Cannabis as medicine: The pros and cons

Michael T Okafor; Uzoamaka A Okoli; Uwamleeka Opoke; Germaine A Okafor; Elvis N Shu; Chikere A Anusiem

doi:10.4103/ijmh.IJMH_69_22

REVIEW ARTICLE

Year : 2023 | Volume : 28 | Issue : 2 | Page : 81-86

Cannabis as medicine: The pros and cons

Michael T Okafor¹, Uzoamaka A Okoli¹, Uwamleeka Opoke², Germaine A Okafor³, Elvis N Shu⁴, Chikere A Anusiem⁴
¹ Department of Pharmacology and Therapeutics, Basic and Translational Cancer Research Group, College of Medicine, University of Nigeria, Nsukka, Enugu, Nigeria; Department of Pharmacology and Therapeutics, Immune Optimization Intervention Research Group, College of Medicine, University of Nigeria, Nsukka, Enugu, Nigeria
² Department of Pharmacology and Therapeutics, Immune Optimization Intervention Research Group, College of Medicine, University of Nigeria, Nsukka, Enugu, Nigeria
³ Department of Pharmacology and Therapeutics, Lagos University Teaching Hospital, Lagos, Nigeria
⁴ Department of Pharmacology and Therapeutics, College of Medicine, University of Nigeria, Nsukka, Enugu, Nigeria

Date of Submission	01-Nov-2022
Date of Decision	03-Dec-2022
Date of Acceptance	07-Feb-2023
Date of Web Publication	21-Mar-2023

Correspondence Address:
Michael T Okafor
Department of Pharmacology and Therapeutics, College of Medicine, University of Nigeria, Enugu Campus, Nsukka, Enugu
Nigeria

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijmh.IJMH_69_22

Abstract

The use of cannabis for medical purposes has been a subject for discussion for so many years. Cannabis as a source of medical treatment first came to light in the 19^th century. However, origins of cultivation of marijuana as a medical plant can be traced back to thousands of years. Attempts to completely legalize the use of cannabis for medical purposes are strongly contested in many places due to some of its negative effects on users physically, psychologically, and socially. This review is aimed to discuss the mechanism of action and pharmacogenetics of cannabinoids to elucidate its uses as medicine as well as negative effects. Online searches on the following database: Google Scholar, PubMed, Biomed Central, and SciELO were done. An attempt was made to review articles with keywords such as cannabis, cannabinoid receptors, genes, and medical marijuana. This review has highlighted with evidence the importance of genomic profiling to prevent side effects associated with predisposing genes for the benefit of patients who are medical candidates for medicinal cannabis use. Medical profiling via cannabinoid gene expression studies of patients who are medical candidates of cannabis could prevent the negative effects associated with its use.

Keywords: Cannabis, genomics, medicine

How to cite this article:
Okafor MT, Okoli UA, Opoke U, Okafor GA, Shu EN, Anusiem CA. Cannabis as medicine: The pros and cons. Int J Med Health Dev 2023;28:81-6

How to cite this URL:
Okafor MT, Okoli UA, Opoke U, Okafor GA, Shu EN, Anusiem CA. Cannabis as medicine: The pros and cons. Int J Med Health Dev [serial online] 2023 [cited 2023 Jun 3];28:81-6. Available from: https://www.ijmhdev.com/text.asp?2023/28/2/81/372157

Introduction

Cannabis plant is a plant used for its psychoactive as well as medicinal properties. It has been cultivated for thousands of years as hemp fiber, food, and medicine by the Chinese.^[1],[2] Archaeologists discovered traces of cannabis seeds in Siberia dating as far back as 3000 BC.^[3] Cannabis was used recreationally up until 1961 when it was included as a controlled substance in the United Nations’ Single Convention on Narcotic Drugs.^[4],[5] Recently about 33 states in the United States have legalized the use of cannabis for recreational and medicinal use.^[6] Cannabis remains the most widely used drug globally, with an estimated 188 million people having used the drug. It was estimated that 5.5% of the global population aged 15–64 have used cannabis recreationally.^[7]

Currently, medical cannabis is fully legal in 50 countries, representing over 25%. Whereas there are 15 countries with partial legality or controlled usage, bringing the number to a total of 65 (33%).^[8]

In the modern era, the use of cannabis for medical purposes was first legalized in 1992 in the district of California United States. This was followed 5 years later by Canada in 2001. Since the beginning of the 20^th century, medical marijuana has become popular, and more studies have sprung up in order to discover how its properties could help advance modern medicine.

Cannabis refers to the genus of cannabis stavia plant and all the products are derived from the cannabis plant. Other common names include marijuana, joint, grass, herb, ganja, pot, Mary Jane, hemp, hashish (cannabis resins), and a vast number of other slang terms.^[9] Some people smoke cannabis or marijuana in pipe, hand-rolled cigarettes (joints), in blunts (cannabis rolled in cigar wraps), and water pipes (bongs). Cannabis can also be consumed as brewed tea, particularly when it is for medicinal purposes. It is frequently mixed into foods such as cookies, brownies, or candies. Vaporizers are also increasingly used to consume cannabis. Sinsemilla (from female cannabis plants) and concentrated resins are increasingly popular among those who use them both medically and recreationally.^[7]

Cannabis sativa is the source of a set of compounds known collectively as phytocannabinoids or plant cannabinoids. The cannabis plant contains about 540 chemical substances. The main cannabinoids are tetrahydrocannabinol (THC) and cannabinol (CBD1) [Figure 1]. Medicinal cannabis is sometimes referred to as medicinal marijuana, but they are practically not the same because marijuana contains more of the psychoactive agent which is the ∆⁹-THC acts on cannabinoid 1 (CB1) receptor.^[10] cannabidiol (CBD1) acts on cannabinoid 2 (CB2) receptor and lacks psychoactivity but works in synergy with Δ⁹-THC to minimize “highs” and maximize analgesic properties.^[10]

Figure 1: Graphical abstract showing the main cannabinoids including tetrahydrocannabinol and cannabinol and targetable genes in different disorders of a diverse population

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In this review, we shall attempt to elucidate the pharmacogenetics of cannabis on cannabinoid receptors to highlight receptors that can be screened via gene expression studies to better profile patients for medical marijuana.

Endogenous cannabinoid system and cannabis mechanism of action

In the early 90s, it was discovered that the human body produces molecules that act similar to the cannabinoid found in cannabis plant. This interesting discovery led to the development of the Endogenous Cannabinoid System or Endocannabinoid System (ECS).

Why does our body produce cannabinoids? The reasons for the presence of the ECS are still the subject of study and research by medical experts around the world; however, we know that it helps with sleep, mood, appetite, memory, reproduction, and fertility.^[11] The endogenous cannabinoid system comprises of endocannabinoid, cannabinoid receptor, and the enzymes that are responsible for the synthesis and degradation of the endocannabinoids.^[12]

Two major active ingredients of cannabis show medicinal promise: ∆⁹-THC and cannabinol. They bind to the specific cannabinoid receptors and mimic the action of endocannabinoids.^[13] Endocannabinoids in human include anandamide (N-arachidonoylethanolamine—AEA) and 2-arachdonoylglycerol (2AG). They are fatty acid neurotransmitters/neuromodulators ligands derived from arachidonic acid.^[13],[14] The endocannabinoid system modulates neurotransmitter networks throughout the body, through CB1 and CB2 receptors.

AEA discovery and history have been discussed.^[15],[16] AEA operates throughout the endocarnabinoid system. It has been identified as the source of the “runners high” experienced during and after an intense workout. This contradicts the knowledge of the effects of endorphin which has been believed to be the main actors as pain relievers in the body. 2AG has more presence in the central nervous system and has been associated with cardiovascular health, protection from seizures and emotional states, and contented feeling after sexual intercourse.^[12] AEA acts as a partial agonist whereas 2AG acts as a full agonist. These endogenous cannabinoids produce many of the same pharmacological effects as the exogenous cannabinoids including hypomotility and antinociception.^[17]

CB1 and CB2 receptors

The cannabinoid receptors are guanidine nucleotide binding protein (G-Protein) coupled receptors, SKR6 (CB1) and CX5 (CB2).^[18],[19] The CB1 and CB2 receptors have been identified and cloned in the 90’s.^{[17],[18],[19]} This has immensely contributed to the understanding of cannabinoids.^[20] CB1 receptors are preferentially distributed in basal ganglia, hippocampus, cerebellum, and cerebral cortex of the brain, whereas CB2 receptors are prominent in gut and immune tissues.^[21],[22]

The cannabinoid receptors on activation by the binding of specific ligands inhibit the adenyl cyclase, protein phosphorylation, and certain voltage dependent calcium channels. This process is cAMP-dependent and leads to the activation of mitogen activating protein kinase (MAPK). MAPK modulates the G-protein coupled Ca⁺ and K⁺ channels (causing inward arrangement of K⁺ channels). AEA, 2AG, and N-arachidonoyl-dopamine act at vanilloid receptor (transient receptor potential vanilloid type 1, TRPV1, a ligand gated channel [Figure 2]. In addition, THC and CBD1 at high concentration have been identified to act as an agonist of ANKTM1 channel, a type of TRP channel, which may suggest that TRP may be inotropic cannabinoid receptor.^[15] There is a ubiquitous distribution of receptors, proteins, and channels in the ECS, and their role in the regulation of a variety of normal human physiologic pathways should be explored in drug discoveries. Drugs that target different aspects of this system are already benefiting disease conditions such as AIDS, metabolic syndrome, and cancers.^{[20],[23],[24],[25],[26]}

Figure 2: Cannabinoids and endocannabinoid metabolism

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Materials and Methods

Online searches on the following databases: Google Scholar, PubMed, Biomed Central, and SciELO were done. An attempt was made to review articles with keywords: Cannabis, cannabinoid receptors, genes, and medical marijuana.

Highlights of cannabinoids pharmacogenetics

By studying the pharmacogenetics of Cannabinoids in the individual human organism, we may understand the effects of medical cannabis and how it impacts the health of its user. What we will learn about molecules and the proteins involved in the transport, mechanism of action, and metabolism of cannabinoids can lead to the prediction of variations in human genes that are responsible for the therapeutic and adverse effects of medical cannabinoid-based drugs.^[20],[26] CNR1, CNR2, TRPV1 genes encode CB1, CB2, and TRP receptors, respectively. Other receptor genes include GPR55, GABRA2, and OPRM1. Cannabinoid transport genes include ABCB1, ABCG2, SLC6A4, and COMT. Enzymes involved in the metabolism of cannabinoids include CYPs and UGTs while genes involved in the biosynthesis of endocannabinoids include FAAH, COX2, MAGL, ABHD6, and ABHD12.^{[20],[26],[27]} Aforementioned.

Short nucleotide polymorphism (SNP) in genes encoding the endocannabinoids, cannabinoids have been associated with different human disorders. Polymorphism of CNR1 and CNR2 genes has been associated with human disorders including, posttraumatic stress disorder, drug dependency, osteoporosis, obesity, depression, and ADHD.^[26]

Studies have demonstrated a variety of interaction of opioids, cannabinoids, and genes encoding TRPV1 receptors in pain modulation.^[24],[28] Another study examined CNRI, CNR2, TRPV1, and FAAH gene expression profile and SNP relationship in individuals with acute or chronic low back pain.^[29] They demonstrated that CNR2 mRNA was significantly upregulated in patients with low back pain. There was increased FAAH and TRPV1 mRNA in patients with chronic low back pain compared to acute low back pain and healthy study participants.^[29] A list of the genes as potential targets and actions as inhibitor, agonist, and antagonist have been reported based on animal models and systems.^[3]

We believe that genetic profiling for a maze of genes that code cannabinoid receptors, enzymes, and transport for medical purposes should predict the responses of patients to medical marijuana.

Clinical efficacy and adverse effects of cannabinoid-based drugs

Chemotherapy-induced nausea and vomiting

Antiemetic options exist to manage nausea-induced chemotherapy. They include neurokinin receptor antagonist and serotonin antagonists. Other classes include antihistamines, benzodiazepines, anticonvulsants, and dopamine receptor antagonist and cannabinoids. Evidence of the efficacy of dronabinol as monotherapy or in combination is discussed as follows. A meta-analysis study was carried out between 1975 and 1996. During this study, 30 randomized comparisons of cannabis with antiemetics were made involving 1366 patients.^[30] Oral dronabinol, oral nabilone and intramuscular levonantradol were administered. They demonstrated that cannabinoids were more effective antiemetics than metoclopramide, prochlorperazine, thiethylperazine, chlorpromazine, domperidone, haloperidol, or alizapride. They also showed that cannabis was not effective in patient with recurring emetogenic chemotherapy. However, harmful side effects occurred more often with the administration of cannabinoids which includes dizziness, hallucination, paranoia, arterial hypotension, euphoria, sedation, or drowsiness.^[31] The downside of it was that patients given cannabinoids were more likely to redraw.

Two prescription cannabinoids approved by FDA are available, dronabinol (synthetic ∆⁹-THC) and Nabilone (a THC congener). These are drugs for the treatment of chemotherapy-induced nausea and vomiting.

Epilepsy

There are various data on the efficacy and safety of cannabinol in various epilepsies..^{[32],[33],[34],[35],[36]} A randomized trial has shown that purified cannabinol – Epidiolex as an add on to existing epileptic drugs has shown efficacy in treating seizures associated with Dravet syndrome and Lennox–Gastaut syndrome.^{[32],[33],[35]} Other open trails have supported the efficacy in the aforementioned. The open trials by^[35]suggested that cannabinol might have adequate safety profile in children and young adults with high treatment-resistant epilepsy and reduced seizure frequency.^[34],[36] The common adverse effects of CBD1 are well documented, and they include somnolence, pyrexia, decreased appetite, ataxia, vomiting, and abnormal behavior and sedation.^[34],[36]

Another case report has shown the interaction between warfarin and cannabinol.^[37] Little is known about the long-term effect of Epidiolex on hormone regulation, cognition/memory, fertility, and pregnancy.^[38] Although, current evidence suggests that cannabis use during pregnancy and lactation may adversely affect brain development with negative impact on behavioral, neuropsychiatric, and executive functioning.^[39]

Chronic pain and multiple sclerosis

Opioids and anti-inflammatory drugs are usually the first line treatment toward pain associated with malignant diseases. Sometimes they do not achieve satisfactory results^[40] Pharmacodynamic studies have demonstrated the effect of cannabinoids on capsaicin-induced hyperalgesia, neuropathic pain in HIV/AIDS patients, painful spasms in patients with multiple sclerosis-provoked somatic pain (e.g., thermal stimulation).^[40] Dronabinol and Nabilone have shown efficacy in the treatment of pain and distress.^[10]

Although cannabis plant has not been approved for medical use, several drugs that contain individual cannabinoids have been approved by FDA as shown in [Table 1].

Table 1: Approved FDA cannabis product^[41]

Click here to view

Conclusions

In conclusion, the complexity of the cannabinoid pathway as well as individual genetic predisposition is responsible for the different body responses to cannabinoid. A maze of genes involved in the ECS as well as genes involved in the metabolism of exogenous cannabis should be profiled before use as medicine. The study of gene expression will help medical experts to predict the patients who may react adversely to medical marijuana. This will catalyze more studies and possible discoveries as to the potential use of medical marijuana in health.^[42]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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