pharmaceuticals Review A Systematic Review and Meta-Analysis of the In Vivo Haemodynamic Effects of D9-Tetrahydrocannabinol Salahaden R. Sultan 1,2, Sophie A. Millar 1 ID , Saoirse E. O’Sullivan 1 and Timothy J. England 1,* ID 1 Division of Medical Sciences & Graduate Entry Medicine, School of Medicine, University of Nottingham, Derby DE22 3DT, UK; [email protected] (S.R.S.); [email protected] (S.A.M.); [email protected] (S.E.O.) 2 Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia * Correspondence: [email protected]; Tel.: +44-1332-724668 Received: 4 December 2017; Accepted: 26 January 2018; Published: 31 January 2018 Abstract: D9-Tetrahydrocannabinol (THC) has complex effects on the cardiovascular system. We aimed to systematically review studies of THC and haemodynamic alterations. PubMed, Medline, and EMBASE were searched for relevant studies. Changes in blood pressure (BP), heart rate (HR), and blood flow (BF) were analysed using the Cochrane Review Manager Software. Thirty-one studies met the eligibility criteria. Fourteen publications assessed BP (number, n = 541), 22 HR (n = 567), and 3 BF (n = 45). Acute THC dosing reduced BP and HR in anaesthetised animals (BP, mean difference (MD) −19.7 mmHg, p < 0.00001; HR, MD −53.49 bpm, p < 0.00001), conscious animals (BP, MD −12.3 mmHg, p = 0.0007; HR, MD −30.05 bpm, p < 0.00001), and animal models of stress or hypertension (BP, MD −61.37 mmHg, p = 0.03) and increased cerebral BF in murine stroke models (MD 32.35%, p < 0.00001). Chronic dosing increased BF in large arteries in anaesthetised animals (MD 21.95 mL/min, p = 0.05) and reduced BP in models of stress or hypertension (MD −22.09 mmHg, p < 0.00001). In humans, acute administration increased HR (MD 8.16 bpm, p < 0.00001). THC acts differently according to species and experimental conditions, causing bradycardia, hypotension and increased BF in animals; and causing increased HR in humans. Data is limited, and further studies assessing THC-induced haemodynamic changes in humans should be considered. Keywords: D9-Tetrahydrocannabinol; THC; cardiovascular system; blood pressure; heart rate; blood flow 1. Introduction D9-Tetrahydrocannabinol (THC) is the most abundant and widely studied phytocannabinoid, first discovered in 1964 [1]. THC is a partial agonist of both cannabinoid receptors CB1 and CB2 and other targets including G protein-coupled receptors GPR55 and GPR18 [2–4]. THC possesses interesting therapeutic potential as an antiemetic, appetite stimulant, and analgesic, and for the treatment of glaucoma, epilepsy, Parkinson‘s disease, and multiple sclerosis [5–7]. THC has been shown to be effective against refractory nausea and vomiting in cancer patients undergoing chemotherapy [8]. However, its use as a therapeutic agent is limited by its recognised psychogenic side effects including hallucinations, euphoria, dizziness, mood changes, nausea, and fatigue [8–10]. THC has numerous cardiovascular effects in animals and humans. In vitro studies have shown that THC causes endothelium-independent vasorelaxation of rabbit superior mesenteric arteries [11] and vasorelaxation of the rat mesenteric artery through sensory nerves via a CB1 and CB2 receptor-independent mechanism [12]. Other studies have found THC to activate a G Pharmaceuticals 2018, 11, 13; doi:10.3390/ph11010013 www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2018, 11, 13 2 of 19 Pharmaceuticals 2018, 11, x FOR PEER REVIEW 2 of 19 protein-coupled receptor, inhibit calcium channels, and activate potassium channels in the rat Inmesenteric contrast,vasculature other studies [13 have] and shown to cause that endothelium-dependent THC causes vasoconstriction and time-dependent in guinea pig vasorelaxation pulmonary arteriesin the rat [16] aorta, rat [mesenteric14,15]. In contrast, arteries and other aorta studies [14,17] have, and shown rabbit that ear THCarteries causes [18]. vasoconstriction in guineaIn pigvivo pulmonary studies arterieshave reported [16], rat mesentericdifferent arterieshaemodynamic and aorta responses [14,17], and post rabbit-THC. ear arteriesAn acute [18]. administrationIn vivo studies of THC have caused reported hypotension different and haemodynamicbradycardia in anesthetised responses post-THC. dogs (intravenously; An acute i.v.),administration conscious bats of THC (intraperitoneal; caused hypotension i.p.), and and humans bradycardia (oral) [19 in– anesthetised21]. In contrast, dogs tachycardia (intravenously; and hypertensioni.v.), conscious were bats reported (intraperitoneal; in rats after i.p.), i.p. and administration humans (oral) of THC [19–21 [22,23]]. In contrast,. More complex tachycardia effects and on BPhypertension were induced were by reportedTHC in anaesthetised in rats after i.p.rats administration[24]. The available of THCevidence [22,23 to]. date More suggests complex that effects THC alterson BP the were haemodynamics induced by THC in in animals anaesthetised and humans, rats [24 ].albeit The availablewith conflicting evidence results to date variable suggests with that species,THC alters route the of haemodynamics administration, inand animals experimental and humans, conditions. albeit withTherefore, conflicting the aim results this variablestudy was with to systematicallyspecies, route ofreview administration, and meta- andanalyse experimental the in vivo conditions. literature assessing Therefore, the the effects aim this of studyTHC on was the to cardiovascularsystematically reviewsystem in and all meta-analyse species under the different in vivo conditions. literature assessing the effects of THC on the cardiovascular system in all species under different conditions. 2. Results 2. Results From the initial 2743 search results, 1935 relevant publications were identified and evaluated from Fromthree thedatabases initial2743 (Medline, search EMBASE, results, 1935 and relevant PubMed). publications Of these, 30 were articles identified met the and inclusion evaluated criteria from andthree 1 databases article was (Medline, added manually EMBASE, (Figure and PubMed). 1). A summary Of these, 30of articlesthe data met extracted the inclusion from the criteria included and 1 studiesarticle was is shown added in manually Table 1. (Figure1). A summary of the data extracted from the included studies is shown in Table1. Figure 1. Flow chart for study retrieval and selection. Figure 1. Flow chart for study retrieval and selection. Pharmaceuticals 2018, 11, 13 3 of 19 Table 1. Summary of the included studies divided according to the experimental conditions. Author & Species, Model Time of THC Time of Haemodynamic Basal Study Description Sample Size THC Dose THC Route Outcomes and Comments Year (Anaesthetic & Route) Administration Measurements Parameters * Anaesthetised animals Investigate the THC altered distribution of Cavero Dogs Anaesthetised Continues for 30 m haemodynamic 11 2.5 mg/kg i.v. Post-anaesthesia - regional BF, and reduced HR 1972 [25] (pentobarbital, iv) post-drug effects of THC and BP. C: HR:169, Investigate the THC caused reduction in HR Cavero Dogs Anaesthetised Continues for 2 h BP:91.7; T: haemodynamic 23 39 µg/kg–2.5 mg/kg i.v. Post-anaesthesia and BP mediated via central 1973a [26] (pentobarbital, iv) post-drug HR:165.7, effects of THC nervous system. BP:93.5 Characterise the THC induced reduction in HR Cavero mechanism of Dogs Anaesthetised Continues for 140 m 29 39 µg/kg–5 mg/kg i.v. Post-anaesthesia - through alteration of autonomic 1973b [27] action of THC (pentobarbital, iv) post-drug innervation to myocardium. on HR Investigate the Dogs (heart bypass) C: HR:156, THC caused reduction in HR Cavero Pre-drug and continues effect of THC on Anaesthetised 8 2.5 mg/kg i.v. Post-anaesthesia BP:85.8; T: and BP, and reduced 1974 [19] for 30 m post-drug venous return (dibucaine, spinal) HR:147, BP:85. venous return. Investigate the THC reduced HR and BP Daskalopoulos Cats Anaesthetised mechanism of THC 40 30–300 µg/kg i.v. Post-anaesthesia 20 m post-drug - mediated via central 1975 [28] (urethane, iv) on CV system nervous system. THC caused reduction in HR C: HR:316.2, and biphasic BP response (" BP Adams Examined the CV Rats Anaesthetised Continues for 30 min BP:76.2; T: 72 0.1–3 mg/kg i.v. Post-anaesthesia followed by # BP), suggesting 1976 [29] effects of THC (urethane, ip) post-drug HR:314.8, that THC depressed CV BP:73.5. reflex functions. Chronic THC antagonised the Evaluated possible Twice/day for Jandhyala Dogs Anaesthetised On the 7th day elevation in HR induced by the interaction with 12 1 mg/kg s.c. 7 days - 1976 [30] (pentobarbital) post-anaesthesia anaesthetic agent via THC on HR Pre-anaesthesia vagal stimulation. Determined chronic Twice/day for Jandhyala administration of Dogs Anaesthetised On the 7th day Chronic THC had no effect on 16 1 mg/kg s.c. 7 days - 1977 [31] THC on (pentobarbital) post-anaesthesia haemodynamics. Pre-anaesthesia CV function Investigated Chronic THC increased BF in Jandhyala prolonged THC Dogs Anaesthetised Single dose per On the 35th day 16 2 mg/kg s.c. - femoral and mesenteric arteries 1978 [32] effects on (pentobarbital) day for 35 days post-anaesthesia with no effect on HR or BP. CV system Examined the Cats Anaesthetised THC had no effect in stimulated McConnell Continues for 1 h effects of THC on (urethane & 20 0.1–2 mg/kg i.v. Post-anaesthesia - salivary flow of cats. THC 1978 [33] post-drug salivary flow pentobarbital, ip) caused a reduction in HR and BP. Pharmaceuticals 2018, 11, 13 4 of 19 Table 1. Cont. Author & Species, Model Time of THC Time of Haemodynamic Basal Study Description Sample Size THC Dose THC Route Outcomes and Comments Year (Anaesthetic & Route) Administration Measurements Parameters * Anaesthetised animals THC induced triphasic BP response (# BP via vagal stimulation, then " BP not Siqueira Clarify the triple BP Rats Anaesthetised Continues for 70 m 50 1–10 mg/kg i.v. Post-anaesthesia - dependent on sympathetic 1979 [24] response post-THC (urethane, ip) post-drug activity followed by # BP due to central decrease in sympathetic tone).