Cannabis sativa L. has a long history of medicinal use. CBD and THC are the two components with the highest concentrations in Cannabis sp. (Figure 1) [31]. In recent years, especially since the endocannabinoid system was discovered, these compounds have received much attention [32]. The endocannabinoid system includes cannabinoid receptors (CB1 and CB2-G protein-coupled receptors), their endogenous ligands (endocannabinoids AEA—Anandamide and 2-AG—2-Arachidonoylglycerol), and the enzymes responsible for their degradation and synthesis [33]. The main enzyme involved in AEA production is N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD), whereas 2-AG synthesis is dependent on a specific phospholipase C followed by the sn-1-diacylglycerol lipase (DAGL) activity [34]. The AEA activity is terminated by a fatty acid amide hydrolase (FAAH) resulting in arachidonate and ethanolamine. 2-AG is hydrolyzed by a specific monoacylglycerol lipase (MAGL), as well as serine hydrolase alpha-beta-hydrolase domain 6 (ABHD6), resulting in arachidonate and glycerol [35,36]. Endocannabinoids act principally through the cannabinoid receptor (CB1 and CB2). Their implications were illustrated in several physiological and pathological conditions, including appetite, fertility, memory, immune system, cancer, and pain management [37].

CB1 receptors are primarily expressed in the peripheral and central nervous systems, while CB2 receptors are highly expressed in the immune system. Both CB1 and CB2 receptors are negatively correlated with adenylate cyclase activity [38].

A large number of cannabinoid receptors have been described in the brain stem emetic centers and in regions involved in the behavioral effects of cannabinoids, including the hippocampus, basal ganglia, amygdala, and cerebellum. CB1 receptors are located predominantly in the presynaptic membrane and are therefore modulators of synaptic release [39].

It has been assumed that cannabinoids relieve pain by activating specific CB1 and CB2 receptors. However, the matter becomes more complex when plant-derived and endogenous cannabinoids influence multiple pain targets, including G protein-coupled receptor 55 (GPCR55), GPCR18, serotonin, and opioid receptors [40,41,42,43]. Moreover, cannabinoids can modulate transient receptor potential channels (TRPA, TRPV, and TRPM), Cys-loop ligand-gated ion channels, and nuclear receptors [44]. In addition, several studies have indicated multiple interactions at the molecular level between opioids, TRPV1, and cannabinoid receptors in pain modulation and perception.

The administration of cannabinoids has been shown to suppress all neurophysiological and behavioral responses to nociceptive stimuli. These compounds were found to exert their anti-nociceptive effect by an action on the peripheral nerves, direct activity in the brain, or direct spinal activity [45]. Therefore, rapidly after crossing the brain–blood barrier, the cannabinoids can interact with the rostral ventrolateral-medulla (RVM) and periaqueductal gray (PAG), inhibiting spinal nociceptive neurotransmission [46]. Other studies have demonstrated a potential peripheral site of action for cannabinoids [47]. Hence, in a tumor-bearing mouse model, the intraplantar administration of WIN 55,212-2, a non-selective cannabinoid receptor agonist, diminished the response produced by mechanical stimulation of C-fiber nociceptors [48]. These findings could further support new drug development with improved clinical efficacy and fewer side effects [49]. The general overview of the endocannabinoid system mechanism is depicted in (Figure 2).

THC is the primary psychoactive ingredient of cannabis and can promote dependency among chronic users as it interacts with the dopaminergic system [50]. THC has an affinity for the CB1 and CB2 receptors similar to that of AEA. In addition to its psychoactive effect, THC is responsible for most of the pharmacological outcomes of cannabis, including analgesic, antioxidant, anti-inflammatory, bronchodilator, antipruritic, and anti-spastic activities [51].

CBD is the second most abundant component of cannabis and has broader medical applications than THC. However, CBD does not have THC-like or toxic drug effects but has been reported to reduce inflammation, muscle spasms, seizures, and anxiety [52]. There are studies in humans, non-human primates, and rodents that suggest the potential that CBD has in mitigating the effects of THC (mostly related to memory and behavior). There are also preclinical studies showing that CBD actually potentiates the effects of THC [53] The current state of knowledge suggests that CBD has a poor affinity for cannabinoid receptors, and its mechanism of action is different from that of the endocannabinoid system. The effects of CBD are often reported to be mediated by various orphan GPCRs and serotoninergic 5-HT1A receptors [54]. Moreover, studies have indicated that CBD can regulate pain perception by interacting with other G-coupled receptors, including δ-opioid, μ-opioid, and dopamine receptor D2 [55].

Cannabinoids are highly lipophilic substances that are stored in spleen and adipose tissues. After inhalation, peak plasma levels of CBD and THC are rapidly achieved within 3–10 min [56]. The bioavailability of inhaled THC varies considerably due to the differences between cannabis products and inhalation techniques, ranging between 10 and 35%, whereas inhaled CBD has an average bioavailability of 31%. In contrast, when administered orally, the peak plasma level of both compounds is obtained within approximately 1–2 h, and it is considerably lower than that obtained by smoking due to hepatic first-passage metabolism [57]. When inhaled by smoking, the analgesic effect of cannabinoids is experienced shortly after the first breath. However, the combustion products inhaled while smoking cannabis constitute a significant disadvantage and may negatively affect the respiratory tract [58]. On the other hand, the major limitation of oral cannabinoids is their poor pharmacokinetic profile, with highly variable absorption, slow onset of clinical effects, and unpredictable psychoactive effects [59].

The use of cannabis for recreational or medical purposes has been banned for decades. Several cannabinoid drugs have been developed to date. Nabiximols (Sativex^®) is an almost 1:1 ratio of plant-based THC and CBD and is licensed for treating spasticity in multiple sclerosis [60]. Epidiolex, an oral CBD solution, was recently approved for the treatment of severe pediatric epilepsy, including Dravet and Lennox-Gastauld syndromes [61].

Dronabinol and nabilone are synthetic forms of THC licensed to treat chemotherapy-related nausea and vomiting in patients refractory to conventional antiemetics, and weight loss in patients with AIDS [62].