A randomised controlled trial of vaporised Δ9-tetrahydrocannabinol and cannabidiol alone and in combination in frequent and infrequent cannabis users: acute intoxication effects
Access to cannabis and cannabinoid products is increasing worldwide for recreational and medicinal use. Two primary compounds within cannabis plant matter, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are both psychoactive, but only THC is considered intoxicating. There is significant interest in potential therapeutic properties of these cannabinoids and of CBD in particular. Some research has suggested that CBD may ameliorate adverse effects of THC, but this may be dose dependent as other evidence suggests possible potentiating effects of THC by low doses of CBD. We conducted a randomised placebo controlled trial to examine the acute effects of these compounds alone and in combination when administered by vaporisation to frequent and infrequent cannabis users. Participants (n = 36; 31 male) completed 5 drug conditions spaced one week apart, with the following planned contrasts: placebo vs CBD alone (400 mg); THC alone (8 mg) vs THC combined with low (4 mg) or high (400 mg) doses of CBD. Objective (blind observer ratings) and subjective (self-rated) measures of intoxication were the primary outcomes, with additional indices of intoxication examined. CBD showed some intoxicating properties relative to placebo. Low doses of CBD when combined with THC enhanced, while high doses of CBD reduced the intoxicating effects of THC. The enhancement of intoxication by low-dose CBD was particularly prominent in infrequent cannabis users and was consistent across objective and subjective measures. Most effects were significant at p < .0001. These findings are important to consider in terms of recommended proportions of THC and CBD in cannabis plant matter whether used medicinally or recreationally and have implications for novice or less experienced cannabis users.
Trial registration: ISRCTN Registry Identifier: ISRCTN24109245.
KeywordsΔ9-Tetrahydrocannabinol (THC) Cannabidiol (CBD) Cannabis Cannabinoids Intoxication Synergistic effects
The study was funded by the National Health and Medical Research Council of Australia (NHMRC Project Grant 1007593). NS was supported by the Australian Research Council (ARC Future Fellowship FT110100752). The authors are grateful to Professor Antonio Zuardi and Dr Arno Hazekamp for advice around dosing and drug administration at the commencement of the study; to Clare Bate, Camilla Beale, Andrew Bonney, Gary Chan, Francesca Fernandez, Sarah Gallagher, David Garne, Madeleine Godber, Stuart Johnstone, Lisa Lole, Elke Macdonald, Philip McGuire, Jelena Novakovic, Nagesh Pai, Gabrielle Puckett, Karina Rovere, Beth Shaw and Lara Tramazzo for assistance with participant, trial and data management and logistics; and to Storz & Bickel, Tuttlingen, Germany for supplying a Volcano® Vaporiser used in this study. Cannabinoid compounds were purchased from STI Pharmaceuticals, UK.
Compliance with ethical standards
This study was approved by the University of Wollongong and Illawarra Shoalhaven Local Health District Health and Medical Human Research Ethics Committee and registered as a clinical trial (ISRCTN24109245 ). Participants provided written informed consent prior to participating in the study and at the start of each drug session.
Conflict of interest
The authors declare that they have no conflict of interest.
- 23.Murphy M, Mills S, Winstone J, Leishman E, Wager-Miller J, Bradshaw H, Mackie K (2017) Chronic adolescent ∆(9)-tetrahydrocannabinol treatment of male mice leads to long-term cognitive and behavioral dysfunction, which are prevented by concurrent cannabidiol treatment. Cannabis Cannabinoid Res 2:235–246CrossRefGoogle Scholar
- 25.Solowij N, Broyd SJ, Beale C, Prick J-A, Greenwood L-M, van Hell H, Suo C, Galettis P, Pai N, Fu S, Croft RJ, Martin JH, Yücel M (2018) Therapeutic effects of prolonged cannabidiol treatment on psychological symptoms and cognitive function in regular cannabis users: a pragmatic open-label clinical trial. Cannabis Cannabinoid Res 3:21–34CrossRefGoogle Scholar
- 27.Zuardi AW, Teixeira NA, Karniol IC (1984) Pharmacological interaction of the effects of delta 9-trans-tetrahydrocannabinol and cannabidiol on serum corticosterone levels in rats. Arch Int Pharmacodyn Ther 269:12–19Google Scholar
- 29.Hayakawa K, Mishima K, Hazekawa M, Sano K, Irie K, Orito K, Egawa T, Kitamura Y, Uchida N, Nishimura R, Egashira N, Iwasaki K, Fujiwara M (2008) Cannabidiol potentiates pharmacological effects of ∆9-tetrahydrocannabinol via CB1 receptor-dependent mechanism. Brain Res 1188:157–164CrossRefGoogle Scholar
- 33.Todd SM, Zhou C, Clarke DJ, Chohan TW, Bahceci D, Arnold JC (2017) Interactions between cannabidiol and ∆9-THC following acute and repeated dosing: rebound hyperactivity, sensorimotor gating and epigenetic and neuroadaptive changes in the mesolimbic pathway. Eur Neuropsychopharmacol 27:132–145CrossRefGoogle Scholar
- 35.Hindocha C, Freeman TP, Schafer G, Gardener C, Das RK, Morgan CJ, Curran HV (2015) 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 25:325–334CrossRefGoogle Scholar
- 44.Rakhshan F, Day TA, Blakely RD, Barker EL (2000) Carrier-mediated uptake of the endogenous cannabinoid anandamide in RBL-2H3 cells. J Pharmacol Exp Ther 292:960–967Google Scholar
- 46.Zuardi AW, Karniol IG (1983) Effects on variable-interval performance in rats of delta 9-tetrahydrocannabinol and cannabidiol, separately and in combination. Braz J Med Biol Res 16:141–146Google Scholar
- 50.Hložek T, Uttl L, Kadeřábek L, Balíková M, Lhotková E, Horsley RR, Nováková P, Šíchová K, Štefková K, Tylš F, Kuchař M, Páleníček T (2017) Pharmacokinetic and behavioural profile of THC, CBD, and THC + CBD combination after pulmonary, oral, and subcutaneous administration in rats and confirmation of conversion in vivo of CBD to THC. Eur Neuropsychopharmacol 27:1223–1237CrossRefGoogle Scholar
- 51.Bornheim LM, Kim KY, Li J, Perotti BY, Benet LZ (1995) Effect of cannabidiol pretreatment on the kinetics of tetrahydrocannabinol metabolites in mouse brain. Drug Metab Dispos 23:825–831Google Scholar
- 61.Demirakca T, Sartorius A, Ende G, Meyer N, Welzel H, Skopp G, Mann K, Hermann D (2011) Diminished gray matter in the hippocampus of cannabis users: possible protective effects of cannabidiol. Drug Alcohol Depend 114:242–245Google Scholar
- 64.Sheehan DV, Lecrubier Y, Sheehan KH et al (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59(Suppl 20):22–33Google Scholar
- 65.Spielberger CD, Gorsuch RL, Lushene R, Vagg PR, Jacobs GA (1983) Manual for the State-Trait Anxiety Inventory. Consulting Psychologists Press, Palo AltoGoogle Scholar
- 72.Galettis P (2016) Development of a simple LCMSMS method for THC and metabolites in plasma. Asia Pac J Clin Oncol 12:13–34Google Scholar
- 86.Taylor L, Gidal B, Blakey G, Tayo B, Morrison G (2018) A phase I, randomized, double-blind, placebo-controlled, single ascending dose, multiple dose, and food effect trial of the safety, tolerability and pharmacokinetics of highly purified cannabidiol in healthy subjects. CNS Drugs 32:1053–1067CrossRefGoogle Scholar
- 88.Fleming A (2018) Cannabis health products are everywhere—but do they live up to the hype? The Guardian. https://www.theguardian.com/lifeandstyle/2018/oct/15/cannabis-health-products-live-up-to-hype-cannabidiol-cbd. Accessed 15 Oct 2018
- 89.Solowij N (2012) Vulnerability markers in the association between cannabis and schizophrenia: a randomised controlled trial of acute cannabinoid administration. Curr Controll Trials 5:5Google Scholar