Introduction

Cannabis (marijuana) is one of the most widely consumed psychoactive substances in the world. The term marijuana is of Mexican origin. For a long time, botanists believed that cannabis and hemp were two species. There are three uses of the plant:

Cannabis leaves and flowers contain at least 489 compounds and 100 different phytocannabinoids.² There are three main species of cannabis: Cannabis sativa, Cannabis indica and Cannabis ruderalis.³ The primary cannabinoids that have been studied to date include delta-9-tetrahydrocannabinol (Δ9-THC, the most widely studied, responsible for most physical and psychotropic effects of cannabis), cannabidiol, cannabinol, cannabigerol and tetrahydrocannabivarin.⁴ The most abundant cannabinoids that the plant produces in different proportions are Δ9-THC and cannabidiol.⁵ Phytocannabinoids (cannabinoids of plant origin) have been used for millennia, and exogenous cannabinoid ligands tetrahydrocannabinol and cannabidiol were isolated from them.⁶

Recently, the endocannabinoid system was discovered, which consists of receptors, ligands and enzymes that are widely expressed in the brain and the periphery (Table 1), where they act to maintain balance in several homeostatic processes.⁷,⁸

Receptors

A G-protein-coupled receptor was isolated from murine neuroblastoma cells, called type 1 cannabinoid receptor (CB1),⁹ which is the most abundant G-protein-coupled receptor expressed in the mammalian brain, and has a neuromodulatory function; it is found at varying grades in all brain structures and in the periphery of almost all organs of the mammalian body.⁸ CB1 is expressed at the presynaptic (in glutamatergic and gamma-aminobutyric-ergetic neurons’ terminals) and postsynaptic levels, associated with astrocytes, to regulate the release of neurotransmitters.¹⁰

Cannabinoid receptor type 2 (CB2) was isolated from human leukemia cells, and is is abundantly found in immune cells, in microglia and activated astrocytes.

The transient receptor potential vanilloid-1 (TRPV1) channel, known as capsaicin receptor (the active ingredient in chili peppers), is linked to a number of ligands other than capsaicin, including endocannabinoid ligands, and can be activated by physical and mechanical stimuli such as low pH, high temperatures or changes in osmotic concentration.

Finally, the G 55 protein-coupled GPR55 receptor, has an endogenous ligand, lysophosphatidylinositol; its role is not clear; it is expressed in cortical areas, in the striatum, the hippocampus and the cerebellum, and produces the opposite effect versus the CB1 receptor: it activates the release of neurotransmitters in presynaptic cells. It is also found in the periphery of the gastrointestinal tract, in osteoblasts and adipocytes.⁶

Ligands

The endogenous cannabinoid or endocannabinoid receptor ligand, N-arachidonoylethanolamine (AEA) or anandamide has been isolated from the pig’s brain.¹¹ The 2-arachidonoyl glycerol (2-AG) ligand has been isolated from canine intestinal tissue.⁹

When a presynaptic neuron releases a neurotransmitter to stimulate a postsynaptic neuron, the ligands spread passively and retrogradely to the presynaptic cell; they bind to the CB1 cannabinoid receptor and initiate a cascade that inhibits the release of neurotransmitters from the presynaptic cell and thus stops synaptic transmission.¹⁰-¹² Therefore, AEA can be more active in acute processes and 2-AG in chronic processes.

Biosynthetic and degrading enzymes

Biosynthetic and degrading enzymes are the third main component of the endocannabinoid system; they modulate the synthesis and degradation of endogenous ligands, which influences on the system functionality: N-arachidonoylethanolamine (AEA) or anandamide, diacylglycerol lipase (DAGL) a or b, fatty acid amide hydrolase (FAAH) of the serine hydrolase and monoacrylic glycerol lipase (MAGL) enzymes. There is still much to learn about these processes: FAAH and MAGL are promising for pharmacological manipulation of the signaling pathways of the endocannabinoid system.

Relationship of phytocannabinoids and the endocannabinoid system

Exogenous cannabinoids or natural-origin phytocannabinoids⁷,⁸ interact with the endocannabinoid system. The quintessential cannabinoid compound, Δ9-THC, binds to receptors CB1 and CB2 as a weak partial agonist; CB1 binding is believed to be primarily responsible for the intoxicating and psychotropic effects of the cannabis plant. Cannabidiol has low affinity for receptors CB1 or CB2, inhibits the binding of tetrahydrocannabinol to CB1, and can enhance or inhibit a variety of final effects on cells, from modulating intracellular calcium levels to the capacity to exert antioxidant properties; its activation has been shown to reduce the release of pro-inflammatory cytokines, which suggests its role in modulating inflammation and nociceptive responses to infection and injury. Unlike tetrahydrocannabinol, cannabidiol does not induce an intoxicating or psychotropic effect in the patient or user.¹³,¹⁴

TRPV1 receptor activation modulates a different pain stimulation pathway than those occupied by endocannabinoids. TRPV1 is also of potential use in the treatment of seizures and epilepsy; however, the precise mechanism whereby TRP channels influence on epilepsy remains unclear.

Cannabis is commonly consumed via inhalation or ingestion, and less frequently through ophthalmic, rectal, sublingual and dermal preparations.¹⁵ It is possible that persistent use of cannabis results in lasting neurocognitive deficits and that it affects brain structure and function.¹⁶ These neurophysiological alterations should be considered both in research and in clinical applications.¹⁷ There are studies that show a direct relationship between the risk of schizophrenia and the use of cannabis.¹⁸

Despite the above, there is no consensus in the scientific literature regarding the exact nature, magnitude and duration of brain changes, which may depend on the frequency, quantity, duration and age at the beginning of cannabis use, as well as abstinence duration. In addition, it is also not clear whether the identified alterations are a consequence of or precede consumption. Additional longitudinal studies evaluating larger samples, particularly prior to the start of cannabis use, are needed in order to determine a causal route between cannabis use and these alterations. Something similar happened with tobacco: it was necessary for 30 or more years of consumption to be elapsed to know the consequences on health.¹⁹

The use of medicinal cannabis has legal, ethical and social implications. In the United States, marijuana is currently recognized by the Drug Enforcement Agency (DEA) as a type I controlled substance. The Food and Drugs Administration (FDA) does not approve marijuana as a safe or effective drug for any indication. The European Medicines Agency (EMA) gives tetrahydrocannabinol and cannabidiol the designation of “orphan drugs”, with the consequent therapeutic utility and safety in rare diseases.²⁰

Marijuana must be processed in a laboratory to extract tetrahydrocannabinol, which is responsible for the intoxicating and psychotropic effects of cannabis, and leave cannabidiol, the product that can be marketed. Cannabis products can become contaminated by improper preparation and storage and develop any microorganism, particularly bacteria and fungi (molds). There are reports of bacterial contamination with Salmonella and Enterobacter, Streptococcus and Klebsiella, as well as cases of fungal spores, including Aspergillus strains.²¹

Some studies attribute cannabidiol great potential for therapeutic use as an antiepileptic, analgesic, anxiolytic, antipsychotic, anti-inflammatory and neuroprotective drug.²² There are inconsistent findings on the efficacy of cannabinoids in neuropathic pain and painful spasms in multiple sclerosis, as well as regarding the tolerability and safety of cannabis-based medications for any chronic pain.²³ There is also limited evidence of their association with the risk of short-term adverse effects and potential mental adverse effects, such as psychosis.²⁴

There are not enough well-designed randomized trials to confirm the benefits and harms of cannabis use. Cannabinoids adverse effects are unclear because there is scarce methodological evidence to quantify them. Much of what is known about medicinal cannabis adverse effects comes from studies related to marijuana recreational use. Therefore, long-term investigations around the assessment of adverse effects associated with medicinal cannabis chronic use are necessary, in order to conclusively assess the risks with an extended period of use.²⁵

In view of the considerable limitations of available studies, and in accordance with the conclusions of several meta-analyses, it is not possible to recommend cannabis or cannabis-based medicine as a treatment for musculoskeletal pain, arthritis or fibromyalgia. There is an imperious need for well-controlled clinical trials of a larger scope.²²,²⁶

Conclusion

Cannabis medicinal use needs more evidence obtained with scientific criteria, since there have not been well-designed clinical studies with substantial samples and sufficient duration, which are factors that are essential for research quality and reliability.