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A cannabinoid receptor modulator is a compound that bind to the cannabinoid receptors, which are receptors in the human body that regulate multiple physiological responses, including pain sensation, mood regulation, and appetite. The two main targets of cannabinoid receptors modulators are cannabinoid receptor 1 (CBR1) and cannabinoid receptor 2 (CBR2). By stimulating or inhibiting these receptors, the modulators can achieve different therapeutic effects, such as relieving pain, reducing vomiting, improving appetite and maintaining muscle tone.

Dronabinol, nabiximol, cannabidiol and nabilone are cannabinoid receptor modulators marketed as drugs for various therapeutic uses.[1][2] These drugs also share some common adverse effects, including dizziness, headache, alteration in mental state, and diarrhoea. Recent research studies have explored other therapeutic potentials of the modulators, such as the antitumor effect of cannabidiol. Other cannabinoid receptor modulators are also under investigations.

Cannabinoid receptor modulators interfere with the activity regulated by cannabinoid receptors (CBR1 and CBR2)

Cannabinoid receptors

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Cannabinoid receptor 1 (CBR1) and Cannabinoid receptor 2 (CBR2) are the two main binding targets in the endocannabinoid system.[3] They share similar molecular shape and signalling mechanisms, but differ in their tissue distribution and effects.[3][1]

CB1R mainly presents in the central nervous system, with its activation commonly associated with the regulation of mood, pain and appetite.[3][4] CB2R is abundant in the immune tissues, for example spleen, lymph nodes and bone marrow.[3][1] Its activation causes immunosuppressive effects.[3]

Therapeutic uses

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Given that the endocannabinoid system maintains an internal balance in various body systems, cannabinoid receptor modulators, as compounds that interfere with the endocannabinoid system by interacting with its receptors, carry multiple therapeutic potentials.[5]

Cannabinoid receptor 1 (CBR1) are a potential target for treating pain and cognitive impairment.[4] However, modulators of CBR1 (molecules that interact with CB1R) have limited medical use due to psychotropic side effects (e.g. depression and anxiety) associated with CB1R interference. As the activation of cannabinoid receptor 2 (CBR2) has no psychotropic effects, modulators of CB2R (molecules that interact with CB2R) are investigated for various therapeutic potentials.[3][1] CB2 receptor agonist (molecules that stimulate the activity of the receptors) has been investigated as treatment for pain, inflammation, immune disorders and brain diseases, whereas CB2 inverse agonist or antagonist (molecules that inhibit the activity of the receptors) for weight loss, mental disorder and osteoporosis.[1]

Although the efficacy of cannabinoid receptor modulators is supported by preclinical evidence, only four cannabinoid receptor modulators are approved for therapeutic uses, with the rest under trials.[1][2]

Examples

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Dronabinol

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Chemical structure of dronabinol

Indications

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Dronabinol, also known as tetrahydrocannabinol (THC), is a natural compound extracted from plants.[5] It is available as Marinol® and Syndros®.[5] It is used as an appetite stimulant in anorexia-associated weight loss in HIV/AIDS patients. An increase in patients' appetite and daily calorie intake with minimal improvement in weight and nausea is reported.[5][6] Dronabinol is also indicated for chemotherapy-induced nausea and vomiting in cancer patients failing to respond to conventional antiemetics. Dronabinol is also used for cancer-related chronic pain in Europe.[5]

Mechanism of action

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Dronabinol partially stimulates both the cannabinoid receptor 1 (CBR1) and cannabinoid receptor 2 (CBR2), with a stronger stimulatory effect observed in the former.[7] Dronabinol prevents nausea and vomiting and stimulates appetite by directly acting on the CB1 receptors in the vomiting and appetite control centres in the brain.[6]

Adverse effects

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The common side effects associated with the use of Dronabinol are diverse but generally mild.[8] They generally resolved in a few days.[6] Common side effects include dizziness, dry mouth and headache. Others are related to an alteration of mental state, such as euphoria, mood changes, anxiety, drowsiness and abnormal thinking.[5] Yet, impairment of cognitive performance, including memory and alertness, is not reported.[6] The incidence of side effects may be reduced with a delayed dosing to near bedtime.[6] Dose reduction should be considered in patients with continual side effects.[6]

Pharmacokinetics

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Dronabinol reaches its highest concentration in blood within 1–2 hours of administration.[5] Food intake increases the time and extent of drug absorption, causing a higher drug concentration in blood at a later time.[6] The high lipid solubility of Dronabinol causes its accumulation in fatty organs such as the heart, liver and spleen.[5]

Dronabinol is mostly metabolized by CYP2C9 (an enzyme majorly found in the liver) into 11-hydroxy-delta-9-THC, an active molecule that can enter the brain and cause depression or anxiety.[6] More side effects may be seen in patients with diminished CYP2C9 enzyme activity due to the reduced dronabinol metabolism.[9] Dronabinol is majorly eliminated from the body with faeces.[6]

Nabilone

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Chemical structure of nabilone

Indications

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Nabilone, marketed under the brand name Cesamet®, is a synthetic form of tetrahydrocannabinol (THC). It is used to treat chemotherapy-induced nausea and vomiting in cancer patients who fail to have sufficient response to conventional antiemetic treatments.[10] It is also used to treat anorexia and weight loss in AIDS patients.[11]

Mechanism of action

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Nabilone weakly stimulates cannabinoid receptor 1(CBR1) and cannabinoid receptor 2 (CBR2) in the central nervous system. It reduces vomiting mainly by interacting with CBR1. Nabilone shares some similarity with tetrahydrocannabinol (THC) in terms of chemical structure, but nabilone is also considered to be twice as active as THC.[11]

Adverse effects

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The most common adverse effects of nabilone include drowsiness, dizziness, dry mouth, euphoria, concentration difficulties, ataxia, and headache.[5] It has the potential to affect the central nervous system, resulting in anxiety, disorientation, depression, hallucinations and psychosis. Moreover, it may lead to cardiovascular side effects such as orthostatic hypotension and tachycardia. Gastrointestinal adverse reactions also include anorexia, constipation, nausea, vomiting, and oral paresthesia (sensation of tingling in the mouth).[12]

Pharmacokinetics

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Nabilone can be readily absorbed from the small intestine into the systemic circulation.[12] The rate and extent of absorption of nabilone are not affected by food intake. It takes around 2 hours to reach its highest concentration in blood.[13] It is distributed extensively and quickly in various body tissues including liver where it is rapidly metabolised into several active metabolites. CYP450 enzymes may also be involved in some of its metabolism.[13] Nabilone is mainly excreted with faeces.[11]

Cannabidiol (CBD)

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Chemical structure of cannabidiol

Indications

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Cannabidiol, available as Epidiolex® in high concentration, is a synthetic non-classical cannabinoid marketed for the treatment of refractory epilepsy in patients with Dravet syndrome (epilepsy condition since infancy), Lennox-Gastaut syndrome (severe epilepsy in children), and tuberous sclerosis (a genetic condition causing the formation of non-cancerous tumours in different body areas) in patients aged 1 or above.[3][2][14][15] A reduction in the frequency seizures (uncontrolled shaking of body due to abnormal brain activity) and a better seizure control are seen among patients.[15]

Mechanism of action

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Cannabinoid inhibits the activity of both cannabinoid receptor 1 (CBR1) and cannabinoid receptor 2 (CBR2), with a stronger inhibitory effect observed in the former.[5] Cannabidiol also interacts with non-cannabinoid receptors, including serotonin 1A receptors.[5][14][16] Yet, the mechanism of cannabinoid in controlling seizures is not clearly established.[14]

Adverse effects

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Cannabidiol use is associated with a reduction in appetite, diarrhoea, dry mouth, sedation and dizziness.[8][14][15] These adverse events are mild and generally diminish with continued use.[8][15] Additionally, an increased risk of blurred vision and interference with liver function with elevated levels of liver enzymes are reported.[8] Due to potential liver injury, dose adjustment may be required in patients with liver diseases or taking other medications that interfere with the metabolism of cannabidiol.[15]

Pharmacokinetics

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Due to high lipid solubility, cannabidiol is poorly absorbed in the intestine.[5] The absorbed cannabidiol accumulates in adipose tissue or albumin (proteins in blood), which prolongs its elimination from the body.[16] Most absorbed cannabidiol is converted into other metabolites by various enzymes in the liver and intestine, including CYP2C19 and CYP3A4.[16] Cannabidiol is mainly excreted from the body with faeces.[5]

Nabiximol

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Indications

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Nabiximol, sold under the trade name Sativex®, is a natural mixture of tetrahydrocannabinol (THC) and cannabidiol (CBD) in a 1:1 ratio. Although not approved in the United States, Nabiximol is approved in some European countries as well as Canada for use as an buccal spray for symptomatic relief of spasticity and neuropathic pain in multiple sclerosis (MS). Different reviews were conducted to examine the effects of nabiximol on spasticity in multiple sclerosis, but their results were inconsistent.[17] As some systemic reviews concluded that nabiximols is efficient in refractory spasticity of multiple sclerosis not responsive to other standard treatment, it may be considered as an adjuvant therapy to the standard therapy.[18]

Mechanism of action

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One of the components in nabiximol, tetrahydrocannabinol (THC), weakly stimulates cannabinoid receptor 1(CBR1) and cannabinoid receptor 2 (CBR2) to produce analgesic effect (pain relief).[19] Another component of nabiximol, cannabidiol (CBD), slightly inhibits the proliferation of T cells (a type of immune cells) and the activity of microglia (cells within the brain that regulate neural activity and repair).[5]

Adverse effects

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The most commonly reported adverse effects of nabiximol is dizziness, followed by drownsiness, fatigue, and nausea.[20] Other adverse effects include anorexia, constipation, diarrhea, dysgeusia (taste disorder), oral ulcer, staining of tooth, upper abdominal pain, vomiting, xerostomia (dry mouth), confusion, and disorientation.[20]

Pharmacokinetics

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Nabiximol is rapidly absorbed from the buccal mucosa (membranes inside the mouth).[21] It is then widely distributed in different body tissues, especially fatty tissues due to its high lipophilicity.[19] Thus, it may be stored in the fatty tissues for as long as four weeks, which then slowly release back into the blood stream. THC and CBD, the two components of nabiximol is mainly metabolised in the liver via CYP450 enzymes (2C9, 2C19, 2D6 and 3A4) to 11-hydroxy-tetrahydrocannabinol and 7-hydroxy-cannabidiol respectively.[22] Excretion is primarily in faeces.[19]

Rimonabant

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Chemical structure of rimonabant

Rimonabant was originally approved as an anti-obesity drug.[16] It confers a weight-lowering effect by inhibiting the appetite stimulating effect of cannabinoid receptor 1 (CBR1).[16] Weight loss is achieved with continued treatment, but rebound upon stopping.[16] Despite its efficacy, Rimonabant was withdrawn worldwide due to increased risks of depression, anxiety and suicide.[4][16]

Its withdrawal dispelled research interest on CBR1 modulators, with recent investigation on pharmacological strategies to avoid serious side effects.[16]

Research progress

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Cannabinoids have multiple therapeutic potentials, including pain, nausea and vomiting, feeding disorder, glaucoma, neurodegeneration, multiple sclerosis, schizophrenia, cancer, epilepsy, stress and anxiety.[23] There are ongoing investigations on the currently marketed drugs, exploring their therapeutic potentials on top of the existing medical uses. For instance, some recent studies have illustrated the antitumor effects of CBD, with the underlying mechanisms being the induction of cell cycle arrest and autophagy, promotion of apoptosis, modulation of angiogenesis, and inhibition of tumor cell migration and invasion.[24] Several clinical reports also showed that CBD can be used to treat cancer.[24]

The use of other cannabinoid receptor modulators are also under investigations. Olorinab, Ajulemic acid, NTRX-07 and CNTX-6016 are examples of the new cannabinoid receptors modulators undergoing different stages of clinical trials for their respective therapeutic uses, such as treating Alzheimer's disease and diabetic neuropathy.[3]

References

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  1. 1 2 3 4 5 6 Naikoo RA, Painuli R, Akhter Z, Singh PP (December 2024). "Cannabinoid receptor 2 (CB2) modulators: A patent review (2016-2024)". Bioorganic Chemistry. 153 107775. doi:10.1016/j.bioorg.2024.107775. PMID 39288632.
  2. 1 2 3 Tijani AO, Thakur D, Mishra D, Frempong D, Chukwunyere UI, Puri A (June 2021). "Delivering therapeutic cannabinoids via skin: Current state and future perspectives". Journal of Controlled Release. 334: 427–451. doi:10.1016/j.jconrel.2021.05.005. PMID 33964365.
  3. 1 2 3 4 5 6 7 8 Kosar M, Mach L, Carreira EM, Nazaré M, Pacher P, Grether U (August 2024). "Patent review of cannabinoid receptor type 2 (CB2R) modulators (2016-present)". Expert Opinion on Therapeutic Patents. 34 (8): 665–700. doi:10.1080/13543776.2024.2368745. PMID 38886185.
  4. 1 2 3 Tian L, Qiang T, Liu S, Zhang B, Zhang Y, Zhang B, et al. (March 2025). "Cannabinoid receptor 1 ligands: Biased signaling mechanisms driving functionally selective drug discovery". Pharmacology & Therapeutics. 267 108795. doi:10.1016/j.pharmthera.2025.108795. PMID 39828030.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Pagano C, Navarra G, Coppola L, Avilia G, Bifulco M, Laezza C (March 2022). "Cannabinoids: Therapeutic Use in Clinical Practice". International Journal of Molecular Sciences. 23 (6): 3344. doi:10.3390/ijms23063344. PMC 8952215. PMID 35328765.
  6. 1 2 3 4 5 6 7 8 9 Badowski ME, Yanful PK (2018). "Dronabinol oral solution in the management of anorexia and weight loss in AIDS and cancer". Therapeutics and Clinical Risk Management. 14: 643–651. doi:10.2147/TCRM.S126849. PMC 5896684. PMID 29670357.
  7. ↑ Bajtel Á, Kiss T, Tóth B, Kiss S, Hegyi P, Vörhendi N, et al. (January 2022). "The Safety of Dronabinol and Nabilone: A Systematic Review and Meta-Analysis of Clinical Trials". Pharmaceuticals. 15 (1). Basel, Switzerland: 100. doi:10.3390/ph15010100. PMC 8778752. PMID 35056154.
  8. 1 2 3 4 Chhabra M, Ben-Eltriki M, Mansell H, Lê ML, Huntsman RJ, Finkelstein Y, et al. (November 2024). "Cannabinoids Used for Medical Purposes in Children and Adolescents: A Systematic Review and Meta-Analysis". JAMA Pediatrics. 178 (11): 1124–1135. doi:10.1001/jamapediatrics.2024.3045. PMC 11406456. PMID 39283619.
  9. ↑ Dean L, Kane M (2012). "Dronabinol Therapy and CYP2C9 Genotype". In Pratt VM, Scott SA, Pirmohamed M, Esquivel B (eds.). Medical Genetics Summaries. Bethesda (MD): National Center for Biotechnology Information (US). PMID 33211456.
  10. ↑ Hesketh PJ, Kris MG, Basch E, Bohlke K, Barbour SY, Clark-Snow RA, et al. (August 2020). "Antiemetics: ASCO Guideline Update". Journal of Clinical Oncology. 38 (24): 2782–2797. doi:10.1200/JCO.20.01296. PMID 32658626.
  11. 1 2 3 Sholler DJ, Huestis MA, Amendolara B, Vandrey R, Cooper ZD (December 2020). "Therapeutic potential and safety considerations for the clinical use of synthetic cannabinoids". Pharmacology, Biochemistry, and Behavior. 199 173059. doi:10.1016/j.pbb.2020.173059. PMC 7725960. PMID 33086126.
  12. 1 2 Ladha KS, McLaren-Blades A, Goel A, Buys MJ, Farquhar-Smith P, Haroutounian S, et al. (January 2021). "Perioperative Pain and Addiction Interdisciplinary Network (PAIN): consensus recommendations for perioperative management of cannabis and cannabinoid-based medicine users by a modified Delphi process". British Journal of Anaesthesia. 126 (1): 304–318. doi:10.1016/j.bja.2020.09.026. PMID 33129489.
  13. 1 2 Pergolizzi JV, Taylor R, LeQuang JA, Zampogna G, Raffa RB (March 2017). "Concise review of the management of iatrogenic emesis using cannabinoids: emphasis on nabilone for chemotherapy-induced nausea and vomiting". Cancer Chemotherapy and Pharmacology. 79 (3): 467–477. doi:10.1007/s00280-017-3257-1. PMID 28235999.
  14. 1 2 3 4 Spanagel R, Bilbao A (September 2021). "Approved cannabinoids for medical purposes - Comparative systematic review and meta-analysis for sleep and appetite". Neuropharmacology. 196 108680. doi:10.1016/j.neuropharm.2021.108680. PMID 34181977.
  15. 1 2 3 4 5 Talwar A, Estes E, Aparasu R, Reddy DS (January 2023). "Clinical efficacy and safety of cannabidiol for pediatric refractory epilepsy indications: A systematic review and meta-analysis". Experimental Neurology. 359 114238. doi:10.1016/j.expneurol.2022.114238. PMID 36206805.
  16. 1 2 3 4 5 6 7 8 Bosquez-Berger T, Szanda G, Straiker A (2023-08-30). "Requiem for Rimonabant: Therapeutic Potential for Cannabinoid CB1 Receptor Antagonists after the Fall". Drugs and Drug Candidates. 2 (3): 689–707. doi:10.3390/ddc2030035. ISSN 2813-2998.
  17. ↑ Nielsen S, Germanos R, Weier M, Pollard J, Degenhardt L, Hall W, et al. (February 2018). "The Use of Cannabis and Cannabinoids in Treating Symptoms of Multiple Sclerosis: a Systematic Review of Reviews". Current Neurology and Neuroscience Reports. 18 (2) 8. doi:10.1007/s11910-018-0814-x. PMID 29442178.
  18. ↑ Kleiner D, Horváth IL, Bunduc S, Gergő D, Lugosi K, Fehérvári P, et al. (2023). "Nabiximols is Efficient as Add-On Treatment for Patients with Multiple Sclerosis Spasticity Refractory to Standard Treatment: A Systematic Review and Meta-Analysis of Randomised Clinical Trials". Current Neuropharmacology. 21 (12): 2505–2515. doi:10.2174/1570159X21666230727094431. PMC 10616923. PMID 37519000.
  19. 1 2 3 Tanasescu R, Constantinescu CS (September 2013). "Pharmacokinetic evaluation of nabiximols for the treatment of multiple sclerosis pain". Expert Opinion on Drug Metabolism & Toxicology. 9 (9): 1219–1228. doi:10.1517/17425255.2013.795542. PMID 23621668.
  20. 1 2 Prieto González JM, Vila Silván C (May 2021). "Safety and tolerability of nabiximols oromucosal spray: a review of real-world experience in observational studies, registries, and case reports". Expert Review of Neurotherapeutics. 21 (5): 547–558. doi:10.1080/14737175.2021.1904896. PMID 33749480.
  21. ↑ Black N, Stockings E, Campbell G, Tran LT, Zagic D, Hall WD, et al. (December 2019). "Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: a systematic review and meta-analysis". The Lancet. Psychiatry. 6 (12): 995–1010. doi:10.1016/S2215-0366(19)30401-8. PMC 6949116. PMID 31672337.
  22. ↑ Karschner EL, Darwin WD, Goodwin RS, Wright S, Huestis MA (January 2011). "Plasma cannabinoid pharmacokinetics following controlled oral delta9-tetrahydrocannabinol and oromucosal cannabis extract administration". Clinical Chemistry. 57 (1): 66–75. doi:10.1373/clinchem.2010.152439. PMC 3717338. PMID 21078841.
  23. ↑ Alexander SP (January 2016). "Therapeutic potential of cannabis-related drugs". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 64: 157–166. doi:10.1016/j.pnpbp.2015.07.001. PMID 26216862.
  24. 1 2 Ma L, Liu M, Liu C, Zhang H, Yang S, An J, et al. (April 2024). "Research Progress on the Mechanism of the Antitumor Effects of Cannabidiol". Molecules. 29 (9). Basel, Switzerland: 1943. doi:10.3390/molecules29091943. PMC 11085351. PMID 38731434.
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