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Publication Title | Effect of D-9-Tetrahydrocannabinol and Cannabidiol on Nocturnal Sleep and Early-Morning

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Original Contribution

Effect of D-9-Tetrahydrocannabinol and Cannabidiol on Nocturnal Sleep and Early-Morning

Behavior in Young Adults

Anthony N. Nicholson, MD, PhD,* Claire Turner, BSc,* Barbara M. Stone, PhD,* and Philip J. Robson, MDy

Abstract: The effects of cannabis extracts on nocturnal sleep, early- morning performance, memory, and sleepiness were studied in 8 healthy volunteers (4 males, 4 females; 21 to 34 years). The study was double-blind and placebo-controlled with a 4-way crossover design. The 4 treatments were placebo, 15 mg D-9-tetrahydrocan- nabinol (THC), 5 mg THC combined with 5 mg cannabidiol (CBD), and 15 mg THC combined with 15 mg CBD. These were formulated in 50:50 ethanol to propylene glycol and administered using an oromucosal spray during a 30-minute period from 10 PM. The electroencephalogram was recorded during the sleep period (11 PM to 7 AM). Performance, sleep latency, and subjective assessments of sleepiness and mood were measured from 8:30 AM (10 hours after drug administration). There were no effects of 15 mg THC on nocturnal sleep. With the concomitant administration of the drugs (5 mg THC and 5 mg CBD to 15 mg THC and 15 mg CBD), there was a decrease in stage 3 sleep, and with the higher dose combi- nation, wakefulness was increased. The next day, with 15 mg THC, memory was impaired, sleep latency was reduced, and the subjects reported increased sleepiness and changes in mood. With the lower dose combination, reaction time was faster on the digit recall task, and with the higher dose combination, subjects reported increased sleepiness and changes in mood. Fifteen milligrams THC would appear to be sedative, while 15 mg CBD appears to have alerting properties as it increased awake activity during sleep and counter- acted the residual sedative activity of 15 mg THC.

(J Clin Psychopharmacol 2004;24:305–313)

Apotential therapeutic benefit of the use of cannabis-based extracts in the relief of pain and other chronic symptoms

*QinetiQ Ltd, Centre for Human Sciences, Cody Technology Park, Farnborough, Hampshire, UK; yDepartment of Psychiatry, Warneford Hospital, Oxford, UK.

Received May 5, 2003; accepted after revision December 23, 2003. Address correspondence and reprint requests to Prof Anthony N. Nicholson, QinetiQ Ltd, Centre for Human Sciences, Ively Road, Farnborough,

Hampshire GU14 0LX, UK. E-mail: annicholson@QinetiQ.com. Copyright n 2004 by Lippincott Williams & Wilkins

ISSN: 0271-0749/04/2403-0305

DOI: 10.1097/01.jcp.0000125688.05091.8f

is an improvement in sleep quality. This may be due to hypnotic activity in addition to the therapeutic properties of cannabinoids.1 Indeed, early studies indicated that sleep may be modulated.2–8 However, these studies used various modes of administration, involved wide dose ranges, and were carried out in subjects of variable status with respect to their use of such drugs. Furthermore, the experimental designs were not amenable to analyses that could indicate the pharmaco- logic activity of individual substances. In some studies, extracts were used in which, although D-9-tetrahydrocannab- inol (THC) could be measured, there were undetermined amounts of cannabidiol (CBD) and cannabinol. Nevertheless, the impression gained from these studies was that certain doses of THC, particularly with repeated ingestion, may reduce rapid eye movement (REM) activity and increase slow-wave sleep.

We have, therefore, investigated the effect on sleep of individual cannabinoids and cannabinoids in combination. The current studies with THC and CBD have been carried out using the doses that are currently under investigation for the relief of pain. The former cannabinoid is believed to be the principal psychoactive extract of cannabis, an effect mediated via cannabinoid (CB)1 receptors. CBD may be free of such central activity but may have useful therapeutic potential arising from its reported myorelaxant and anticonvulsant properties, in addition to the attenuation of some of the effects of THC, such as euphoria and tachycardia.9–12 The mecha- nism by which CBD exerts these effects is uncertain, as it cannot be completely explained in terms of CB1 and CB2 receptor binding. We have studied the effect of THC alone and in combination with CBD on the sleep process and on mood, performance, and sleep latencies during the morning of the day after administration.

METHODS

Protocol

The protocol was approved by the QinetiQ Ethics Committee, and the subjects were under medical supervision

Journal of Clinical Psychopharmacology Volume 24, Number 3, June 2004 305 Copyright © Lippincott Williams & Wilkins.Unauthorized reproduction of this article is prohibited.

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