Chronic Cannabidiol Administration Mitigates Excessive Daytime Sleepiness and Fatigue in Patients with Primary Hypertension: Insights from a Randomized Crossover Trial
Restricted accessResearch articleFirst published online August, 2025
Chronic Cannabidiol Administration Mitigates Excessive Daytime Sleepiness and Fatigue in Patients with Primary Hypertension: Insights from a Randomized Crossover Trial
The chronic effects of cannabidiol (CBD) supplementation on factors that could impact the quality of life (anxiety, sleeping quality, memory, etc.) are poorly explored. Hence, the aim of this study was to establish whether chronic CBD supplementation will improve self-reported outcomes related to quality of life.
Methods:
In this randomized crossover trial, 64 patients with primary hypertension were assigned to receive CBD (225–450 mg) for 5 weeks followed by 5 weeks of placebo or vice versa, with a 2-week washout in-between the two. Self-reported outcomes were assessed using short form-36 (SF-36), Pittsburgh sleep quality index (PSQI), Epworth sleepiness scale (ESS), memory complaint questionnaire (MAC-Q), and state-trait anxiety inventory (STAI).
Results:
Five-week administration of CBD, but not of placebo, resulted in improvement of ESS score (F = 6.738, p = 0.011), as well as fatigue/vitality (ΔCBD = 5.0, p < 0.001) and psychological well-being dimensions of SF-36 (ΔCBD = 7.4, p = 0.039). No overall benefit of CBD on quality of life was noted (p = 0.674). No changes were seen in total scores of MAC-Q, PSQI, or STAI (p = 0.151, p = 0.862, p = 0.702, respectively). No significant correlations were found between plasma CBD concentrations and any of the scores.
Conclusions:
Chronic CBD administration reduced excessive daytime sleepiness, despite the fact that no change was observed in self-reported quality of sleep. Furthermore, self-reported fatigue and psychological well-being dimensions of quality of life also improved following chronic CBD use.
Get full access to this article
View all access options for this article.
References
1.
GreenR, KhalilR, MohapatraSS, et al.Role of cannabidiol for improvement of the quality of life in cancer patients: potential and challenges. Int J Mol Sci, 2022; 23(21):12956; doi: 10.3390/ijms232112956
2.
HardyJ, HaywoodA, GognaG, et al.Oral medicinal cannabinoids to relieve symptom burden in the palliative care of patients with advanced cancer: a double-blind, placebo-controlled, randomized clinical trial of efficacy and safety of 1:1 delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Trials, 2020; 21(1):611; doi: 10.1186/s13063-020-04541-6
3.
PortenoyRK, Ganae-MotanED, AllendeS, et al.Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain, 2012; 13(5):438–449; doi: 10.1016/j.jpain.2012.01.003
4.
FallonMT, LuxEA, McQuadeR, et al.Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies. Br J Pain, 2017; 11(3):119–133; doi: 10.1177/2049463717710042
5.
BelgersV, RöttgeringJG, DouwL, et al.Cannabinoids to improve health-related quality of life in patients with neurological or oncological disease: a meta-analysis. Cannabis Cannabinoid Res, 2023; 8(1):41–55; doi: 10.1089/can.2021.0187
6.
BlessingEM, SteenkampMM, ManzanaresJ, et al.Cannabidiol as a potential treatment for anxiety disorders. Neurotherapeutics, 2015; 12(4):825–836; doi: 10.1007/s13311-015-0387-1
7.
BergamaschiMM, QueirozRH, ChagasMH, et al.Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology, 2011; 36(6):1219–1226; doi: 10.1038/npp.2011.6
8.
CrippaJAS, Nogueira DerenussonG, Borduqui FerrariT, et al.Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol, 2011; 25(1):121–130; doi: 10.1177/0269881110379283
9.
MasatakaN. Anxiolytic effects of repeated cannabidiol treatment in teenagers with social anxiety disorders. Front Psychol, 2019; 10:2466; doi: 10.3389/fpsyg.2019.02466
10.
ShannonS, LewisN, LeeH, et al.Cannabidiol in anxiety and sleep: a large case series. Perm J, 2019; 23:18–041; doi: 10.7812/TPP/18-041
11.
DujicG, KumricM, VrdoljakJ, et al.Chronic effects of oral cannabidiol delivery on 24-h ambulatory blood pressure in patients with hypertension (HYPER-H21-4): a randomized, placebo-controlled, and crossover study. Cannabis Cannabinoid Res, 2023; doi: 10.1089/can.2022.0320
12.
KumricM, DujicG, VrdoljakJ, et al.CBD supplementation reduces arterial blood pressure via modulation of the sympatho-chromaffin system: a substudy from the HYPER-H21-4 trial. Biomed Pharmacother, 2023; 160:114387; doi: 10.1016/j.biopha.2023.114387
13.
KumricM, DujicG, VrdoljakJ, et al.Effects of CBD supplementation on ambulatory blood pressure and serum urotensin-II concentrations in Caucasian patients with essential hypertension: a sub-analysis of the HYPER-H21-4 trial. Biomed Pharmacother, 2023; 164:115016; doi: 10.1016/j.biopha.2023.115016
14.
UrlicH, KumricM, DujicG, et al.Antihypertensive effects of CBD are mediated by altered inflammatory response: a sub-study of the HYPER-H21-4 trial. J Funct Foods, 2023; 110:105873; doi: 10.1016/j.jff.2023.105873
15.
KumricM, BozicJ, DujicG, et al.Chronic effects of effective oral cannabidiol delivery on 24-h ambulatory blood pressure and vascular outcomes in treated and untreated hypertension (HYPER-H21-4): Study protocol for a randomized, placebo-controlled, and crossover study. J Pers Med, 2022; 12(7):1037; doi: 10.3390/jpm12071037
16.
WilliamsB, ManciaG, SpieringW, et al.ESC Scientific Document Group. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J, 2018; 39(33):3021–3104; doi: 10.1093/eurheartj/ehy339
17.
BatinicA, SutlovicD, KuretS, et al.Differences in plasma cannabidiol concentrations in women and men: a randomized, placebo-controlled, crossover study. Int J Mol Sci, 2023; 24(12):10273; doi: 10.3390/ijms241210273
18.
BatinicA, SutlovićD, KuretS, et al.Trial of a novel oral cannabinoid formulation in patients with hypertension: a double-blind, placebo-controlled pharmacogenetic study. Pharmaceuticals (Basel), 2023; 16(5):645; doi: 10.3390/ph16050645
19.
Maslić SersićD, VuletićG. Psychometric evaluation and establishing norms of Croatian SF-36 health survey: framework for subjective health research. Croat Med J, 2006; 47(1):95–102.
20.
JohnsMW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep, 1991; 14(6):540–545; doi: 10.1093/sleep/14.6.540
21.
BuysseDJ, ReynoldsCF, MonkTH, et al.The Pittsburgh sleep quality index: a new instrument for psychiatric practice and research. Psychiatry Res, 1989 May;28(2):193–213; doi: 10.1016/0165-1781(89)90047-4
22.
SpielbergerCD, GorsuchRL, LusheneRE. Manual for the state-trait anxiety inventory. 1970.
23.
CrookTH, FeherEP, LarrabeeGJ. Assessment of memory complaint in age-associated memory impairment: the MAC-Q. Int Psychogeriatr, 1992; 4(2):165–176; doi: 10.1017/s1041610292000991
24.
AbramsDI. The therapeutic effects of cannabis and cannabinoids: an update from the national academies of sciences, engineering and medicine report. Eur J Intern Med, 2018; 49:7–11; doi: 10.1016/j.ejim.2018.01.003
25.
KaulM, ZeePC, SahniAS. 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
26.
SuraevAS, MarshallNS, VandreyR, et al.Cannabinoid therapies in the management of sleep disorders: a systematic review of preclinical and clinical studies. Sleep Med Rev, 2020; 53:101339; doi: 10.1016/j.smrv.2020.101339
27.
Murillo-RodríguezE, Millán-AldacoD, Palomero-RiveroM, et al.The nonpsychoactive cannabis constituent cannabidiol is a wake-inducing agent. Behav Neurosci, 2008; 122(6):1378–1382; doi: 10.1037/a0013278
28.
NicholsonAN, TurnerC, StoneBM, et al.Effect of delta-9-tetrahydrocannabinol and cannabidiol on nocturnal sleep and early-morning behavior in young adults. J Clin Psychopharmacol, 2004; 24(3):305–313; doi: 10.1097/01.jcp.0000125688.05091.8f
29.
Murillo-RodríguezE, Sarro-RamírezA, SánchezD, et al.Potential effects of cannabidiol as a wake-promoting agent. Curr Neuropharmacol, 2014; 12(3):269–272; doi: 10.2174/1570159X11666131204235805
30.
LauxLC, BebinEM, CheckettsD, et al.CBD EAP study group. Long-term safety and efficacy of cannabidiol in children and adults with treatment resistant Lennox-Gastaut syndrome or Dravet syndrome: Expanded access program results. Epilepsy Res, 2019; 154:13–20.
31.
BoggsDL, SurtiT, GuptaA, et al.The effects of cannabidiol (CBD) on cognition and symptoms in outpatients with chronic schizophrenia a randomized placebo controlled trial. Psychopharmacology (Berl), 2018; 235(7):1923–1932.
32.
DevinskyO, CrossJH, LauxL, et al.Cannabidiol in Dravet Syndrome Study Group. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med, 2017; 376(21):2011–2020.
33.
KollaBP, HayesL, CoxC, et al.The effects of cannabinoids on sleep. J Prim Care Community Health, 2022; 13:21501319221081277.
34.
FerreraG, RicciE, VignoliA, et al.Highly purified cannabidiol in the treatment of drug-resistant epilepsies: a real-life impact on seizure frequency, quality of life, behavior, and sleep patterns from a single Italian center. Epilepsy Behav, 2023; 147:109409; doi: 10.1016/j.yebeh.2023.109409
35.
BergeriaCL, StricklandJC, SpindleTR, et al.A crowdsourcing survey study on the subjective effects of delta-8-tetrahydrocannabinol relative to delta-9-tetrahydrocannabinol and cannabidiol. Exp Clin Psychopharmacol, 2023; 31(2):312–317; doi: 10.1037/pha0000565
36.
VelzeboerR, MalasA, BoerkoelP, et al.Cannabis dosing and administration for sleep: a systematic review. Sleep, 2022; 45(11):zsac218; doi: 10.1093/sleep/zsac218
37.
OsborneAL, SolowijN, Weston-GreenK. A systematic review of the effect of cannabidiol on cognitive function: relevance to schizophrenia. Neurosci Biobehav Rev, 2017; 72:310–324; doi: 10.1016/j.neubiorev.2016.11.012
38.
FagherazziEV, GarciaVA, MaurmannN, et al.Memoryrescuing effects of cannabidiol in an animal model of cognitive impairment relevant to neurodegenerative disorders. Psychopharmacology (Berl), 2012; 219(4):1133–1140.
39.
HindochaC, FreemanTP, SchaferG, et al.Acute effects of delta-9- tetrahydrocannabinol, cannabidiol and their combination on facial emotion recognition: a randomised, double-blind, placebo-controlled study in cannabis users. Eur Neuropsychopharmacol, 2015; 25(3):325–334.
40.
EnglundA, MorrisonPD, NottageJ, et al.Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol, 2013; 27(1):19–27.
41.
MorganCJA, FreemanTP, HindochaC, et al.Individual and combined effects of acute delta-9-tetrahydrocannabinol and cannabidiol on psychotomimetic symptoms and memory function. Transl Psychiatry, 2018; 8(1):181; doi: 10.1038/s41398-018-0191-x
42.
EnglundA, OliverD, ChesneyE, et al.Does cannabidiol make cannabis safer? a randomised, double-blind, cross-over trial of cannabis with four different CBD:THC ratios. Neuropsychopharmacology, 2023 May;48(6):869–876; doi: 10.1038/s41386-022-01478-z
43.
LawnW, TrinciK, MokryszC, et al.The acute effects of cannabis with and without cannabidiol in adults and adolescents: a randomised, double-blind, placebo-controlled, crossover experiment. Addiction, 2023; 118(7):1282–1294; doi: 10.1111/add.16154
44.
BhattacharyyaS, MorrisonPD, Fusar-PoliP, et al.Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology, 2010; 35(3):764–774; doi: 10.1038/npp.2009.184
45.
KosibaJD, MaistoSA, DitreJW. Patient-reported use of medical cannabis for pain, anxiety, and depression symptoms: systematic review and meta-analysis. Soc Sci Med, 2019; 233:181–192; doi: 10.1016/j.socscimed.2019.06.005
46.
SouzaJDS, ZuardiAW, GuimarãesFS, et al.Maintained anxiolytic effects of cannabidiol after treatment discontinuation in healthcare workers during the COVID-19 pandemic. Front Pharmacol, 2022; 13:856846; doi: 10.3389/fphar.2022.856846
47.
ChesworthR, ChengD, StaubC, et al.Effect of long-term cannabidiol on learning and anxiety in a female Alzheimer’s disease mouse model. Front Pharmacol, 2022; 13:931384; doi: 10.3389/fphar.2022.931384
48.
WampoldBE, MinamiT, TierneySC, et al.The placebo is powerful: estimating placebo effects in medicine and psychotherapy from randomized clinical trials. J Clin Psychol, 2005; 61(7):835–854; doi: 10.1002/jclp.20129
49.
KirschI. Response expectancy and the placebo effect. Int Rev Neurobiol, 2018; 138:81–93; doi: 10.1016/bs.irn.2018.01.003
50.
GrecoR, FrancavillaM, DemartiniC, et al.Characterization of the biochemical and behavioral effects of cannabidiol: implications for migraine. J Headache Pain, 2023; 24(1):48; doi: 10.1186/s10194-023-01589-yPMC10155373
51.
DeianaS, WatanabeA, YamasakiY, et al.Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour. Psychopharmacology (Berl), 2012; 219(3):859–873; doi: 10.1007/s00213-011-2415-0).
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
