB1 receptor downregulation has been shown to be associated with decreased anxiety and depressive-like behaviors in preclinical studies (23,24). This suggests that chronic cannabis use may have therapeutic potential for certain psychiatric disorders, such as anxiety and depression, although further research is needed to confirm these findings. Furthermore, CB1 receptor downregulation has been associated with reduced inflammation and neurotoxicity in animal models of brain injury and neurodegenerative diseases (25,26). These findings suggest that cannabis or cannabinoids may have potential therapeutic applications in these areas, although further research is needed to determine the optimal dosing and duration of treatment.
It is important to note that while there may be potential benefits of CB1 receptor downregulation, these benefits must be weighed against the potential negative consequences, such as the development of tolerance and the potential for cognitive impairment with chronic use (27). Additionally, the mechanisms underlying CB1 receptor downregulation are not fully understood and likely vary depending on individual factors such as genetics and frequency of use. Future research is needed to fully understand the implications of CB1 receptor downregulation and to develop safe and effective therapeutic strategies for the use of cannabis and cannabinoids.
IV. Potential Harms of CB1 Receptor Downregulation
The potential harms associated with CB1 receptor downregulation are an area of concern in the use of cannabis and cannabinoid-based therapies. Chronic use of cannabis has been shown to result in decreased CB1 receptor density and signaling efficacy, leading to the development of tolerance and potential cognitive impairment (28). Additionally, studies have shown that downregulation of CB1 receptors can result in decreased anti-inflammatory effects, potentially leading to increased neuroinflammation and neurodegeneration (29).
Furthermore, genetic factors can also play a role in CB1 receptor downregulation, with mutations in the CNR1 gene resulting in altered expression levels and localization of the receptor (30). This variability in response to cannabis and cannabinoids based on genetic factors can lead to unpredictable outcomes and potential harm to the individual. Other potential harms of CB1 receptor downregulation include the potential for increased risk of addiction and withdrawal symptoms, as well as the potential for negative impacts on mental health (27). As such, it is important for individuals to carefully consider the potential risks and benefits before using cannabis or cannabinoid-based therapies, and to be aware of the potential for CB1 receptor downregulation and associated harms.
V. Implications for Healthcare Professionals
Healthcare professionals should be aware of the implications of CB1 receptor downregulation and potential harms associated with it. One important consideration is the potential for addiction and withdrawal symptoms with chronic use of cannabis (12). Patients who regularly use cannabis may eventually require higher doses to achieve the desired effects due to downregulation of the CB1 receptor, which could further exacerbate the downregulation of CB1 receptors (32). Furthermore, CB1 receptor downregulation has been linked to cognitive impairment and may be particularly problematic for patients living with certain psychiatric disorders, several of which have been linked to decreased levels of CB1 receptors (33,34). Additionally, the potential for negative impacts on mental health should be considered, as downregulation of CB1 receptors has been implicated in chronic stress, anxiety, and depressive disorders (34,35).
To address these concerns, healthcare professionals should prioritize providing education on the potential risks associated with chronic use of cannabinoids, particularly when higher levels of THC are used. Additionally, patients who are at increased risk of cognitive impairment from certain pre-existing mental health disorders should be closely monitored and may benefit more from alternative treatment options. Research into the genetic factors that contribute to CB1 receptor downregulation may also be valuable in identifying patients who may be particularly susceptible to these risks. Overall, healthcare professionals must balance the potential therapeutic benefits of cannabis with the risks associated with CB1 receptor downregulation to provide effective a safe treatment options for their patients.
Stefan Broselid, Ph.D.
Editor-In-Chief, Aurea Care Medical Science Journal
- Pacher, P., & Kunos, G. (2013). Modulating the endocannabinoid system in human health and disease–successes and failures. FEBS Journal, 280(9), 1918-1943. doi: 10.1111/febs.12260
- Di Marzo, V., & Piscitelli, F. (2015). The Endocannabinoid System and its Modulation by Phytocannabinoids. Neurotherapeutics, 12(4), 692-698. doi: 10.1007/s13311-015-0374-6
- Pertwee RG. The pharmacology of cannabinoid receptors and their ligands: An overview. Int J Obes (Lond). 2006;30(S1):S13-S18. doi:10.1038/sj.ijo.0803272
- Hill KP. Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems: A Clinical Review. JAMA. 2015;313(24):2474-2483. doi:10.1001/jama.2015.6199
- Yanes JA, McKnight KS, Tseng KY. The Endocannabinoid System in Brain Reward Processes. Pharmaceuticals. 2020;13(11):337. doi:10.3390/ph13110337
- Schreiner AM, Dunn ME. Residual effects of cannabis use on neurocognitive performance after prolonged abstinence: A meta-analysis. Exp Clin Psychopharmacol. 2012;20(5):420-429. doi:10.1037/a0029117
- Bermudez-Silva FJ, Cardinal P, Cota D. The role of the endocannabinoid system in the neuroendocrine regulation of energy balance. J Psychopharmacol. 2012;26(1):114-124. doi:10.1177/0269881111419260
- Hirvonen J, Goodwin RS, Li CT, et al. Quantification of brain CB1 receptors with [11C]OMAR PET during a randomized, placebo-controlled, double-blind pilot study. Neuroimage. 2012;60(3):457-467. doi:10.1016/j.neuroimage.2011.12.044
- Russo EB, Marcu J, Hohmann AG. Cannabis and the Endocannabinoid System: Focus on the Benefits and Harms of Cannabinoid Receptor Ligands. ACS Pharmacol Transl Sci. 2020;3(4):292-327. doi:10.1021/acsptsci.0c00056
- Volkow ND, Swanson JM, Evins AE, et al. Effects of Cannabis Use on Human Behavior, Including Cognition, Motivation, and Psychosis: A Review. JAMA Psychiatry. 2016;73(3):292-297. doi:10.1001/jamapsychiatry.2015.3278
- Weinstein A, Livny A, Weizman A. Brain Imaging Studies on the Cognitive, Pharmacological and Neurobiological Effects of Cannabis in Humans: Evidence from Studies of Adult Users. Curr Pharm Des. 2016;22(42):6366-6379. doi:10.2174/1381612822666160822151323
- Hirvonen J, Goodwin RS, Li CT, et al. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Mol Psychiatry. 2012;17(6):642-649. doi:10.1038/mp.2011.82
- Byrd AL, Jarrett MA, Wolff B, et al. Genetic variation in the endocannabinoid system and response to Cognitive Behavior Therapy for child anxiety disorders. J Anxiety Disord. 2020;74:102273. doi:10.1016/j.janxdis.2020.102273
- Howlett AC, Barth F, Bonner TI, et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002;54(2):161-202.
- Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Vogt LJ, Sim-Selley LJ. Chronic delta9-tetrahydrocannabinol treatment produces a time-dependent loss of cannabinoid receptors and cannabinoid receptor-activated G proteins in rat brain. J Neurochem. 1999;73(6):2447-2459. doi:10.1046/j.1471-4159.1999.0732447.x
- Gyombolai P, Boros E, Hunyady L, Turu G. Differential β-arrestin2 requirements for constitutive and agonist-induced internalization of the CB1 cannabinoid receptor. Mol Cell Endocrinol. 2013;372(1-2):116-127. doi:10.1016/j.mce.2013.03.013
- Grotenhermen F, Müller-Vahl K. The therapeutic potential of cannabis and cannabinoids. Dtsch Arztebl Int. 2012;109(29-30):495-501. doi:10.3238/arztebl.2012.0495
- reivogel CS, Childers SR, Deadwyler SA, Hampson RE, Vogt LJ, Sim-Selley LJ. Chronic delta9-tetrahydrocannabinol treatment produces a time-dependent loss of cannabinoid receptors and cannabinoid receptor-activated G proteins in rat brain. J Neurochem. 1999;73(6):2447-2459. doi:10.1046/j.1471-4159.1999.0732447.x
- Silvestri C, Di Marzo V. The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell Metab. 2013;17(4):475-490. doi:10.1016/j.cmet.2013.03.001
- Soria G, Mendizábal V, Touriño C, et al. Lack of CB1 cannabinoid receptor impairs cocaine self-administration. Neuropsychopharmacology. 2005;30(9):1670-1680. doi:10.1038/sj.npp.1300707
- Patel S, Roelke CT, Rademacher DJ, Cullinan WE, Hillard CJ. Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal axis. Endocrinology. 2004;145(12):5431-5438. doi:10.1210/en.2004-0450
- Guindon J, Hohmann AG. The endocannabinoid system and pain. CNS Neurol Disord Drug Targets. 2009;8(6):403-421. doi:10.2174/187152709789824660
- Hill MN, Patel S, Campolongo P, Tasker JG, Wotjak CT, Bains JS. Functional interactions between stress and the endocannabinoid system: from synaptic signaling to behavioral output. J Neurosci. 2010;30(45):14980-14986. doi:10.1523/JNEUROSCI.4283-10.2010
- McLaughlin RJ, Hill MN, Gorzalka BB. A critical role for prefrontocortical endocannabinoid signaling in the regulation of stress and emotional behavior. Neurosci Biobehav Rev. 2014;42:116-131. doi:10.1016/j.neubiorev.2014.02.006
- Jiang T, Zhang YD, Zhou JS, et al. CB1 receptor downregulation attenuates neuroinflammation and neurodegeneration in a mouse model of traumatic brain injury. J Neuroinflammation. 2019;16(1):234. doi:10.1186/s12974-019-1623-3.
- Cao C, Li Y, Liu H, et al. Cannabinoids for treatment of Alzheimer’s disease: moving toward the clinic. Front Pharmacol. 2019;10:1220. doi:10.3389/fphar.2019.01220
- Volkow ND, Baler RD, Compton WM, Weiss SR. Adverse health effects of marijuana use. N Engl J Med. 2014;370(23):2219-2227. doi:10.1056/NEJMra1402309
- Parolaro D, Realini N, Vigano D, Guidali C, Rubino T. The endocannabinoid system and psychiatric disorders. Exp Neurol. 2010;224(1):3-14. doi:10.1016/j.expneurol.2010.03.018
- Lopez-Rodriguez AB, Siopi E, Finn DP, Marchand-Leroux C, Garcia-Segura LM, Jafarian-Tehrani M, Viveros MP. CB1 receptor downregulation attenuates neuroinflammation and neurodegeneration in a mouse model of traumatic brain injury. J Neurosci. 2015;35(7): 2516-2531. doi: 10.1523/JNEUROSCI.2812-14.2015.
- Colizzi M, Fazio L, Ferranti L, et al. Functional genetic variation of the cannabinoid receptor 1 and cannabis use interact on prefrontal connectivity and related working memory behavior. Neuropsychopharmacology. 2015;40(3):640-649. doi:10.1038/npp.2014.213
- Bonnet U, Preuss UW. The cannabis withdrawal syndrome: current insights. Subst Abuse Rehabil. 2017;8:9-37. Published 2017 Apr 27. doi:10.2147/SAR.S109576
- Colizzi M, Bhattacharyya S. Cannabis use and the development of tolerance: a systematic review of human evidence. Neurosci Biobehav Rev. 2018;93:1-25. doi:10.1016/j.neubiorev.2018.07.014
- D’Souza DC, Sewell RA, Ranganathan M. Cannabis and psychosis/schizophrenia: human studies. Eur Arch Psychiatry Clin Neurosci. 2009;259(7):413-431. doi:10.1007/s00406-009-0024-2
- Hill MN, Patel S, Carrier EJ, et al. Downregulation of endocannabinoid signaling in the hippocampus following chronic unpredictable stress. Neuropsychopharmacology. 2005;30(3):508-515. doi:10.1038/sj.npp.1300601
- Koethe D, Llenos IC, Dulay JR, et al. Expression of CB1 cannabinoid receptor in the anterior cingulate cortex in schizophrenia, bipolar disorder, and major depression. J Neural Transm (Vienna). 2007;114(8):1055-1063. doi:10.1007/s00702-007-0660-5