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Results of a randomized and double-blind controlled trial evaluating the effect of the non-psychoactive cannabinoid, cannabidiol, on sleep, mental health, and immune function were recently published in Nutrients. In this 8-week trial, 28 healthy college-age participants (median age of 25.9) received either 50mg cannabidiol or a calorie-matched placebo (consisting of medium chain triglycerides), taken 1 to 1.5 hours before bed. Participants were also advised to take their daily pill following their last meal, as the bioavailability of cannabidiol has previously been shown to be significantly improved with food, particularly lipid-rich meals. For example, in a previously published phase I trial an extremely high dose of cannabidiol (1500mg) was shown to increase plasma cannabidiol levels 4-5 fold more when administered following a high-fat breakfast versus when fasting.
Several assessments of mental health were employed in this trial, including Beck’s Depression Inventory (BDI), General Anxiety Disorder-7 (GAD-7), Piper Fatigue Scale (PFS), and Ferrans and Powers Quality of Life Index (QOL). Sleep was assessed by both the Leeds Sleep Evaluation Questionnaire (LSEQ) as well as a wrist actigraphy sleep tracker (Fitbit), and several markers of immune function were evaluated, including immunophenotyping and cytotoxic analyses of peripheral blood mononuclear cell (PBMCs).
Over the 8-week study period, no significant differences were found in markers of mental health. However, a 27.8% increase in the LSEQ was observed among the group receiving cannabidiol, indicating a significant improvement in perception of overall sleep, as well as a 79.2% increase in the QOS (quality of sleep) subscale. Other subjective sleep scores suggest those receiving cannabidiol felt more awake in the morning, as indicated by a 53.9% increase in the AFS (awake following sleep) subscale. No significant differences in sleep between groups were tracked by wrist actigraphy despite the improvements in subjective sleep. In addition to improved sleep perception, an increase in cytotoxic activity by NK cells was observed in PBMCs in the active group. Among participants who received cannabidiol, a 29.2% decrease in a line of leukemic cells was observed, compared to a 27.1% increase in the control group, suggesting a possible improvement in immunosurveillance against cancer cells.
This is not the first controlled study to demonstrate an improvement in sleep following supplementation with cannabinoid extracts. In 2021, results of perhaps the first randomized and placebo-controlled crossover trial were published in Sleep, describing the effects of a cannabinoid extract on symptoms of insomnia among participants with chronic insomnia. This trial used a combination containing delta-9-tetrahydrocannabinol (THC) 20 mg/mL, cannabinol (CBN) 2 mg/mL, and cannabidiol 1 mg/mL, dosed at between ½ to 1 mL an hour before bedtime. Twenty-three participants completed this 2-week trial (with a one-week washout between study periods), which was shown to improve insomnia symptoms, sleep quality and sleep duration, assessed both subjectively and by actigraphy (but not by polysomnography). The lack of additional well-controlled trials suggests that the optimal dose and formulation of cannabinoids are not well determined, at least when used as a sleep aid.
Yet research into the molecular mechanisms of cannabinoids is growing at a rapid pace. A review published in 2020 described 13 general molecular targets of cannabidiol alone, with quite complex physiology. For example, while cannabidiol acts as an antagonist to the CB1 and CB2 receptors, it may actually increase cannabinoid-mediated effects through these receptors. This increased effect is mediated by inhibition of the enzyme fatty acid amide hydrolase (FAAH), which degrades the naturally occurring endocannabinoid anandamide, a natural agonist of the CB1 and CB2 receptors. Additionally, given the wide variety of molecular targets of cannabidiol, it’s difficult to pin down which of its actions contribute to an overall effect on sleep. Many of its effects are thought to be mediated by activation of the 5‐HT1A and TRPV1 receptors, though it’s also an agonist of dopamine, adenosine and PPARγ receptors. Mixtures of cannabinoids are also well known to have different effects than the individual components, as they may interact with one another’s metabolism and molecular targets, and preclinical and clinical data suggests that cannabidiol may both potentiate and ameliorate some of the effects of THC (which is primarily a partial agonist of the CB1 receptor).
There is also a substantial amount of research on the potential immunomodulatory effects of cannabinoids, as also suggested by this recent clinical trial, with most data suggesting that endocannabinoids play a major regulatory role for the immune system and immune responses. Endocannabinoids clearly have an anti-inflammatory function, possibly mediated through the CB2 receptor, something demonstrated in a model of intestinal inflammation. Many immune cells express the CB2 receptor, including NK cells, and it is possible (as the authors suggest) that cannabidiol “may modify CB2 receptor activation such that NK cells experience a functional increase in their cellular cytotoxicity”. Further details of the role of endocannabinoids in modulating immune function can be found here. This recent clinical trial had a number of limitations, including its use only among healthy young individuals as well as taking place during the height of COVID-19, yet its encouraging results will hopefully prompt further controlled trials.
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