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Although cannabis has been used throughout human history, the scientific investigation of its effects only began with the isolation of THC in the 1960’s. Once discovered it was another 20 years before the mechanism by which THC produces its psychoactive effects in the brain, the CB₁ receptor, was discovered. Cannabis contains over 80 cannabinoid compounds, but THC is the only intoxicating compound. Recent preclinical research is being directed towards evaluating the therapeutic potential of other cannabinoid compounds found in cannabis, including CBD. The pharmacokinetics of THC, methods of administration, and dosing issues are explored in Chapter 1.

The plant Cannabis, which has been traditionally employed for the treatment of gastrointestinal ailments, contains both psychotropic phytocannabinoids, such as Δ‎⁹-tetrahydrocannabinol and nonpsychotropic phytocannabinoids (e.g. cannabidiol, cannabigerol, Δ‎⁹-tetrahydrocannabivarin, and cannabichromene). Such phytocannabinoids have been shown to modulate, through different mechanisms, a number of gastrointestinal functions, including gastric acid secretion, intestinal motility, visceral sensation, inflammation, and cell proliferation. This chapter focuses on the pharmacology and the potential therapeutic application of Cannabis-derived cannabinoids (phytocannabinoids) in gastrointestinal diseases, with a special reference to irritable bowel syndrome, inflammatory bowel disease, and colon cancer.

Phytocannabinoids are terpenoid-like compounds of which more than 100 have been found in the marijuana plant, Cannnabis sativa. These include Δ‎⁹-tetrahydrocannabinol (THC), the major psychoactive component, and the nonpsychotropic compounds cannabidiol (CBD) and cannabinol (CBN). Although THC has been reported to inhibit immune responses in vitro and in vivo, CBD and CBN also possess anti-inflammatory properties. Investigation of the functional relevance of plant-derived cannabinoids such as THC led to the discovery of selective cell membrane-associated receptors, the synthesis of cognate receptor agonists and antagonists, and the identification of an endogenous cannabinoid (endocannabinoid) system. While the immunomodulatory properties of THC have been attributed primarily to activation of cannabinoid receptors, CBD and CBN have been implicated in noncannabinoid receptor-mediated actions. In this chapter a review of the functional relevance of phytocannabinoids in modulating immune responses in vitro and in vivo is presented along with potential translational relevance to the human host.

Among over 60 terpeno-phenols derived from the cannabis plant, delta-9-tetrahydrocannabinol (Δ‎⁹-THC) has by far been the most studied for its potential to reduce nausea and vomiting. Indeed, the first approved medical use of Δ‎⁹-THC was for nausea and vomiting. However, the remaining compounds in the plant have received relatively less investigation. This chapter reviews recent research on the potential of the phytocannabinoids, cannabidiol (CBD), cannabidiolic acid (CBDA), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), cannabivarin (CBDV), and cannabigerol (CBG) to reduce nausea and vomiting in animal models. CBD and CBDA attenuate nausea and vomiting via indirect agonism of the 5-HT_1A receptor, while CBG acts as a 5-HT_1A receptor antagonist, reversing the suppressive effect of CBD on nausea and vomiting. THCA potently reduces nausea and vomiting, possibly by a CB₁ receptor mechanism of action. Finally, CBDV, as well as a high dose of THCV, also attenuate nausea. These phytocannabinoids have therapeutic potential that merits further exploration.

Appetite stimulation is one of the most often anecdotally documented actions of cannabis preparations used for recreational purposes. After the discovery of the cannabinoid CB₁ and CB₂ receptors for the cannabis component mostly responsible for this effect, i.e. delta-9-tetrahydrocannabinol (Δ‎⁹-THC), and of the endogenous ligands for these receptors, the endocannabinoids, much progress has been made in the understanding of how this endogenous signaling system controls food intake. However, the application of this knowledge to the development of efficacious and safe treatments for cachexia and, particularly, anorexia, has lagged behind. This chapter reviews some of the aspects of cannabis and Δ‎⁹-THC stimulatory effects on appetite and of the role of the “endocannabinoid system” in food intake regulation. The translation of these concepts into the development of new treatments for cachexia and anorexia, as well as new knowledge about the pharmacology of non-Δ‎⁹-THC phytocannabinoids, such as Δ‎⁹-tetrahydrocannabivarin and cannabidiol, is also discussed

This chapter describes the emerging potential of cannabidiol and, possibly, other phytocannabinoids, as new therapeutic agents in schizophrenia, taking into account both preclinical data obtained using in vivo animal models and available clinical data. Results reported so far, although to some extent controversial, support the potential of cannabidiol as an antipsychotic with a profile resembling atypical antipsychotic drugs, but with reduced side effects. The precise mechanism of action responsible for cannabidiol’s antipsychotic effect is still unknown but its ability to affect the endocannabinoid system as well as other systems favors the idea that its multitarget action could be particularly useful in the treatment of a puzzling and multifaceted disease such as schizophrenia.

Epilepsy is a progressive neurological disorder affecting approximately 1% of people whilst cannabis has a long, anecdotal history of use against seizures which has been studied clinically and preclinically to a limited extent. Clinical studies remain conflicted although an overall anticonvulsant effect of cannabis and its two principal components, Δ‎⁹-tetrahydrocannabinol and cannabidiol are supported. In preclinical models, cannabis is largely untested in modern models whilst the effects of Δ‎⁹-tetrahydrocannabinol, Δ‎⁹-tetrahydrocannabivarin, cannabidiol, cannabidvarin, and cannabinol are typically anticonvulsant. Potential proconvulsant effects and concerns about psychoactivity remain problem for Δ‎⁹-tetrahydrocannabinol in epilepsy but the entirely anticonvulsant effects of CBD and CBDV in numerous preclinical and (for cannabidiol) clinical settings argue for human clinical trials of these cannabinoids in people with drug resistant epilepsies.

There is increasing evidence that phytocannabinoids may exert beneficial effects in inflammatory, cardiovascular, metabolic, liver, and kidney disorders. This chapter briefly discusses the potential therapeutic targets and applications of phytocannabinoids, primarily based on in vivo studies. The focus is on the therapeutic effects of cannabidiol (CBD), the most abundant non-psychotropic constituent of Cannabis sativa (marijuana), and on the therapeutic and undesirable effects of Δ‎⁹-tetrahydrocannabinol (THC), the psychoactive constituent of marijuana initially thought to be responsible for the whole spectrum of the biological effects of marijuana. The therapeutic potential of Δ‎⁹-tetrahydrocannabivarin (Δ‎⁹THCV), a natural cannabinoid found in marijuana plant, and (E)-β‎-caryophyllene (BCP; FDA-approved food additive), a natural sesquiterpene found in many essential oils of spice including in Cannabis sativa, will also be highlighted based on several recent studies.

This chapter presents a pharmacological history of cannabis, primarily in the form of a detailed chronology highlighting key developments from various cultures around the world that employed either cannabidiol-predominant hemp or tetrahydrocannabinol-predominant cannabis chemovars, dating from the third millennium BCE to the twenty-first century CE. Subsequently, select topics are covered in greater depth focusing on problems wherein cannabis was employed therapeutically in the past, but for which more modern study is required, specifically: tinnitus, tetanus, burns, and pediatric indications. An extensive bibliography of primary source references follows. It is hoped that these examples of past documentation may serve as a useful guide to subsequent fruitful clinical research areas.

Cannabis is known to be the source of several pharmacologically active phytocannabinoids that do not share the ability of Δ‎⁹-tetrahydrocannabinol, the main psychotropic constituent of cannabis, to activate cannabinoid receptors. These are cannabichromene; cannabidiol and its propyl analogue, cannabidivarin, and acid, cannabidiolic acid; cannabigerol and its propyl analogue, cannabigerovarin, and acid, cannabigerolic acid; and two other cannabinoid acids, Δ‎⁹-tetrahydrocannabinolic acid, and its propyl analogue, Δ‎⁹-tetrahydrocannabivarinic acid. This review describes the actions that each of these phytocannabininoids has been discovered to display to-date, in vitro, at nanomolar or micromolar concentrations, and/or in vivo. These actions include the activation, blockade or apparent allosteric modulation of certain receptors and ion channels, and the inhibition of certain enzymes and cellular uptake processes. Brief mention is also made of the ability of some of these phytocannabinoids to affect the fluidity of cell membranes, modulate cytokine release, reduce oxidative stress, and/or induce signs of neuroprotection.