Cannabinoids have been shown to modulate a variety of immune cell functions in humans and animals [87-91]. It seems that cannabinoids and their agonists can exert both immunomodulatory and neuroprotective effects . For example, CBD can inhibit immune cell migration and thus induce anti-inflammatory effects . In addition, JWH-015, a synthetic CB2-selective agonist triggered apoptosis in thymocytes in vitro and inhibited the proliferative response of T and B cells to mitogens through the induction of apoptosis .
Knockout mice without the CB1 receptor exhibited increased anxiety-like behavior in light/dark box . It has been suggested that amygdala, hippocampus, hypothalamus and cingulate cortex are candidate brain sites and pathways of the anxiolytic action of CBD . Beyond the 5-HT1A receptor, several additional mechanisms have been proposed for anxiolytic effects of cannabinoids, including the free-acid amidhydrolase (FAAH) inhibition, COX-2 inhibition and TRPV1 blockade characteristics . Note, that in contrast to several positive reports [51, 52], a systematic review and meta-analysis failed to find an anxiolytic effect of cannabinoids [53, 54].
Anxiolytic and antidepressant effects may be found as a result of the interaction between cannabinoid and NA/5-HT systems . Others suggest that the anxiolytic effect results from the presynaptic CB1 receptor-mediated inhibition of acetylcholine released by preganglionic sympathetic neurons , although CBD’s attachment to the CB-1 and CB-2 receptors is controversial. Biochemical studies indicate that CBD may enhance endogenous signaling of the endocannabinoid anandamide indirectly. This is by inhibiting the intracellular degradation of anandamide catalyzed, by the enzyme fatty acid amide hydrolase . In addition, another arousal mechanism that is mediated by cannabinoids is the inhibition of adrenaline secretion in adrenal glands and this may account for the decrease in plasma adrenaline concentration found following cannabinoid administration in rabbits . However, while known to modulate neuroendocrine function, the precise acute and chronic dose-related effects of cannabinoids in humans remain to be studied carefully .
2.1. Potential Mechanisms
Mood disorders are the most prevalent mental conditions encountered in psychiatric practice. Numerous patients suffering from mood disorders present with treatment-resistant forms of depression, co-morbid anxiety, other psychiatric disorders and bipolar disorders. Standardized essential oils (such as that of Lavender officinalis) have been shown to exert clinical efficacy in treating anxiety disorders. As endocannabinoids are suggested to play an important role in major depression, generalized anxiety and bipolar disorders, Cannabis sativa was suggested for their treatment. The endocannabinoid system is widely distributed throughout the body including the brain, modulating many functions. It is involved in mood and related disorders, and its activity may be modified by exogenous cannabinoids. CB1 and CB2 receptors primarily serve as the binding sites for endocannabinoids as well as for phytocannabinoids, produced by cannabis inflorescences. However, ‘cannabis’ is not a single compound product but is known for its complicated molecular profile, producing a plethora of phytocannabinoids alongside a vast array of terpenes. Thus, the “entourage effect” is the suggested positive contribution derived from the addition of terpenes to cannabinoids. Here, we review the literature on the effects of cannabinoids and discuss the possibility of enhancing cannabinoid activity on psychiatric symptoms by the addition of terpenes and terpenoids. Possible underlying mechanisms for the anti-depressant and anxiolytic effects are reviewed. These natural products may be an important potential source for new medications for the treatment of mood and anxiety disorders.
Standardized essential oils (such as that of Lavender officinalis) have been shown to exert clinical efficacy in treating anxiety disorders. This supports the assessment that these natural products are an important potential source for new anxiolytic drugs. A systematic review of essential oils, their bioactive constituents, and anxiolytic-like activity in animal models has been published . According to the authors, the highest potent essential oil is that of Lavendula angustifolia, which has already been tested in controlled clinical trials with positive anxiolytic results. Different research groups, using different routes of administration supported the results that Lavender and Citrus aurantium essential oils have significant anxiolytic-like effects in several animal models such as the open field, elevated plus maze and marble burying tests as well. Other promising essential oils are those of Citrus synesis and bergamot oil, which showed some clinical anxiolytic actions. The potential antidepressant activity of these essential oils is of interest.
May cannabis consumption affect the microbiota-gut-brain axis? Only few evidences up to date support such a connection. In mice, THC altered the microbiota, including an increase in the presence of Akkermansia muciniphilia bacterial strain that is associated with reducing insulin resistance, weight loss, and improving intestinal barrier function . However, whether THC or other cannabis-derived compounds may directly affect the microbiota-gut-brain axis remains to be determined.
1.3. Involvement of Cannabinoids in the Treatment of Mood Disorders
In general, of the 400 terpenes known in cannabis, very few have been examined at the functional level . A positive effect of terpenes on various psychiatric endophenotypes has been shown [67, 74]. For instance, propolis essential oil that contains several terpenes, such as cinnamyl alcohol, α- and β-Caryophyllene, Cadinene, Guaiol and Eudesmol revealed, in restraint-stressed mice, significant improvement in anxiety-like behavior . The essential oil, as in many other studies on terpenes, had no effect on locomotor activity and significantly antagonized the hyperfunction of hypothalamic–pituitary–adrenal (HPA) axis, indicating that propolis essential oil contains therapeutic effects on anxiety . Likewise, crocins – related hydrophilic carotenoids found in flowers, given to rats in doses of 30 and 50 mg/kg reduced mCPP-induced amplified self-grooming. These effects of crocins could not be attributed to changes in locomotor activity .
Earlier studies have suggested that oxidative stress may play a role in the pathophysiology of BD. In a rat model of BD, it has been concluded that CBD protects against D-AMPH-induced oxidative protein damage and increases BDNF levels in the reversal model and these effects vary depending on the brain regions evaluated and doses of CBD administered . The protective effects of CBD against glutamate toxicity may have a mood-stabilizing action similar to some other antiepileptic drugs of validated value in BD [22, 56, 57]. However, the empirical results reported are not always positive. In an animal study, CBD was not able to prevent or reverse the hyperlocomotion induced by D-AMPH, an animal model for mania-like behavior . Based on small size studies on BD and taken together a recent review concluded that CBD may not be effective in manic episodes .
Various sources highlight the limited therapeutic index of pure THC, when given intravenously (D’Souza et al., 2004) or orally (Favrat et al., 2005), especially in people previously naïve to its effects. Acute overdose incidents involving THC or THC-predominant cannabis usually consist of self-limited panic reactions or toxic psychoses, for which no pharmacological intervention is generally necessary, and supportive counselling (reassurance or ‘talking down’) is sufficient to allow resolution without sequelae. CBD modulates the psychoactivity of THC and reduces its adverse event profile (Russo and Guy, 2006), highlighted by recent results above described. Could it be, however, that other cannabis components offer additional attenuation of the less undesirable effects of THC? History provides some clues.
Next morning there was an ordinary appetite, much torpidity, great defect and shortness of memory, extreme apparent protraction of time, but no peculiarity of articulation or other effect; and these symptoms lasted until 2 P.M., when they ceased entirely in a few minutes after taking lemonade.
Caryophyllene oxide ( Table 2 ) is a sesquiterpenoid oxide common to lemon balm (Melissa officinalis), and to the eucalyptus, Melaleuca stypheloides, whose EO contains 43.8% (Farag et al., 2004). In the plant, it serves as an insecticidal/anti-feedant (Bettarini et al., 1993) and as broad-spectrum antifungal in plant defence (Langenheim, 1994). Analogously, the latter properties may prove therapeutic, as caryophyllene oxide demonstrated antifungal efficacy in a model of clinical onychomycosis comparable to ciclopiroxalamine and sulconazole, with an 8% concentration affecting eradication in 15 days (Yang et al., 1999). Caryophyllene oxide is non-toxic and non-sensitizing (Opdyke, 1983). This agent also demonstrates anti-platelet aggregation properties in vitro (Lin et al., 2003). Caryophyllene oxide has the distinction of being the component responsible for cannabis identification by drug-sniffing dogs (Stahl and Kunde, 1973).
Conclusions and suggestions for future study
Calamus root is the best antidote for the ill effects of marijuana. . . . if one smokes a pinch of calamus root powder with the marijuana, this herb will completely neutralize the toxic side effects of the drug.
CBD is the most common phytocannabinoid in fibre (hemp) plants, and second most prevalent in some drug chemotypes. It has proven extremely versatile pharmacologically ( Table 1 ) (Pertwee, 2004; Mechoulam et al., 2007), displaying the unusual ability to antagonize CB1 at a low nM level in the presence of THC, despite having little binding affinity (Thomas et al., 2007), and supporting its modulatory effect on THC-associated adverse events such as anxiety, tachycardia, hunger and sedation in rats and humans (Nicholson et al., 2004; Murillo-Rodriguez et al., 2006; Russo and Guy, 2006). CBD is an analgesic (Costa et al., 2007), is a neuroprotective antioxidant more potent than ascorbate or tocopherol (Hampson et al., 1998), without COX inhibition (Stott et al., 2005), acts as a TRPV1 agonist analogous to capsaicin but without noxious effect (Bisogno et al., 2001), while also inhibiting uptake of AEA and weakly inhibiting its hydrolysis. CBD is an antagonist on GPR55, and also on GPR18, possibly supporting a therapeutic role in disorders of cell migration, notably endometriosis (McHugh et al., 2010). CBD is anticonvulsant (Carlini and Cunha, 1981; Jones et al., 2010), anti-nausea (Parker et al., 2002), cytotoxic in breast cancer (Ligresti et al., 2006) and many other cell lines while being cyto-preservative for normal cells (Parolaro and Massi, 2008), antagonizes tumour necrosis factor-alpha (TNF-α) in a rodent model of rheumatoid arthritis (Malfait et al., 2000), enhances adenosine receptor A2A signalling via inhibition of an adenosine transporter (Carrier et al., 2006), and prevents prion accumulation and neuronal toxicity (Dirikoc et al., 2007). A CBD extract showed greater anti-hyperalgesia over pure compound in a rat model with decreased allodynia, improved thermal perception and nerve growth factor levels and decreased oxidative damage (Comelli et al., 2009). CBD also displayed powerful activity against methicillin-resistant Staphylococcus aureus (MRSA), with a minimum inhibitory concentration (MIC) of 0.5–2 µg·mL −1 (Appendino et al., 2008). In 2005, it was demonstrated that CBD has agonistic activity at 5-hydroxytryptamine (5-HT)1A at 16 µM (Russo et al., 2005), and that despite the high concentration, may underlie its anti-anxiety activity (Resstel et al., 2009; Soares Vde et al., 2010), reduction of stroke risk (Mishima et al., 2005), anti-nausea effects (Rock et al., 2009) and ability to affect improvement in cognition in a mouse model of hepatic encephalopathy (Magen et al., 2009). A recent study has demonstrated that CBD 30 mg·kg −1 i.p. reduced immobility time in the forced swim test compared to imipramine (P < 0.01), an effect blocked by pre-treatment with the 5-HT1A antagonist WAY100635 (Zanelati et al., 2010), supporting a prospective role for CBD as an antidepressant. CBD also inhibits synthesis of lipids in sebocytes, and produces apoptosis at higher doses in a model of acne (vide infra). One example of CBD antagonism to THC would be the recent observation of lymphopenia in rats (CBD 5 mg·kg −1 ) mediated by possible CB2 inverse agonism (Ignatowska-Jankowska et al., 2009), an effect not reported in humans even at doses of pure CBD up to 800 mg (Crippa et al., 2010), possibly due to marked interspecies differences in CB2 sequences and signal transduction. CBD proved to be a critical factor in the ability of nabiximols oromucosal extract in successfully treating intractable cancer pain patients unresponsive to opioids (30% reduction in pain from baseline), as a high-THC extract devoid of CBD failed to distinguish from placebo (Johnson et al., 2010). This may represent true synergy if the THC–CBD combination were shown to provide a larger effect than a summation of those from the compounds separately (Berenbaum, 1989).
Phytocannabinoids and terpenoids are synthesized in cannabis, in secretory cells inside glandular trichomes ( Figure 1 ) that are most highly concentrated in unfertilized female flowers prior to senescence (Potter, 2004; Potter, 2009). Geranyl pyrophosphate is formed as a precursor via the deoxyxylulose pathway in cannabis (Fellermeier et al., 2001), and is a parent compound to both phytocannabinoids and terpenoids ( Figure 2 ). After coupling with either olivetolic acid or divarinic acid, pentyl or propyl cannabinoid acids are produced, respectively, via enzymes that accept either substrate (de Meijer et al., 2003), a manifestation of Mechoulam’s postulated ‘Nature’s Law of Stinginess’. Although having important biochemical properties in their own right, acid forms of phytocannabinoids are most commonly decarboxylated via heat to produce the more familiar neutral phytocannabinoids ( Table 1 ). Alternatively, geranyl pyrophosphate may form limonene and other monoterpenoids in secretory cell plastids, or couple with isopentenyl pyrophosphate in the cytoplasm to form farnesyl pyrophosphate, parent compound to the sesquiterpenoids, that co-localizes with transient receptor potential vanilloid receptor (TRPV) 1 in human dorsal root ganglion, suggesting a role in sensory processing of noxious stimuli (Bradshaw et al., 2009), and which is the most potent endogenous ligand to date on the G-protein coupled receptor (GPR) 92 (Oh et al., 2008).
Phytocannabinoid activity table
Government-approved cannabis supplied to patients in national programmes in the Netherlands and Canada is gamma-irradiated to sterilize coliform bacteria, but the safety of this technique for a smoked and inhaled product has never been specifically tested. Gamma-radiation significantly reduced linalool titres in fresh cilantro (Fan and Sokorai, 2002), and myrcene and linalool in orange juice (Fan and Gates, 2001).