Exploring CB1, CB2 in Various Neurological Conditions

Cannabis has gained momentum and legal status for medicinal use in the majority of the United States. Expanding legalization for both its medicinal and recreational uses is anticipated in the coming years.¹ Although advocates for medicinal use describe its therapeutic applications for a number of conditions, formal scientific inquiry into its efficacy and safety for most of these conditions remains in its infancy.² Epilepsy has been the focus of a recent foray in research, and early trial results recently led to the FDA approval of cannabidiol (CBD; Epidiolex, GW Pharmaceuticals), the first cannabis-derived medication for intractable childhood seizures.^2,3

Additionally, cannabis is now being investigated for a variety of other neurologic conditions, such as Alzheimer disease, Parkinson disease, and migraine. As its use expands and its efficacy is better understood, the rudiments of the endocannabinoid pathway, the cannabinoid mechanisms of action, FDA guidelines, and the emerging neurotherapeutic applications become paramount.

The Endocannabinoid Pathway

CBD is the most widely described of up to 113 phytocannabinoids found in cannabis.^4,5 Like CBD, most of these compounds are nonpsychoactive, with the notable exception of tetrahydrocannabinol (THC), a CBD isomer known for the “high” it provides recreational users.⁵ Research has also led to the discovery of synthetic cannabinoids and endogenous cannabinoids. Synthetic cannabinoids may be structurally similar or distinct from phytocannabinoids. Endogenous cannabinoids include 2 well-known compounds: N-arachidonoyl-ethanolamine (AEA),and 2-arachidonoylglycerol (2-AG). Several other endogenous peptides and arachidonic acid derivatives also act within the endocannabinoid pathway, but these mechanisms have yet to be fully elucidated.⁵

In the absence of exogenous agents, the endocannabinoid pathway is primarily mediated by endocannabinoid AEA and 2-AG interactions with 2 G-protein coupled receptors: cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2; see FIGURE).^5,6 AEA and 2-AG have distinct affinities for these receptors. AEA is a strong partial agonist to CB1 and a very weak agonist to CB2, whereas 2-AG exhibits moderate to weak affinity for both receptors.^7,8 Contrasting views suggest that AEA and 2-AG may be either synthesized “on demand” or stored and released as required. Both CB1 and CB2 are found throughout the body in various densities; however, CB1 is predominantly expressed in the brain and skeletal muscle, while CB2 is most common in immune and hematopoietic cells.^9,10

>> READ: DEA Reschedules Epidiolex, Allowing Therapy to Enter US Market

The long form of CB1 has been the focus of most neurologic research due to its high expression in the brain.5 Three other isoforms of CB1 exist. A shorter spliced variant of CB1 is found in hepatocytes and pancreatic islet cells where it influences metabolism.¹¹ Knowledge remains vague concerning the other 2 CB1 variants, in part due to species-specific characteristics that limit the reliability of animal models.¹²

Interspecies differences are also common with CB2, which shares less than half of its sequence homology with CB1.^5,13,14 Two isoforms of CB2 are known; one occurs in the lower brain and testis and the second is expressed in the lower brain and spleen.¹⁴ Other novel cannabinoid receptors exist, including G-protein coupled receptors ion channel receptors, and nuclear receptors.⁵ The recent discovery that CBD binds with the G-protein coupled receptor 3 (GPR3), G-protein coupled receptor 6 (GPR6), and G-protein coupled receptor 12 (GPR12) dxemplifies this principle.¹⁵

FDA Approval and Panel Guidance

Three cannabinoid medications have been approved by the FDA: Marinol/Syndros (dronabinol), Cesamet (nabilone), and Epidiolex.

Dronabinol is synthetic THC, and nabilone is a synthetic analogue of THC; therefore, both agents have psychoactive properties. Dronabinol and nabilone are labeled for refractory nausea and vomiting in patients with cancer receiving chemotherapy.¹⁶ Dronabinol is also approved for inappetence in patients with AIDS.

On June 25, 2018, Epidiolex received FDA approval.¹⁷ It is cannabis-derived concentrated CBD labeled for patients 2 years or older with Dravet syndrome or Lennox-Gastaut syndrome (LGS), 2 refractory severe forms of childhood epilepsy that are associated with abnormal brain development and death.¹⁸ Approval was granted following the publication of results from 3 randomized controlled studies and a unanimous FDA panel decision.

The first study involved 120 children and young adults with Dravet syndrome. In patients treated with 20 mg/kg of CBD daily, the median number of seizures per month decreased from 12.4 to 5.9 compared with a decrease of 14.9 to 14.1 in patients receiving placebo (P = .01). Almost half of the patients (43%) receiving CBD had at least a 50% reduction in seizures compared with 27% receiving placebo (odds ratio, 2.00; P = .08).¹⁹

The second study involved 179 patients with LGS. Patients in the CBD group showed a reduction of 43.9% in seizure activity compared with 21.8% for placebo. The estimated median difference between groups was —17.21 (P = .0135).²⁰

The third study involved 225 patients with LGS. Three treatment groups were defined: CBD 20 mg, CBD 10 mg, and placebo. Median drop-seizure frequency decreased 41.9% in the 20-mg group, 37.2% in the 10-mg group, and 17.2% in the placebo group (20 mg vs placebo, P = .005; 10 mg vs. placebo, P = .002).²¹

Collectively, the 3 trials’ findings demonstrated that CBD is an effective treatment for refractory epilepsy. The most common adverse events were sleep disturbances (sleepiness, poor quality of sleep, and insomnia), fatigue, lethargy, rash, weakness, malaise, diarrhea, infections, and elevated liver enzymes. The drug label for Epidiolex warns of other risks of CBD that include agitation, new or worsening depression, panic attacks, aggression, suicide ideation, and attempts to commit suicide.¹⁸

Controversy Clarification

In consideration of the controversy surrounding marijuana-derived medications, such as Epidiolex, FDA Commissioner Scott Gottlieb, MD, said, “This is an important medical advance. But it’s also important to note that this is not an approval of marijuana or all of its components. This is the approval of one specific CBD medication for a specific use. And it was based on well-controlled clinical trials evaluating the use of this compound in the treatment of a specific condition. Moreover, this is a purified form of CBD. It’s being delivered to patients in a reliable dosage form and through a reproducible route of delivery to ensure that patients derive the anticipated benefits. This is how sound medical science is advanced.”¹⁷

Although the exact mechanism of action of Epidiolex is unknown, investigators suspect that it is not due to cannabidiol receptor binding.18 As previously described, CBD binds with a variety of other receptors, including G-protein coupled receptor 1 (GPR1), G-protein coupled receptor 2 (GPR2), GPR3, G-protein coupled receptor 18 (GPR18), G-protein coupled receptor 55 (GPR55), etc; adenosine receptors; acetylcholine nicotinic receptors; serotonin receptors; opioid receptors, glycine receptors, peroxisome proliferator—activated receptors; and at least 32 enzymes.^15,22 Researchers suggest that this broad receptor activity may reveal applications for inflammation, ischemia, fibrosis, diabetes, cancer, depression, and anxiety. Of these, there are several notable neurologic applications under investigation.

Infantile Spasms

The results of a phase 2 study published in 2015 show that CBD may hold potential for the treatment of infantile spasms.²³ The patient population exhibited very severe disease, but 1 of 9 patients showed a significant clinical improvement. Findings from another 2015 open-label study of 9 patients with refractory infantile or epileptic spasms show that approximately half of the patients had a 50% or greater reduction of seizure activity.²⁴ As such, a phase 3 clinical trial is currently investigating the use of CBD, adjunctive to vigabatrin (Sabril), for this condition in almost 200 patients (NCT03421496).

Alzheimer Disease

CBD has demonstrated potential to protect against cognitive behavioral models of neurodegeneration and neurotoxic impacts of beta amyloid peptide in cell culture.²⁵ In a mouse model of Alzheimer disease (AD), CBD protected hippocampal long-term potentiation. This activity was via peroxisome proliferator—activated receptors, rather than serotonin, adenosine, or CB1 receptors. Other studies’ results have demonstrated that CBD may promote neurogenesis and reduce reactive gliosis and neuroinflammation associated with AD.²⁶ Additional rodent models of AD have shown that CBD may reverse and prevent cognitive deficits, and some suggest that a combination of CBD and THC may provide even greater benefits than CBD alone. Researchers have noted that CBD limits the psychoactive properties of THC, and a phase 2 trial is underway to investigate a combination of THC and CBD, in a 1:20 ratio, for agitation related to dementia in 60 patients (NCT03328676).

Parkinson Disease

CBD may also provide a neuroprotective effect in patients with Parkinson disease (PD) via antioxidant activity and modulation of glial cells. In a study involving 21 patients with PD without dementia or comorbid psychiatric abnormalities, treatment with 300-mg/day CBD led to improved well-being and quality of life as measured by the Parkinson’s Disease Questionnaire-39 (PDQ-39; P = .05).²⁷ The University of Colorado is conducting 2 clinical trials to assess the impact of CBD on motor function and tremors in PD. One is a phase 2 crossover trial in 60 patients with tremor (NCT02818777) and the second is a phase 2 trial of 75 patients with motor symptoms (NCT03582137).

Migraine

The Clinical Endocannabinoid Deficiency hypothesis suggests that migraines occur due to an imbalance within the endocannabinoid pathway. As migraine pain may be due to activation of pronociceptive transient receptor potential cation channel subfamily V member receptors as well as inactivation of antinociceptive cannabidiol receptors, treatment with cannabis-derived or synthetic cannabinoids may restore this imbalance and therefore reduce pain. Despite this, well-designed clinical trials in this area are lacking.²⁸

REFERENCES

1. National Conference of State Legislatures. State Medical Marijuana Laws. National Conference of State Legislatures website. ncsl.org/research/health/state-medical-marijuana-laws.aspx. Published June 27, 2018. Accessed August 23, 2018.

2.The Lancet Neurology. Clearing the haze around medicinal cannabis. Lancet Neurol. 2018;17(3):211-21

doi

: 10.1016/S1474-4422(18)30049-8.

3. Cannabidiol (CBD) Pre-Review Report. World Health Organization website. who.int/medicines/access/ controlled-substances/5.2_CBD.pdf. Published November 2017. Accessed August 23, 2018.

4. Aizpurua-Olaizola O, Soydaner U, Öztürk E, et al. Evolution of the cannabinoid and terpene content during the growth of cannabis

sativa

plants from different chemotypes. J Nat Prod. 2016;79(2):324-331.

doi

: 10.1021/

acs

.jnatprod.5b00949.

5. Zou S, Kumar U. Cannabinoid receptors and the endocannabinoid system: Signaling and function in the central nervous system. Int J Mol Sci. 2018;19(3).

doi

: 10.3390/ijms19030833.

6. Begg M, Pacher P, Bátkai S, et al. Evidence for novel cannabinoid receptors. Pharmacol Ther. 2005;106(2):133- 145.

doi

: 10.1016/j.pharmthera.2004.11.005.

7. Pertwee RG, Howlett a C, Abood ME, et al. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their

ligands :

beyond CB1 and CB2. Pharmacol Rev. 2010;62(4):588-631.

doi

: 10.1124/pr.110.003004.

8. Di Marzo V, De Petrocellis L. Why do cannabinoid receptors have more than one endogenous ligand? Philos Trans R Soc B Biol Sci. 2012;367(1607):3216-322

doi

: 10.1098/rstb.2011.0382.

9. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365(6441):61-65.

doi

: 10.1038/365061a0.

10. Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58(3):389-462.

doi

: 1124/pr.58.3.2.

11. González-Mariscal I, Krzysik-Walker SM, Doyle ME, et al. Human CB1 receptor isoforms, present in hepato­cytes and β-cells, are involved in regulating metabolism. Sci Rep. 2016;6(August):1-12.

doi

:10.1038/srep33302.

12. Ryberg E, Vu HK, Larsson N, et al. Identification and

characterisation

of a novel splice variant of the human CB1 receptor. FEBS Lett. 2005;579(1):259-264.

doi

: 10.1016/j.febslet.2004.11.085.

13. Zhang HY,

Bi

GH, Li X, et al. Species differences in cannabinoid receptor 2 and receptor responses to cocaine self-administration in mice and rats. Neuropsychopharmacology. 2015;40(4):1037-1051.

doi

: 10.1038/npp.2014.297.

14. Liu QR, Pan CH,

Hishimoto

A, et al. Species differences in cannabinoid receptor 2 (CNR2 gene): identifica­tion of novel human and rodent CB2 isoforms, differential tissue expression, and regulation by cannabinoid receptor ligands. Genes Brain Behav. 2009;8(5):519-530.

doi

: 10.1111/j.1601-183X.2009.00498.x.

15. Laun AS, Shrader SH, Brown KJ, Song ZH. GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol [printed online June 25, 2018]. Acta Pharmacol Sin.

doi

: 10.1038/ s41401-018-0031-9.

16. Summary of systematic review for patients and their families: medical marijuana in certain neurological disorders. American Academy of Neurology website. aan.com/guidelines/home/getguidelinecontent/650. Published 2014. Accessed August 26, 2018.

17. FDA Statement by FDA Commissioner Scott Gottlieb, M.D., on the importance of conducting proper research to prove safe and effective medical uses for the active chemicals in marijuana and its components [press release]. Silver Spring, MD: FDA; June 25, 2018. www.fda.gov/newsevents/newsroom/pressannouncements/ ucm611047.htm. Accessed August 26, 2018.

18. Epidiolex [prescribing information]. Carlsbad, CA: Greenwich Biosciences; 20 www.accessdata.fda.gov/ drugsatfda_docs/label/2018/210365lbl.pdf.

19. Devinsky O, Cross H, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet Syndrome. N Engl J Med. 2017;376(21):699-700.

doi

: 10.1056/NEJMoa1611618.

20. Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox- Gastaut syndrome (GWPCARE4): a

randomised

, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391(10125):1085-1096.

doi

: 10.1016/S0140-6736(18)30136-3.

21. Devinsky O, Patel AD, Cross JH, et al; GWPCARE3 Study Group. Effect of cannabidiol on drop seizures in the Lennox—Gastaut syndrome. N Engl J Med. 2018;378(20):1888-1897.

doi

: 10.1056/NEJMoa1714631.

22. Ibeas Bih C, Chen T, Nunn AVW,

Bazelot

M, Dallas M, Whalley BJ. Molecular targets of cannabidiol in neurolog­ical disorders. Neurotherapeutics. 2015;12(4):699-730.

doi

: 10.1007/s13311-015-0377-3.

23. Hussain SA, Zhou R, Jacobson C, et al. Perceived efficacy of cannabidiol-enriched cannabis extracts for treat­ment of pediatric epilepsy: A potential role for infantile spasms and Lennox-Gastaut syndrome. Epilepsy Behav. 2015;47:138-141.

doi

: 10.1016/j.yebeh.2015.04.009.

24. Abati E, Hess E, Morgan A, Bruno P, Thiele E. Cannabidiol treatment of refractory epileptic spasms: an open-label study. Presented at: American Epilepsy Society 69th Annual Meeting; December 4-8, 2015; Philadelphia, PA. aesnet.org/meetings_events/annual_meeting_abstracts/view/2416377

25. Hughes B, Herron CE. Cannabidiol reverses deficits in hippocampal LTP in a model of Alzheimer’s disease [published online March 24, 2018]. Neurochem Res.

doi

: 10.1007/s11064-018-2513-z.

26. Watt G, Karl T. In vivo evidence for therapeutic properties of cannabidiol (CBD) for

alzheimer’s

disease. Front Pharmacol. 2017;8:20.

doi

: 10.3389/fphar.2017.00020.

27. Chagas MH, Zuardi AW, Tumas V, et al. Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial. J Psychopharmacol. 2014;28(11):1088-1092.

doi

: 10.1177/0269881114550355.

28. Leimuranta P, Khiroug L, Giniatullin R. Emerging role of (endo)cannabinoids in

migraine

. Front Pharmacol. 2018;9:420.

doi

: 10.3389/fphar.2018.00420.