Sleep disorders and the medicinal use of Cannabis sativa
Sleeping is a homeostatic need of our organism, which means that it allows us to maintain the balance of our biological system, just like eating or drinking. It is during sleep that the body performs the main restorative functions of the body, such as tissue repair, muscle growth and protein synthesis. Sleep is a vital nervous system function that contributes to brain and body homeostasis, energy levels, cognitive ability and other key functions in a variety of organisms. During this time, it is possible to replenish energy and regulate metabolism, which are essential factors to maintain a healthy body and mind. Sleeping well is, then, a habit that should be included in everyone's routine.
Experts recommend an average of 8 hours of sleep a day, without interruptions. This number may vary according to the age of each individual and their body's development needs, as indicated. Adults need 7 to 8 hours of quality sleep at regular times per day.
Sleep disorders are changes in the ability to sleep properly, whether due to brain changes, dysregulation between sleep and wakefulness, respiratory changes or movement disorders, and some common examples are insomnia, sleep apnea, narcolepsy, somnambulism or sleep syndrome, restless legs. Dysfunctional sleep induces neural problems and is a fundamental part of almost all human psychiatric disorders, including substance abuse disorders.
The hypnogenic effects of cannabinoid drugs have been known for a long time, since 1843, and there has been considerable recent interest in the use of Cannabis sativa derivatives and other cannabinoid compounds as sleep aids. This interest has coincided with renewed research on Cannabis and sleep, including an emphasis on how endogenous cannabinoids (endocannabinoids, eCBs) contribute to normal and disturbed sleep. However, much remains to be learned about the cannabinoid/sleep relationship in both humans and experimental animals.
The eCBs are lipid metabolites that produce neuromodulatory actions mainly through the activation of the type 1 cannabinoid receptor (CB1). The two main eCBs involved are 2-arachidonoyl-glycerol (2-AG) and arachidonoyl ethanolamide (AEA or anandamide). Activation of CB1 produces juxtacrine intracellular signals mainly through presynaptic actions in neurotransmitter release, since receptors are expressed almost exclusively at the terminals of neuronal axons. The eCBs are found throughout the body and brain, as 2-AG can be produced by almost every cell type in the body, and AEA is also produced by many cell types.
In studies performed observing the function of endocannabinoids, including oleoylethanolamide (OEA), anandamide (AEA) and 2-arachidonyl-glycerol (2-AG) in patients with obstructive sleep apnea (OSA) compared to healthy controls, were observed higher concentrations of OEA, but not AEA or 2-AG, among patients with OSA, which have been associated with respiratory distress. This finding suggests that endocannabinoids, specifically OAS, may function to protect the brain from the symptoms of sleep apnea. Additional research was conducted to examine the impact of the combination of Δ-9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) among humans with OSA. The safety, tolerability and efficacy of these compounds in reducing the severity of OSA symptoms in adults have been investigated. The combination of THC and CBD has been observed to be safe, well tolerated and shown to be effective in reducing apneas among adults with OSA.
The hypnotic effects of THC were evaluated
The hypnotic effects of THC were evaluated in the 1970s, and THC was shown to increase Stage 3 sleep and reduce REM sleep. Studies of medical cannabis users have found that individuals commonly report using Cannabis for insomnia. Many Cannabis users cite sleep improvements as the main motivator of use, and accumulated evidence suggests that Cannabis use may offer therapeutic relief for individuals with poor sleep quality related to post-traumatic stress disorder and pain. One of the situations of extreme pain throughout the body is the case of fibromyalgia (FM). FM is a chronic pain syndrome characterized by diffuse body pain with associated pressure allodynia. Diagnosis is clinical, without confirmatory testing, and based on a history of generalized pain and the presence of tenderness in 11 of 18 specific tender point sites.In addition to reporting pain, FM patients have several other somatic symptoms, such as fatigue, mood disorders, and sleep disturbances, which have an important effect on well-being.
Studies performed with cannabinoids have shown that combinations of THC and CBD have been shown to be effective in promoting sleep in FM patients who present with chronic insomnia.
Most studies examining the impact of cannabinoids on sleep have actually been conducted in the context of chronic pain conditions. A review of phase I and II clinical trials suggested that a THC/CBD ratio of 1:1 was associated with improvements in sleep among chronic pain patients.
Another study using the formulation of THC and CBD extracts, containing approximately equal doses of ∼2 mg of THC and CBD, to examine sleep in individuals with pain-related sleep disorders, reported improved sleep with no evidence of drug tolerance.
Another study using the formulation of THC and CBD extracts, containing approximately equal doses of ∼2 mg of THC and CBD, to examine sleep in individuals with pain-related sleep disorders, reported improved sleep with no evidence of drug tolerance.
The substance CBD has been studied for some time regarding its therapeutic effects. New studies demonstrate its effects on sleep. CBD blocked anxiety-induced suppression of REM sleep but had no effect on NREM sleep. This work is further supported by a recent case report in which the administration of CBD oil reduced the symptoms of Post-traumatic stress disorder (PTSD), PTSD-related insomnia and sleep disturbances. Together, these findings suggest that CBD may affect sleep quality through its anxiolytic effects.
In studies performed with THC and CBD, mixed effects of THC and CBD combined were reported, with THC generally increasing sedation and CBD having the opposite wake-enhancing effects. Studies suggest that the concentration, dose and route of administration of cannabinoids may have differential effects on sleep quality and insomnia symptoms.
It is becoming increasingly evident that endocannabinoids play a prominent role in the neurophysiology of sleep, and cannabinoid drugs alter these processes. There are clear overlaps between the brain's eCB system and sleep-wake circuits, and cannabinergic manipulations are capable of altering sleep on a large scale in terms of time spent in specific vigilance states and on a fine scale in terms of sleep architecture and spectral power of specific sleep-related brain rhythms.
The hypnotic effects of cannabis have been known for a long time and there is an increasing use of phytocannabinoids and other formulations such as sleeping pills.
It is increasingly pertinent to understand how phytocannabinoids interact with the eCB system to alter sleep and the therapeutic nature of these effects.
The objective of Piauhy Labs is to carry out studies with cannabinoids, in addition to THC and CBD, terpenes and other substances from the Cannabis sativa plant.
At a later stage, the objective of Piauhy Labs will be to use these substances in studies for the manufacture of medications that improve sleep quality, including in patients with chronic pain.
Piauhy Labs intends to obtain a Certificate of Compliance with Good Laboratory Practices, in accordance with the OECD principles, for the pharmaceutical area.
As a result of the investigation processes, Piauhy Labs intends to create patents and originate intellectual property, with the ultimate goal of producing innovative medicines that improve the health of the population, in this aspect in relation to improving the quality of sleep, including medications for patients with chronic pain.
Elmo Resende, Ph.D.
Director of R&D
Piauhy Labs
Elmo Resende, Ph.D.
Director of R&D
Piauhy Labs
References
Babson, K. A.; Boden, M. T. and Bonn-Miller, M. O. The impact of perceived sleep quality and sleep efficiency/duration on cannabis use during a self-guided quit attempt. Addict. Behav. 38, 2707–2713, 2013.
Babson, K. A.; Sottile, J. and Morabito, D. Cannabis, Cannabinoids, and Sleep: a Review of the Literature. Curr. Psychiatry Rep. 19, 23, 2017.
Belendiuk, K. A.; Babson, K. A.; Vandrey, R. and Bonn-Miller, M. O. Cannabis species and cannabinoid concentration preference among sleep-disturbed medicinal cannabis users. Addict. Behav. 50, 178–181, 2015.
Clendinning, J. Observations on the medicinal properties of the Cannabis Sativa of India. Med. Chir. Trans. 26, 188–210, 1843.
Copersino, M. L.; Boyd, S. J.; Tashkin, D. P.; Huestis, M. A.; Heishman, S. J.; Dermand, J. C. et al. Cannabis withdrawal among non-treatment-seeking adult cannabis users. Am. J. Addict. 15, 8–14, 2006.
Drewes, A. M. Pain and sleep disturbances with special reference to fibromyalgia and rheumatoid arthritis. Rheumatology (Oxford) 38:1035– 8, 1999.
Feinberg, I.; Jones, R.; Walker, J. M.; Cavness, C. and March, J. Effects of high dosage delta-9-tetrahydrocannabinol on sleep patterns in man. Clin. Pharmacol. Ther. 17:458 – 66, 1977.
Freemon, F. R. The effect of chronically administered delta-9- tetrahydrocannabinol upon the polygraphically monitored sleep of normal volunteers. Drug Alcohol Depend. 10, 345–353, 1982.
Kano, M.; Ohno-Shosaku, T.; Hashimotodani, Y.; Uchigashima, M. and Watanabe, M. Endocannabinoid-mediated control of synaptic transmission. Physiol. Rev. 89, 309–380, 2009.
Grant, I. and Cahn, B. R. Cannabis and endocannabinoid modulators: Therapeutic promises and challenges. Clin. Neurosci. Res. 5, 185–199, 2005.
Kesner, A. J. and Lovinger, D. M. Cannabinoids, Endocannabinoids and Sleep. Front. Mol. Neurosci., 22, July, 2020.
Lovinger, D. M. Presynaptic modulation by endocannabinoids. Handb. Exp. Pharmacol. 184, 435–477, 2008.
Murillo-Rodriguez, E.; Machado, S.; Rocha, N. B.; Budde, H.; Yuan, T. F. and Arias-Carrion, O. Revealing the role of the endocannabinoid system modulators, SR141716A, URB597 and VDM-11, in sleep homeostasis. Neuroscience 339, 433–449, 2016.
Russo, E. B.; Guy, G. W. and Robson, P. J. Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine. Chem. Biodivers 4:1729 – 43, 2007.
Babson, K. A.; Boden, M. T. and Bonn-Miller, M. O. The impact of perceived sleep quality and sleep efficiency/duration on cannabis use during a self-guided quit attempt. Addict. Behav. 38, 2707–2713, 2013.
Babson, K. A.; Sottile, J. and Morabito, D. Cannabis, Cannabinoids, and Sleep: a Review of the Literature. Curr. Psychiatry Rep. 19, 23, 2017.
Belendiuk, K. A.; Babson, K. A.; Vandrey, R. and Bonn-Miller, M. O. Cannabis species and cannabinoid concentration preference among sleep-disturbed medicinal cannabis users. Addict. Behav. 50, 178–181, 2015.
Clendinning, J. Observations on the medicinal properties of the Cannabis Sativa of India. Med. Chir. Trans. 26, 188–210, 1843.
Copersino, M. L.; Boyd, S. J.; Tashkin, D. P.; Huestis, M. A.; Heishman, S. J.; Dermand, J. C. et al. Cannabis withdrawal among non-treatment-seeking adult cannabis users. Am. J. Addict. 15, 8–14, 2006.
Drewes, A. M. Pain and sleep disturbances with special reference to fibromyalgia and rheumatoid arthritis. Rheumatology (Oxford) 38:1035– 8, 1999.
Feinberg, I.; Jones, R.; Walker, J. M.; Cavness, C. and March, J. Effects of high dosage delta-9-tetrahydrocannabinol on sleep patterns in man. Clin. Pharmacol. Ther. 17:458 – 66, 1977.
Freemon, F. R. The effect of chronically administered delta-9- tetrahydrocannabinol upon the polygraphically monitored sleep of normal volunteers. Drug Alcohol Depend. 10, 345–353, 1982.
Kano, M.; Ohno-Shosaku, T.; Hashimotodani, Y.; Uchigashima, M. and Watanabe, M. Endocannabinoid-mediated control of synaptic transmission. Physiol. Rev. 89, 309–380, 2009.
Grant, I. and Cahn, B. R. Cannabis and endocannabinoid modulators: Therapeutic promises and challenges. Clin. Neurosci. Res. 5, 185–199, 2005.
Kesner, A. J. and Lovinger, D. M. Cannabinoids, Endocannabinoids and Sleep. Front. Mol. Neurosci., 22, July, 2020.
Lovinger, D. M. Presynaptic modulation by endocannabinoids. Handb. Exp. Pharmacol. 184, 435–477, 2008.
Murillo-Rodriguez, E.; Machado, S.; Rocha, N. B.; Budde, H.; Yuan, T. F. and Arias-Carrion, O. Revealing the role of the endocannabinoid system modulators, SR141716A, URB597 and VDM-11, in sleep homeostasis. Neuroscience 339, 433–449, 2016.
Russo, E. B.; Guy, G. W. and Robson, P. J. Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine. Chem. Biodivers 4:1729 – 43, 2007.
Sleep disorders and the medicinal use of Cannabis sativa
Sleeping is a homeostatic need of our organism, which means that it allows us to maintain the balance of our biological system, just like eating or drinking. It is during sleep that the body performs the main restorative functions of the body, such as tissue repair, muscle growth and protein synthesis. Sleep is a vital nervous system function that contributes to brain and body homeostasis, energy levels, cognitive ability and other key functions in a variety of organisms. During this time, it is possible to replenish energy and regulate metabolism, which are essential factors to maintain a healthy body and mind. Sleeping well is, then, a habit that should be included in everyone's routine.
Experts recommend an average of 8 hours of sleep a day, without interruptions. This number may vary according to the age of each individual and their body's development needs, as indicated. Adults need 7 to 8 hours of quality sleep at regular times per day.
Sleep disorders are changes in the ability to sleep properly, whether due to brain changes, dysregulation between sleep and wakefulness, respiratory changes or movement disorders, and some common examples are insomnia, sleep apnea, narcolepsy, somnambulism or sleep syndrome, restless legs. Dysfunctional sleep induces neural problems and is a fundamental part of almost all human psychiatric disorders, including substance abuse disorders.
The hypnogenic effects of cannabinoid drugs have been known for a long time, since 1843, and there has been considerable recent interest in the use of Cannabis sativa derivatives and other cannabinoid compounds as sleep aids. This interest has coincided with renewed research on Cannabis and sleep, including an emphasis on how endogenous cannabinoids (endocannabinoids, eCBs) contribute to normal and disturbed sleep. However, much remains to be learned about the cannabinoid/sleep relationship in both humans and experimental animals.
The eCBs are lipid metabolites that produce neuromodulatory actions mainly through the activation of the type 1 cannabinoid receptor (CB1). The two main eCBs involved are 2-arachidonoyl-glycerol (2-AG) and arachidonoyl ethanolamide (AEA or anandamide). Activation of CB1 produces juxtacrine intracellular signals mainly through presynaptic actions in neurotransmitter release, since receptors are expressed almost exclusively at the terminals of neuronal axons. The eCBs are found throughout the body and brain, as 2-AG can be produced by almost every cell type in the body, and AEA is also produced by many cell types.
In studies performed observing the function of endocannabinoids, including oleoylethanolamide (OEA), anandamide (AEA) and 2-arachidonyl-glycerol (2-AG) in patients with obstructive sleep apnea (OSA) compared to healthy controls, were observed higher concentrations of OEA, but not AEA or 2-AG, among patients with OSA, which have been associated with respiratory distress. This finding suggests that endocannabinoids, specifically OAS, may function to protect the brain from the symptoms of sleep apnea. Additional research was conducted to examine the impact of the combination of Δ-9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) among humans with OSA. The safety, tolerability and efficacy of these compounds in reducing the severity of OSA symptoms in adults have been investigated. The combination of THC and CBD has been observed to be safe, well tolerated and shown to be effective in reducing apneas among adults with OSA.
The hypnotic effects of THC were evaluated
The hypnotic effects of THC were evaluated in the 1970s, and THC was shown to increase Stage 3 sleep and reduce REM sleep. Studies of medical cannabis users have found that individuals commonly report using Cannabis for insomnia. Many Cannabis users cite sleep improvements as the main motivator of use, and accumulated evidence suggests that Cannabis use may offer therapeutic relief for individuals with poor sleep quality related to post-traumatic stress disorder and pain. One of the situations of extreme pain throughout the body is the case of fibromyalgia (FM). FM is a chronic pain syndrome characterized by diffuse body pain with associated pressure allodynia. Diagnosis is clinical, without confirmatory testing, and based on a history of generalized pain and the presence of tenderness in 11 of 18 specific tender point sites.In addition to reporting pain, FM patients have several other somatic symptoms, such as fatigue, mood disorders, and sleep disturbances, which have an important effect on well-being.
Studies performed with cannabinoids have shown that combinations of THC and CBD have been shown to be effective in promoting sleep in FM patients who present with chronic insomnia.
Most studies examining the impact of cannabinoids on sleep have actually been conducted in the context of chronic pain conditions. A review of phase I and II clinical trials suggested that a THC/CBD ratio of 1:1 was associated with improvements in sleep among chronic pain patients.
Another study using the formulation of THC and CBD extracts, containing approximately equal doses of ∼2 mg of THC and CBD, to examine sleep in individuals with pain-related sleep disorders, reported improved sleep with no evidence of drug tolerance.
Another study using the formulation of THC and CBD extracts, containing approximately equal doses of ∼2 mg of THC and CBD, to examine sleep in individuals with pain-related sleep disorders, reported improved sleep with no evidence of drug tolerance.
The substance CBD has been studied for some time regarding its therapeutic effects. New studies demonstrate its effects on sleep. CBD blocked anxiety-induced suppression of REM sleep but had no effect on NREM sleep. This work is further supported by a recent case report in which the administration of CBD oil reduced the symptoms of Post-traumatic stress disorder (PTSD), PTSD-related insomnia and sleep disturbances. Together, these findings suggest that CBD may affect sleep quality through its anxiolytic effects.
In studies performed with THC and CBD, mixed effects of THC and CBD combined were reported, with THC generally increasing sedation and CBD having the opposite wake-enhancing effects. Studies suggest that the concentration, dose and route of administration of cannabinoids may have differential effects on sleep quality and insomnia symptoms.
It is becoming increasingly evident that endocannabinoids play a prominent role in the neurophysiology of sleep, and cannabinoid drugs alter these processes. There are clear overlaps between the brain's eCB system and sleep-wake circuits, and cannabinergic manipulations are capable of altering sleep on a large scale in terms of time spent in specific vigilance states and on a fine scale in terms of sleep architecture and spectral power of specific sleep-related brain rhythms.
The hypnotic effects of cannabis have been known for a long time and there is an increasing use of phytocannabinoids and other formulations such as sleeping pills.
It is increasingly pertinent to understand how phytocannabinoids interact with the eCB system to alter sleep and the therapeutic nature of these effects.
The objective of Piauhy Labs is to carry out studies with cannabinoids, in addition to THC and CBD, terpenes and other substances from the Cannabis sativa plant.
At a later stage, the objective of Piauhy Labs will be to use these substances in studies for the manufacture of medications that improve sleep quality, including in patients with chronic pain.
Piauhy Labs intends to obtain a Certificate of Compliance with Good Laboratory Practices, in accordance with the OECD principles, for the pharmaceutical area.
As a result of the investigation processes, Piauhy Labs intends to create patents and originate intellectual property, with the ultimate goal of producing innovative medicines that improve the health of the population, in this aspect in relation to improving the quality of sleep, including medications for patients with chronic pain.
Elmo Resende, Ph.D.
Director of R&D
Piauhy Labs
Elmo Resende, Ph.D.
Director of R&D
Piauhy Labs
References
Babson, K. A.; Boden, M. T. and Bonn-Miller, M. O. The impact of perceived sleep quality and sleep efficiency/duration on cannabis use during a self-guided quit attempt. Addict. Behav. 38, 2707–2713, 2013.
Babson, K. A.; Sottile, J. and Morabito, D. Cannabis, Cannabinoids, and Sleep: a Review of the Literature. Curr. Psychiatry Rep. 19, 23, 2017.
Belendiuk, K. A.; Babson, K. A.; Vandrey, R. and Bonn-Miller, M. O. Cannabis species and cannabinoid concentration preference among sleep-disturbed medicinal cannabis users. Addict. Behav. 50, 178–181, 2015.
Clendinning, J. Observations on the medicinal properties of the Cannabis Sativa of India. Med. Chir. Trans. 26, 188–210, 1843.
Copersino, M. L.; Boyd, S. J.; Tashkin, D. P.; Huestis, M. A.; Heishman, S. J.; Dermand, J. C. et al. Cannabis withdrawal among non-treatment-seeking adult cannabis users. Am. J. Addict. 15, 8–14, 2006.
Drewes, A. M. Pain and sleep disturbances with special reference to fibromyalgia and rheumatoid arthritis. Rheumatology (Oxford) 38:1035– 8, 1999.
Feinberg, I.; Jones, R.; Walker, J. M.; Cavness, C. and March, J. Effects of high dosage delta-9-tetrahydrocannabinol on sleep patterns in man. Clin. Pharmacol. Ther. 17:458 – 66, 1977.
Freemon, F. R. The effect of chronically administered delta-9- tetrahydrocannabinol upon the polygraphically monitored sleep of normal volunteers. Drug Alcohol Depend. 10, 345–353, 1982.
Kano, M.; Ohno-Shosaku, T.; Hashimotodani, Y.; Uchigashima, M. and Watanabe, M. Endocannabinoid-mediated control of synaptic transmission. Physiol. Rev. 89, 309–380, 2009.
Grant, I. and Cahn, B. R. Cannabis and endocannabinoid modulators: Therapeutic promises and challenges. Clin. Neurosci. Res. 5, 185–199, 2005.
Kesner, A. J. and Lovinger, D. M. Cannabinoids, Endocannabinoids and Sleep. Front. Mol. Neurosci., 22, July, 2020.
Lovinger, D. M. Presynaptic modulation by endocannabinoids. Handb. Exp. Pharmacol. 184, 435–477, 2008.
Murillo-Rodriguez, E.; Machado, S.; Rocha, N. B.; Budde, H.; Yuan, T. F. and Arias-Carrion, O. Revealing the role of the endocannabinoid system modulators, SR141716A, URB597 and VDM-11, in sleep homeostasis. Neuroscience 339, 433–449, 2016.
Russo, E. B.; Guy, G. W. and Robson, P. J. Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine. Chem. Biodivers 4:1729 – 43, 2007.
Babson, K. A.; Boden, M. T. and Bonn-Miller, M. O. The impact of perceived sleep quality and sleep efficiency/duration on cannabis use during a self-guided quit attempt. Addict. Behav. 38, 2707–2713, 2013.
Babson, K. A.; Sottile, J. and Morabito, D. Cannabis, Cannabinoids, and Sleep: a Review of the Literature. Curr. Psychiatry Rep. 19, 23, 2017.
Belendiuk, K. A.; Babson, K. A.; Vandrey, R. and Bonn-Miller, M. O. Cannabis species and cannabinoid concentration preference among sleep-disturbed medicinal cannabis users. Addict. Behav. 50, 178–181, 2015.
Clendinning, J. Observations on the medicinal properties of the Cannabis Sativa of India. Med. Chir. Trans. 26, 188–210, 1843.
Copersino, M. L.; Boyd, S. J.; Tashkin, D. P.; Huestis, M. A.; Heishman, S. J.; Dermand, J. C. et al. Cannabis withdrawal among non-treatment-seeking adult cannabis users. Am. J. Addict. 15, 8–14, 2006.
Drewes, A. M. Pain and sleep disturbances with special reference to fibromyalgia and rheumatoid arthritis. Rheumatology (Oxford) 38:1035– 8, 1999.
Feinberg, I.; Jones, R.; Walker, J. M.; Cavness, C. and March, J. Effects of high dosage delta-9-tetrahydrocannabinol on sleep patterns in man. Clin. Pharmacol. Ther. 17:458 – 66, 1977.
Freemon, F. R. The effect of chronically administered delta-9- tetrahydrocannabinol upon the polygraphically monitored sleep of normal volunteers. Drug Alcohol Depend. 10, 345–353, 1982.
Kano, M.; Ohno-Shosaku, T.; Hashimotodani, Y.; Uchigashima, M. and Watanabe, M. Endocannabinoid-mediated control of synaptic transmission. Physiol. Rev. 89, 309–380, 2009.
Grant, I. and Cahn, B. R. Cannabis and endocannabinoid modulators: Therapeutic promises and challenges. Clin. Neurosci. Res. 5, 185–199, 2005.
Kesner, A. J. and Lovinger, D. M. Cannabinoids, Endocannabinoids and Sleep. Front. Mol. Neurosci., 22, July, 2020.
Lovinger, D. M. Presynaptic modulation by endocannabinoids. Handb. Exp. Pharmacol. 184, 435–477, 2008.
Murillo-Rodriguez, E.; Machado, S.; Rocha, N. B.; Budde, H.; Yuan, T. F. and Arias-Carrion, O. Revealing the role of the endocannabinoid system modulators, SR141716A, URB597 and VDM-11, in sleep homeostasis. Neuroscience 339, 433–449, 2016.
Russo, E. B.; Guy, G. W. and Robson, P. J. Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine. Chem. Biodivers 4:1729 – 43, 2007.