What is the effect of THC on REM sleep?

Comment by InpharmD Researcher

Available literature regarding the effect of THC on rapid eye movement (REM) sleep is extremely limited, with most EEG studies conducted in animals (i.e., rats). One 2021 review concluded that while acute administration of THC has been associated with decreased REM sleep, while the effects of chronic THC use on the REM stage are not consistent. Larger scale studies are required to confirm these effects and to determine the influences of dose and duration upon the results.

Background

A 2021 review on the effects of cannabinoids on sleep stated the two exogenous cannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD), have different actions on the CB1 and CB2 receptors. The authors noted that CB1 receptors had been shown to enhance the activation of the serotonergic system, causing a regulatory effect on the sleep-wake cycle. While THC mainly works on the CB1 receptors, it may have dose-dependent effects. Most of the studies examining cannabinoid effects on sleep were initially polysomnography-based, including several animal and small human studies. The authors concluded that while acute administration of THC has been associated with decreased rapid eye movement (REM) sleep, the effects of chronic use of THC on the REM stage are not consistent. [1]

A 2017 review included studies on cannabis and specific sleep disorders from 2014 to the time of publication. The authors described that while THC acts on CB1 and produces a dose-based biphasic effect, preclinical studies suggested that circadian rhythms are less affected during THC administration. A study by Nicholson et al. found 15 mg THC increased sleepiness and decreased sleep latency the following morning. Another study by Dzodzomenyo et al. indicated that patients who screened positive for THC had more excessive daytime sleepiness symptoms and were more likely to meet the criteria for narcolepsy. Gorelick and colleagues in a synthetic THC administration study noted that THC decreased the amount of nighttime sleep over time suggesting a potential effect of tolerance. Overall, the authors concluded that the research (dating back to the 1970s) on the impact of cannabis in sleep have shown mixed results with some work showing a decrease in onset latency and wake after sleep onset, others observed an increase in slow wave sleep and a decrease in REM. [2]

A 2019 animal study observed the effects of acute vaporized cannabis on sleep and electrocortical activity in rats. Animals were treated with 0 (control), 40, 80 and 200 mg of cannabis immediately before polysomnographic recordings. While cannabis 200 mg increased non-rapid eye movement (NREM) sleep time during the light phase, no changes in sleep were observed during the dark (active) phase. Total duration of rapid eye movement (REM) phase during the light phase was 33.6 ± 6.1 min in the cannabis 200 mg group vs. 32.6 ± 5 min in the control group. REM episodes duration were similar between the two groups (1.5 ± 0.3 vs. 1.5 ± 0.1). The Cannabis 200 mg group had a greater (non-significant) number of REM episodes (27.0 ± 8.8 vs. 22.5 ± 2.9). The authors suggested that as THC is a partial CB1 agonist, it would cause a greater effect during the lights-on period when the levels of CB1 receptors are high and administration of medicinal cannabis during the resting phase of the day may be optimal to treat sleep difficulties. [3]

References:

[1] Kaul M, Zee PC, Sahni AS. Effects of Cannabinoids on Sleep and their Therapeutic Potential for Sleep Disorders. Neurotherapeutics. 2021;18(1):217-227. doi:10.1007/s13311-021-01013-w
[2] Babson KA, Sottile J, Morabito D. Cannabis, cannabinoids, and sleep: a review of the literature. Curr Psychiatry Rep. 2017;19(4):23. doi:10.1007/s11920-017-0775-9
[3] Mondino A, Cavelli M, González J, et al. Acute effect of vaporized Cannabis on sleep and electrocortical activity. Pharmacol Biochem Behav. 2019;179:113-123. doi:10.1016/j.pbb.2019.02.012

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the effect of THC on REM sleep?

Please see Tables 1-2 for your response.


 

Effects of high dosage delta-9-tetrahydrocannabinol on sleep patterns in man

Design

Single-center, double-blind, placebo-controlled study

N= 4

Objective

To describe the sleep pattern during initial administration of 70 mg/day THC after two weeks of continuous administration of 210 mg/day and after abrupt withdrawal

Study Groups

All subjects (n= 4)

Inclusion Criteria

Male, marijuana users, getting paid to be hospitalized on a psychiatric ward

Exclusion Criteria

Subjects with medical or psychiatric illness

Methods

Eligible subjects received the drug started at 70 mg/day and increased over 2 to 5 days to a fixed level of 210 mg/day. The 210 mg intake was continued for 12 to 16 days. The administration of divided doses around the clock was intended to maximize the possibility of the development of tolerance.

Duration

21 to 30 days

Outcome Measures

Eye movement latency, total REM, percent REM

Baseline Characteristics

 

All patients (n= 7)

     

Age, years

25 (22 to 27)      

Mean educational, years

15 (11 to 17)      

Average duration of marijuana use, years

4      
 

Results

 

All patients (n= 4)

Endpoint

Baseline

Initial drug

70 mg/day

High dose

210 mg/day

Withdrawal 

Eye movement latency, min

79.9 80.2 59.0 33.4*

REM cycle, min

Total

Percent 

 

139.2

32.4

 

107.7*

25.8*

 

117.1*

28.8*

 

154.0

39.5

Complete cycles, min

3.8 3.8 3.8 3.8

 * Differs from baseline; p <0.01

Administration of THC significantly reduced eye movement activity during sleep with rapid eye movements (REM) and, to a lesser extent, the duration of REM itself (p< 0.01).

Withdrawal led to increases above baseline in both measures but the "rebound" effect was greater for eye movement.

Adverse Events

N/A

Study Author Conclusions

Since the pattern of effect on sleep for delta-9-tetrahydrocannabinol (THC) appears to be unique, this drug may prove to be a valuable tool in the elucidation of the pharmacology of sleep. 

InpharmD Researcher Critique

This study only included male subjects and had a small sample size as well as a single-center nature. Additionally, the dosages exceeded those in common social dosage and the results may not be generalized to other populations.



References:

Feinberg I, Jones R, Walker JM, Cavness C, March J. Effects of high dosage delta-9-tetrahydrocannabinol on sleep patterns in man. Clin Pharmacol Ther. 1975;17(4):458-466. doi:10.1002/cpt1975174458

 

Impact of Dronabinol on Quantitative Electroencephalogram (qEEG) Measures of Sleep in Obstructive Sleep Apnea Syndrome

Design

Prospective, single-center trial

N= 15

Objective

To quantify the effects of dronabinol on EEG power distributions and ultradian cycling of EEG power in subjects with obstructive sleep apnea (OSA)

Study Groups

All subjects (n= 15)

Inclusion Criteria

Adults (aged 21 to 64 years) with moderate to severe OSA

Exclusion Criteria

Individuals working night or rotating shifts; taking medications with known effects on sleep architecture; with clinically significant and uncontrolled or progressive medical comorbidity or any other primary sleep disorder

Methods

Subjects were started on oral dronabinol, 2.5 mg/ day 30 minutes before bedtime, for one week. If this dose was well-tolerated, the dose was increased to 5 mg/day during week two, and again as tolerated to 10 mg/day during week three. A total of eight subjects were fully escalated and received 10 mg/day of dronabinol during the third treatment week. Five subjects maintained 5 mg/ day dronabinol during the final treatment week, and 2 subjects remained at a dose of 2.5 mg/day throughout.

Duration

Treatment duration: 3 weeks

Outcome Measures

Slow-wave stage (SWS) percentage and duration, REM percentage and duration

Baseline Characteristics

 

All subjects (n= 15)

 

     

Age, years

51.7 ± 7.9        

Male/Female

6/9        

Body mass index, kg/m2

35.1 ± 7.1        

Apnea hypopnea index (AHI)

44.5 ± 22.8        

Arousal index

42.67 ± 22.76         

There were no statistically significant differences in baseline characteristics.

Results

  All subjects (n= 15) 

Endpoint

0 mg 2.5 mg 5 mg 10 mg (n= 8) p-value 

SWS

Percentage, %

Duration, min

 

7.44 ± 6.36

5.5 ± 10.97

 

6.02 ± 5.94

3.14 ± 4.11

 

4.77 ± 4.17

1.75 ± 1.56

 

7.55 ± 7.76

1.76 ± 1.03

 

0.55

0.32

REM

Percentage, %

Duration, min

 

16.67 ± 6.70

14.74 ± 8.32

 

15.61 ± 5.87

11.80 ± 9.65

 

18.49 ± 8.01

12.18 ± 10.83

 

13.44 ± 6.20

10.24 ± 9.78

 

0.33

0.72

There were no statistically significant changes in the expression of stages SWS or REM as a percentage of total sleep time.

Adverse Events

N/A

Study Author Conclusions

Oral dronabinol may have improved restorative aspects of the sleep process, contributing to the observed decrease in daytime sleepiness, despite the absence of changes in overall sleep stage percentages or sleep efficiency previously reported. Larger scale studies will be needed to confirm and elaborate these effects, and to dissect the potentially interacting influences of dose and time-on-treatment.

InpharmD Researcher Critique

Given the small sample size and the short duration of the study, the results may not be generalized. Moreover, only eight of the subjects reached the full dose of 10 mg/day of dronabinol.



References:

Farabi SS, Prasad B, Quinn L, Carley DW. Impact of dronabinol on quantitative electroencephalogram (qEEG) measures of sleep in obstructive sleep apnea syndrome. J Clin Sleep Med. 2014;10(1):49-56. Published 2014 Jan 15. doi:10.5664/jcsm.3358