Sativex oromucosal cannabis based medicine (photo: Ethan Russo , 2003) 

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... Linnaeus recognized cannabis as narcotica and anodyna in his Materia Medica in the 18th century [31] (p. 214). William B. OShaughnessy reintroduced cannabis to Western medicine from India in the 19th century [32], wherein it produced sleep and pain reduction for victims of rheumatism and many other conditions. Benefits on sleep were noted in various pain states [11] throughout the 19th and early 20th century, when cannabis medicines subsequently fell from common medical usage due to lack of standardization and daunting problems with dosing and quality control. Scientific study of cannabinoids entered the modern era in the early 1960s with the isolation of THC [33]. Early studies revealed that THC reduced sleep latency in normal and insomniac subjects, and caused some suppression of slow wave sleep (Stages 3 and 4) [34], often with a residual hangover effect the next day [35]. No formal studies of cannabinoids to date have included electroencephalography or polysomnography in symptomatic conditions or chronic pain states. In a recent case report [36], treatment with Marinol (dronabinol, synthetic THC) effectively reversed serious insomnia in three patients afflicted with intractable pruritus associated with cholestatic liver disease. Similarly, in a limited trial of Marinol , 2.5 mg at night in five dementia patients, a reduction was observed in nocturnal motor activity ( p 1⁄4 0.028) [37]. A series of experiments with cannabidiol performed in Brazil were summarized in 1981 [38], with observations based on subjective sleep assessments. Of two subjects taking CBD 300 mg twice a day (BID) for 2 d, one reported having slept more heavily, but no performance abnormalities were evident. Ten more subjects took 200 mg CBD vs . placebo on four separate occasions with no significant differences in subjective functioning, or level of alertness. Two of four subjects taking CBD, 10 mg BID for 20 d, complained of isolated episodes of daytime somnolence on rare occasions. Another experiment compared placebo to CBD, 3 mg/kg/d divided BID in eight subjects. One reported somnolence for a week, another for the entire 30 d, and a third reported improvement in baseline insomnia. Subsequently, this group assessed 15 subjects with 40, 80, and 160 mg oral doses of CBD as a hypnotic vs . nitrazepam, 5 mg, and placebo in a double-blind randomized trial. This low dose of benzodiazepine and lower dose of CBD produced little effect on sleep. The highest CBD dose, however, seemed to extend sleep and reduce episodic wakening in 10/15 subjects subjectively, while also reducing dream recall. No hangover symptoms were noted. Cannabinoid Effects on Brain Chemistry in Sleep. – The key role of the endogenous cannabinoid system in regulation of sleep – wake cycles was suggested by the finding that the CB 1 antagonist/inverse agonist SR 141716A produces arousal in rats at the expense of slow-wave sleep [39]. This was further highlighted by the finding that the endocannabinoid anandamide (AEA) seems to mediate sleep induction and interacts with oleamide in this regard [40]. Subsequently, a Japanese group demonstrated the inhibition of serotonin and ketanserin (5-HT 2A antagonist) binding to the 5-T receptors by AEA [41]. A mild but similar response has recently been demonstrated for CBD [42], and cannabis terpenoids [43], suggesting a possible synergy with the CB 1 agonist, THC. Certain terpenoid components of cannabis are sedating in their own right (reviewed in [44], particularly terpineol [45]). Recently, CBD was shown to inhibit uptake of AEA, and weakly inhibit its hydrolysis [46], making it, in effect, an inducer of AEA function, and suggesting a modulatory role for this agent in sleep. Additionally, a functional role for endocannabinoids in regulation of respiratory stability in sleep to prevent sleep apnea has been suggested [47]. Finally, it has recently been demonstrated that CBD administered intracerebroventricularly in rats increased wakefulness in the lights-on period, and increased enhancement of c-FOS expression in hypothalamus and dorsal raphe nucleus [48], supporting a clinical alerting effect for this agent [22], as discussed below. New Data on Sleep Modulation with Cannabis-Based Medicine Extracts (CBMs). – GW Pharmaceuticals received a license from the British Home Office in 1998 to cultivate cannabis and extract it as a standardized botanical drug substance for formulation into finished pharmaceutical products. Early indications have focused on multiple sclerosis (MS) and chronic pain, especially neuropathic, or associated with cancer and rheumatoid arthritis. Chemovars of cannabis were selected via Mendelian genetics to express one predominant phytocannabinoid [49] [50]. Cloned plants undergo liquid CO 2 extraction to produce botanical drug substances that contain predominantly THC ( Tetranabinex ), CBD ( Nabidiolex ), or a 1 : 1 combination of the two ( Sativex ; Fig. 1 ) [51] [52]. Sativex is administered oromucosally via a pump-action spray with each 100- m l pump-action actuation providing 2.7 mg of THC, 2.5 mg of CBD plus other phytocannabinoids, terpenoids, and phytosterols [25], in a base of 50% EtOH and 50% propylene glycol with 0.05% peppermint flavoring. Pharmacokinetic data on this material is available from recent publications [53]. The preparation has onset of activity in 15 – 40 min, which allows patients to titrate dosing requirements according to pain levels or other symptoms with an acceptable profile of adverse events. A total of 1000 patient years of Sativex exposure in over 2000 experimental subjects has been amassed in Phase-II and -III clinical trials. A slight majority of subjects had no previous recreational or medicinal cannabis exposure, but comparative efficacy results have been identical in cannabis-experienced and cannabis-naïve cohorts with no evidence of inadequacy of subject blinding [54] [55]. Patients are generally able to find a stable dose at which they obtain therapeutic relief without unwanted psychoactive effects. All randomized controlled trials (RCTs) were performed with Sativex added as an adjunct to existing drug regimens in patients with intractable symptoms, i.e ., patients considered treatment-resistant and remained on best available analgesic therapy and hypnotic medication, if prescribed. A concerted effort has been made in this review to include data from all available Sativex clinical trials; no negative data were excluded. Sativex was approved in June 2005 for marketing as a prescription medicine in Canada under a Notice of Compliance with Conditions (NOC/c) for central neuropathic pain in multiple sclerosis (MS). An Investigational New Drug (IND) application to study Sativex in intractable cancer pain patients in the USA was approved by the FDA in January 2006. Two independent reviews of Sativex have recently been published [56] [57]. The effects of oromucosal high-THC extract ( Tetranabinex ), 15 mg, and THC- CBD extract doses of 5 and 15 mg of THC-equivalent were assessed by Nicholson et al . in eight subjects with respect to nocturnal sleep, early morning performance, memory, and residual sleepiness in a double-blind placebo-controlled four-way cross-over study with EEG monitoring [58]. While the THC extract, 15 mg, alone produced little effect on sleep architecture, sleep latency was reduced, memory was impaired, and residual sleepiness and mood changes were observed ( p < 0.05). Both dose levels of combined THC-CBD extract decreased Stage 3 sleep ( p < 0.05) over placebo, and the 15-mg doses increased wakefulness ( p < 0.05) compared to 5-mg doses. The 5-mg doses of THC-CBD extract actually produced faster reaction times on the digit recall test ( p < 0.05) over placebo. The authors noted that whereas impaired memory was observed the next day when 15-mg THC extract was given alone overnight, there were no such effects when THC was concomitantly accompanied by 15 mg of CBD, as in Sativex . Conclusions were that THC was sedative, while, in contrast, the presence of CBD was alerting, tended to counteract THC adverse effects on cognition, and impaired wakefulness. In subsequent Phase-II and -III clinical trials, sleep quality was assessed with questionnaires completed by clinical trial subjects. Visual Analogue Scales (VASs) and Numerical Rating Scales (NRSs) are familiar instruments to many clinicians and have traditionally been used to quantify patient-rated subjective experiences. The two types of scale have similar sensitivity and reliability, but NRS is generally preferred by patients for ease of use. NRS and VAS are well-established and validated for the measurement of pain [59]. As is the case with pain, there is no objective gold standard by which to quantify the quality and quantity of sleep in patients participating in clinical trials. For this reason, most of the studies included in this review utilized NRSs or VASs to measure sleep and sleep disturbance. For example, Wade et al . [60] used VASs attached to the following questions: How was your quality of sleep last night ?/ How much sleep did you get last night ?/ How did you feel when you awoke this morning ? The anchors at each extremity of the 10-cm line were best imaginable and worst imaginable for the first two questions, and totally refreshed or totally unrefreshed for the third. As an example of NRS, Rog et al. [61] used an 11-box (0 – 10) scale attached to the following instruction: On a scale of 0 – 10 please indicate how your nerve pain disrupted your sleep last night. Please tick one box only . The anchors were did not disrupt sleep and completely disrupts (unable to sleep due to pain) . Such measures appear to have good face validity. These and other studies of cannabis-based medicines on pain and sleep are summarized in the Table . In a Phase-II study in 24 patients with intractable neurogenic symptoms including MS and chronic pain, ...