3.2.1. Δ9-Tetrahydrocannibinol (Δ9-THC)

Δ9-THC binds to CB1 and CB2 receptors at a more or less equal affinity [138,163,164]. It also acts on CB1-CB2 receptor heterodimers [165]. Δ9-THC is well known for its psychomimetic activities that are exerted by its binding to CB1 receptor in the brain, resulting in a calm and sedated mental state [49]. Besides euphoria, Δ9-THC is an appetite stimulator [166]. Oral Δ9-THC (Dronabinol, Marinol) and its synthetic nabilone (Cesamet) have been used for the treatment of nausea and appetite stimulation for people undergoing chemotherapy and for AIDS wasting syndrome [167,168]. The activation of CB1 by Δ9-THC is believed to mediate its anti-nausea and anti-emetic effects [169]. Sativex, which contains

a combination of Δ9-THC and CBD, has been used for relief of neuropathic pain in multiple sclerosis [170].

## 3.2.2. Cannabidiol (CBD)

The non-psychotropic cannabidiol (CBD) shows low affinity to the CB1 and CB2 receptors [135] and can exert antagonistic modulatory actions on these receptors [138,171]. CBD can also activate the TRPV1 channel, serotonin 1A (5-HT1A) receptors, and opioid receptors [24,172]. CBD has anti-inflammatory, anti-oxidative, anti-epileptic, analgesic, anti-neoplastic, sedative, neuroprotective, and anti-anxiety activities [173–188]. Moreover, CBD inhibits sebocyte lipogenesis by activating the TRPV4 ion channel that interferes with the pro-lipogenic ERK1/2 MAPK pathway [189].

The neuroprotective activity of CBD has been attributed in part to its anti-oxidative activity [190,191]. Based on its immunomodulatory activities, CBD has been implicated in the treatment of various autoimmune diseases [14,21], and its anti-nociceptive activity was found to be beneficial in relieving chronic pain [192]. In addition, CBD has potential uses in psychiatry due to its neuromodulatory activities in the brain that control recognition, emotional and behavioral responses [111,193,194]. CBD has especially been reported to have therapeutic effect for psychopathological conditions, such as substance use disorders, chronic psychosis, and anxiety [193]. CBD has been shown to be well tolerated in humans at concentrations as high as 3500–6000 mg/day [195–197], and the FDA-approved CBD (marketed as Epidiolex) is indicated for preventing epileptic seizures in Lennox–Gastaut syndrome and Dravet syndrome in children [198].

In experimental mice and rat models, CBD has been shown to have immunosuppressive activities [181], which are partly due to inhibition of TNFα production [199,200] and induction of myeloid-derived suppressor cells (MDSCs) [201]. CBD alleviated the symptoms of experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis and prevented the onset of autoimmune diabetes in experimental murine models [199,200,202]. In mice, the anti-inflammatory activity of CBD was found to have a bell-shaped dose–response with an optimal dose of 5 mg/kg [203]. The use of a standardized extract from a CBD-rich, Δ9-THClow *Cannabis indica* cultivar overcame this bell-shaped dose–response, suggesting a synergistic effect among the different compounds of the *Cannabis* extract [199].
