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Table of Contents
REVIEW ARTICLE
Year : 2019  |  Volume : 16  |  Issue : 3  |  Page : 148-151

Neurological uses of cannabis


1 Department of Neurology, Institute of Neurosciences, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi, India
2 Department of Critical Care, FNB Critical Care, Max Super Speciality Hospital, New Delhi, India

Date of Submission11-Jul-2019
Date of Acceptance17-Jul-2019
Date of Web Publication11-Sep-2019

Correspondence Address:
Pushpendra Nath Renjen
C-85, Anand Niketan, New Delhi - 110 021; Institute of Neurosciences, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi-110 076
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/am.am_45_19

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  Abstract 


Cannabis preparations have been used as medications since the 19th century in Europe and much longer as a traditional medicine in other cultures. The American Academy of Neurology recently published a position statement and concluded that medical marijuana is “probably effective” for some symptoms of multiple sclerosis (spasticity, central pain, painful spasms, and urinary dysfunction), “probably ineffective” for levodopa-induced dyskinesias of Parkinson's disease, and of “unknown efficacy” in nonchorea symptoms of Huntington's disease. This article is focused on review of the medicinal use of cannabis in neurological disorders.

Keywords: Cannabinoids, cannabis, marijuana, multiple sclerosis, neurology


How to cite this article:
Renjen PN, Chaudhari DM, Mishra A, Kumar A. Neurological uses of cannabis. Apollo Med 2019;16:148-51

How to cite this URL:
Renjen PN, Chaudhari DM, Mishra A, Kumar A. Neurological uses of cannabis. Apollo Med [serial online] 2019 [cited 2019 Nov 22];16:148-51. Available from: http://www.apollomedicine.org/text.asp?2019/16/3/148/266781




  Introduction Top


Cannabis preparations have been used as medications since the 19th century in Europe and much longer as a traditional medicine in other cultures. In 1999, the Institute of Medicine published a comprehensive review of the literature [1] and concluded that although there are risks, medical cannabis may be helpful for nausea and vomiting, weight loss, pain, anxiety, glaucoma, spasticity, multiple sclerosis (MS), seizures, and movement disorders.

The American Academy of Neurology (AAN) recently published a position statement [2] and concluded that medical marijuana is “probably effective” for some symptoms of MS (spasticity, central pain, painful spasms, and urinary dysfunction), “probably ineffective” for levodopa-induced dyskinesias of Parkinson's disease, and of “unknown efficacy” in nonchorea symptoms of Huntington's disease, Tourette's syndrome, cervical dystonia, and epilepsy. Unfortunately, quality clinical research on cannabis preparations has been limited by the legal status of marijuana. Legal restrictions on the use of marijuana were formalized in 1970 when the Controlled Substance Act included marijuana in the list of Schedule 1 drugs. Substances in this group have been deemed by the US Food and Drug Administration (FDA) and Drug Enforcement Administration to have “no currently accepted medical use in the USA, a lack of accepted safety for use under medical supervision and a high potential for abuse.” Schedule 1 drugs include heroin, lysergic acid diethylamide, methaqualone (Quaalude), and 3,4-methylenedioxymethamphetamine (MDMA or “Ecstasy”) among others.


  Basic Pharmacology Top


Marijuana describes preparations derived from the dried leaves and flowers of the cannabis plant. Synthetic cannabinoids are pharmaceutical agents that are approved as prescription drugs in several countries. These include dronabinol (Marinol) and nabilone (Cesamet), two oral agents that are FDA approved for use in the United States. Nabiximols (Sativex) is an oromucosal spray prepared from the extracts of the cannabis plant, legalized in several other countries but not in the United States.[3],[4]

The genus cannabis includes two species that produce useful amounts of psychoactive cannabinoids: Cannabis sativa and Cannabis indica. A third strain, Cannabis ruderalis, has few psychoactive properties. Cannabis contains many compounds; it is postulated that the C. sativa plant contains over 400 compounds, approximately 60 of which are active.[5],[6],[7] The active compounds are collectively known as cannabinoids, and their potency is variable depending on the species and extraction process. There are three compounds that have been isolated and identified as the most potent: Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannibinol. In the 1960s, THC was established as the cannabinoid primarily responsible for the psychoactive properties of marijuana and the one responsible for most, though not all, of the pharmacologic effects of cannabis.[3],[4],[8],[9]


  Mechanism Top


Cannabis is one of the first plants to have been used medicinally, and the therapeutic properties of marijuana have been known for over 5000 years. However, only recently has its mechanism of action become understood better. In the 1990s, two types of cannabinoid receptors were identified: the cannabinoid-l (CB1) and cannabinoid-2 (CB2) receptors. CB1 receptors are located primarily throughout the central nervous system (CNS) and to a looser extent, in the peripheral tissue.[3],[4],[8],[9] The CB1 receptors are spread throughout the brain and are found in high densities in the neuron terminals of the basal ganglia, cerebellum, hippocampus, neocortex, hypothalamus, and limbic cortex. The periaqueductal gray, dorsal horn, and immune cells also contain CB1 receptors, but to a lesser extent.

A number of neurotransmitters are affected by CB1, including acetylcholine, norepinephrine, dopamine, serotonin, gamma-aminobutyric acid, glutamate, and D-aspartate.[5] These interactions account for many of marijuana's effects on pleasure, memory, thought, concentration, sensory and time perception, and coordination. The CB2 receptors are present mainly on immune cells and peripheral tissues and can have inflammatory, immunosuppressive, and antinociceptive activities.[5],[10] The definitive pharmacologic actions of CB2 receptor binding have yet to be determined, but recently, CB2 receptors were identified in microglia.[3]

Cannabinoids and the central nervous system

To produce their effects, cannabis and cannabinoids appear to activate specific endocannabinoid receptors, mainly in the CNS. Endocannabinoids are endogenous molecules that react and bind to cannabinoid receptors. There are two main cannabinoid receptors: CB1 and CB2. Both types of receptors are G-protein-coupled receptors. G-protein-coupled receptors are transmembrane protein receptors involved in many diseases that represent a target for many pharmacologic medications.[11]

CB1 is found mainly in the CNS, with the highest receptor concentration in the hippocampus, but it is also widely found in the cerebellum, basal ganglia, prefrontal cortex, and limbic system. CB1 binds the endogenous fatty acid-derived cannabinoids anandamide and 2-arachydonylglycerol, both produced mostly in the postsynaptic membrane, to effect adenylate cyclase inhibition.[12],[13] CB2, which is located mainly on immune cells, regulates cytokine release.[14] The endocannabinoid system may have a regulatory role in modulating excessive excitation or inhibition through effects on other neurotransmitters.[15]

Current state of the efficacy of cannabinoids in neurologic disorders

The evidence indicates the effectiveness of cannabinoids (nabiximols, oral cannabis extract, and THC) in treating the central pain and painful spasms caused by MS. Cannabinoids are ineffective in dyskinesias in Parkinson's disease. Evidence specifically supporting inhaled marijuana is lacking, and hence, efficacy is inferred by extrapolation from the effects of marijuana-constituent chemicals. Much remains unknown.

It is interesting that the data are insufficient regarding effectiveness for seizure disorders, largely due to the lack of well-designed studies. However, most states where marijuana has been legalized list seizures as an indication. Recently, the FDA granted orphan drug designation to an oral liquid formulation of plant-derived CBD (Epidiolex) for a clinical trial investigating its effectiveness in Dravet syndrome, Lennox–Gastaut syndrome, and neonatal hypoxic-ischemic encephalopathy. A recent presentation found that Epidiolex in doses up to 25 mg/kg reduced seizure frequencies in multiple drug-resistant epilepsy syndromes and seizure types in an open-label trial.[16]

Consideration of the problems with generating evidence on cannabis

Studying cannabinoids for medicinal use poses interesting challenges. Medical marijuana is available in many forms, each having different methods of administration. Oral extract formulations are standardized and produced by pharmaceutical companies in the United States and other countries. The studies with the best evidence in the recent AAN systematic review were done using these formulations.[2] Many states and countries allow the medicinal usage of marijuana, which is often smoked but can also be ingested or vaporized. These preparations are not standardized and vary widely in the dosage delivery of THC and CBD, which makes comparison of studies especially difficult.

Overall, there is a lack of evidence regarding the efficacy and safety of cannabinoid use in many neurologic illnesses. Most published studies on the use of cannabis in neurologic illness are surveys, case reports, small case series, or nonplacebo-controlled studies. These studies predominantly rely on subjective patient-reported improvement and do not include objective measures. Many of the neurologic symptoms cannabis is proposed to treat are best measured by subjective rating scales, and improvements in patients' perceptions of symptoms should be an important outcome of these studies.

The effects of cannabis are difficult to mask in placebo-controlled studies, and there is a strong placebo effect. This problem may be reduced by using cannabis preparations lower in THC or those that have fewer psychoactive side effects (e.g., CBD).

Patient recruitment is a problem for studies on cannabis. Cannabis may cause dose-related impairment of driving, although scientific study on who is impaired and at what level is insufficient and state laws vary widely on the issue. Limits on driving may deter patient enrolment.

Weighing the risks and benefits: Counseling patients about cannabis use

The use of medical marijuana has received a great deal of public attention in recent years. Marijuana has a long history as an illicit drug, with outspoken proponents and opponents both attempting to influence public opinion and policy. The complex background may color perceptions of medical marijuana use in the eyes of some neurology patients, necessitating an explanation of the effectiveness, side effects, risks, and benefits.

The systematic review is helpful to neurologists in evaluating what quality scientific studies have shown on the use of cannabinoids for a range of neurologic disorders. Medical marijuana does not appear to have curative effects on any neurologic condition, but it may ameliorate unwanted symptoms and ease suffering. Undoubtedly, THC and smoked marijuana may have cognitive side effects that must be weighed against their benefits, particularly in patients already affected cognitively by a primary neurologic disease.[17]

Future considerations

At present, evidence supports the therapeutic benefits of medical marijuana for certain neurologic disorders [Table 1].[18] Additional research may demonstrate more tailored uses of cannabinoids and clarify their role in medical therapeutics. Federal legislation to reclassify marijuana as a Schedule II drug would likely improve the pace and quality of scientific study of medical marijuana.
Table 1: Conclusions of systematic review of medical marijuana in neurology

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Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Institute of Medicine (US); Joy JE, Watson SJ, Benson JA, editors. Marijuana and Medicine: Assessing the Science Base. Washington (DC): National Academies Press (US); 1999.  Back to cited text no. 1
    
2.
Koppel BS, Brust JC, Fife T, Bronstein J, Youssof S, Gronseth G, et al. Systematic review: Efficacy and safety of medical marijuana in selected neurologic disorders: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 2014;82:1556-63.  Back to cited text no. 2
    
3.
Borgelt LM, Franson KL, Nussbaum AM, Wang GS. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy 2013;33:195-209.  Back to cited text no. 3
    
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Gold Standard, Inc. Marijuana, Medical. Clinical Pharmacology. Available from: http://www.clinicalpharmacology.com. [Last accessed on 2014 Mar 15].  Back to cited text no. 4
    
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Ben Amar M. Cannabinoids in medicine: A review of their therapeutic potential. J Ethnopharmacol 2006;105:1-25.  Back to cited text no. 6
    
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Kumar RN, Chambers WA, Pertwee RG. Pharmacological actions and therapeutic uses of cannabis and cannabinoids. Anaesthesia 2001;56:1059-68.  Back to cited text no. 7
    
8.
Pertwee RG. Cannabinoid pharmacology: The first 66 years. Br J Pharmacol 2006;147 Suppl 1:S163-71.  Back to cited text no. 8
    
9.
Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, et al. International union of basic and clinical pharmacology. LXXIX. Cannabinoid receptors and their ligands: Beyond CB1 and CB2. Pharmacol Rev 2010;62:588-631.  Back to cited text no. 9
    
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Ibrahim MM, Porreca F, Lai J, Albrecht PJ, Rice FL, Khodorova A, et al. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci U S A 2005;102:3093-8.  Back to cited text no. 10
    
11.
Overington JP, Al-Lazikani B, Hopkins AL. How many drug targets are there? Nat Rev Drug Discov 2006;5:993-6.  Back to cited text no. 11
    
12.
Lovinger DM. Presynaptic modulation by endocannabinoids. Handb Exp Pharmacol 2008;(184):435-77.  Back to cited text no. 12
    
13.
Vogel Z, Barg J, Levy R, Saya D, Heldman E, Mechoulam R. Anandamide, a brain endogenous compound, interacts specifically with cannabinoid receptors and inhibits adenylate cyclase. J Neurochem 1993;61:352-5.  Back to cited text no. 13
    
14.
Pertwee RG. Pharmacological actions of cannabinoids. Handb Exp Pharmacol 2005;(168):151.  Back to cited text no. 14
    
15.
Caballero A, Tseng KY. Association of cannabis use during adolescence, prefrontal CB1 receptor signaling, and schizophrenia. Front Pharmacol 2012;3:101.  Back to cited text no. 15
    
16.
Devinsky O, Sullivan J, Friedman D, Thiele E, Laux L, Sullivan J, et al. Epidiolex (Cannabidiol) in Treatment Resistant Epilepsy [Press Release]. American Academy of Neurology; 13 April, 2015. Available from: https://www.aan.com/PressRoom/Home/GetDigitalAsset/11570. [Last accessed on 2015 Jun 15].  Back to cited text no. 16
    
17.
Pavisian B, MacIntosh BJ, Szilagyi G, Staines RW, O'Connor P, Feinstein A. Effects of Cannabis on cognition in patients with MS: A psychometric and MRI study. Neurology 2014;82:1879-87.  Back to cited text no. 17
    
18.
Fife TD, Moawad H, Moschonas C, Shepard K, Hammond N. Clinical perspectives on medical marijuana (Cannabis) for neurologic disorders. Neurol Clin Pract 2015;5:344-51.  Back to cited text no. 18
    



 
 
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