1 Introduction:

1.1 One of the most consistent effects of cannabis intoxication is an increased heart rate[i]. For this reason alone it would not be normally recommended for patients with cardiovascular problems. However, THC also acts as a smooth-muscle relaxant, relaxing the walls of the arteries, which can result in lower blood pressure and increased blood flow to the tissues[ii][iii]. The effect taken together is analogous to a car changing down a gear.

1.2 Cannabis intoxication has been found to reduce the level of exercise which can be tolerated before the onset of angina[iv].to a greater extent than a high-nicotine tobacco cigarette[v]. Cardiovascular symptoms have been attributed to cannabis use, either alone (stroke)[vi], or in combination with alcohol and cocaine[vii].

1.3 The presence and action of CB1 cannabinoid receptors in arterial tissue was described by Bilginger et al[viii], who reported: "the data demonstrate that cannabinoid signalling is involved with the regulation of the microvascular environment" Cannabinoids such as CBD and the synthetic HU-211[ix] have been shown to reduce ischaemic cell damage following cardiac arrest or stroke. CBD also counteracts the increase in heart-rate associated with THC[x] - THC and CBN both appear to increase heart rate, while CBD tends to decrease heart rate. There is conflicting evidence as to whether changes in cardiovascular function are related to myocardial contractility[xi][xii]. Animal studies are conflicting, the effect in dogs appears opposite to that in humans[xiii][xiv]. Part of the increase in heart rate can be counteracted by use of beta-blocker drugs[xv], but not by opiate antagonists such as Naloxone[xvi]. From a clinical study of long-term marijuana smokers, Tashkin et al[xvii] concluded "in long-term heavy users of cannabis, marihuana has no significant effect on myocardial contractility independent of its effect on heart rate."

2 Blood Pressure:

2.1 Early studies on rats bred for high blood pressure[xviii] found that THC reduced levels of blood pressure[xix][xx], and that tolerance developed to this effect[xxi]. Mechoulam[xxii] predicted in 1978 "Numerous synthetic cannabinoids are currently being investigated as analgetics and as sedative-relaxants." Zaugg & Kyncl[xxiii] reported "hydroxyacetyl and gamma-hydroxybutyryl (cannabinol) derivatives were potent antihypertensive agents (minimum effective dose, 3-5 mg/kg, orally) of the same order of activity as the highly CNS-active N-propargyl derivatives"

2.2 Hanus et al[xxiv] reported that the specific CB2 receptor agonist HU-308 "reduces blood pressure... The hypotension... produced by HU-308 (is) blocked (or partially blocked) by the CB(2) antagonist SR-144528, but not by the CB(1) antagonist SR-141716A. These results demonstrate the feasibility of discovering novel nonpsychotropic cannabinoids that may lead to new therapies for hypertension..." Garcia et al[xxv] reported "Anandamide produced a dose-dependent decrease in mean arterial pressure due to a drop in systemic vascular resistance (SVR) that was accompanied by a compensatory rise in cardiac output. Anandamide also elicited an increase in both portal venous flow and pressure, along with a decline in mesenteric vascular resistance (MVR). Pretreatment with 3 mg/kg SR-141716A, a CB(1) antagonist, prevented the decline of SVR and MVR from the lower dose of anandamide."

2.3 Gardiner et al[xxvi], rats studying the effects of the cannabinoid receptor agonist WIN 55212-2 in normal (HSD) and hypertensive (TG), concluded "Collectively, the results indicate that the predominant cardiovascular effects of WIN 55212-2 in conscious HSD and TG rats (i.e., pressor and vasoconstrictor actions) can be attributed largely to indirect, pentolinium-sensitive mechanisms, which appear to differ little in the normotensive and hypertensive state, at least in conscious animals. Under the conditions of our experiments, signs of cannabinoid-induced vasodilatation were modest." Studying anandamide in anaesthetised and conscious rats, Gardiner et al[xxvii] reported "At all doses of anandamide, there was a significant, short-lived increase in mean arterial blood pressure associated with vasoconstriction in renal, mesenteric and hindquarters vascular beds. The higher doses (2.5 and 3 mg kg(-1)), caused an initial, marked bradycardia accompanied, in some animals, by a fall in arterial blood pressure which preceded the hypertension. In addition, after the higher doses of anandamide, the hindquarters vasoconstriction was followed by vasodilatation... None of the cardiovascular actions of anandamide were influenced by the CB(1)-receptor antagonist, AM 251"

2.4 Jarai & Kunos[xxviii] noted "cannabinoids were found to be potent CB1-receptor dependent vasodilators in the coronary and cerebrovascular beds" concluding "the endogenous cannabinoid system plays an important role in cardiovascular regulation, and pharmacological manipulation of this system may offer novel therapeutic approaches in a variety of pathological conditions." Wagner et al[xxix] report "Activation of peripheral cannabinoid CB(1) receptors elicits hypotension" and noted "We conclude that cannabinoids elicit profound coronary and cerebral vasodilation in vivo by direct activation of vascular cannabinoid CB(1) receptors, rather than via autoregulation, a decrease in sympathetic tone or, in the case of anandamide, the action of a non-cannabinoid metabolite." However, in a review article for the Bulletin on Narcotics, Husan & Khan[xxx] warned "The use of cannabis causes prominent and predictable effects on the heart, including increased work-load, increased plasma volume and postural hypotension, which could impose threats to the cannabis users with hypertension, cerebrovascular disease or coronary arteriosclerosis." Lake et al[xxxi] noted "in anesthetized rats anandamide elicits bradycardia and a triphasic blood pressure response: transient hypotension secondary to a vagally mediated bradycardia, followed by a brief pressor and prolonged depressor response, the latter two effects being similar to those of delta 9-tetrahydrocannabinol (THC)" Krowicki et al[xxxii] found that, in anaesthetised rats "Intravenously administered delta9-THC evoked ... bradycardia, and hypotension"

2.5 The picture is slowly becoming clearer, indicating that endo-cannabinoids modify aspects of blood flow at a subtle local level. In a 2001 review, Schiffrin[xxxiii] noted "The endothelium produces a variety of substances that play important roles in regulation of the circulation and vascular wall homeostasis. The control of blood vessel wall homeostasis is achieved via production of vasorelaxants and vasoconstrictors. Among the vasorelaxants are ... metabolites of arachidonic acid like epoxyeicosatrienoic acids, and endocannabinoids)"

3 Cerebrovascular Effects:

3.1 Matthew & Wilson[xxxiv] found "In experienced marijuana smokers, marijuana smoking was accompanied by a significant bilateral increase in cerebral blood flow (CBF) especially in the frontal regions and cerebral blood velocity." Tunving et al[xxxv], studying long-term cannabis users found decreases in cerebral blood flow during the early stages of detoxification, reverting to normal after 9-60 day follow-up. Similar results were found by Lundqvist et al[xxxvi] - "Cerebral blood flow (CBF) was measured in 12 long-term cannabis users shortly after cessation of cannabis use (mean 1.6 days). The findings showed significantly lower mean hemispheric blood flow values and significantly lower frontal values in the cannabis subjects compared to normal controls" Ellis et al[xxxvii] found "Anandamide (AN) and delta 9-THC similarly induced a dose-dependent dilation (of cerebral arterioles) starting at concentrations as low as 10(-12) M. Maximum dilation for AN was 25% and that for delta 9-THC 22%. Topical coapplication of indomethacin, a cyclooxygenase inhibitor, completely blocked dilation"

3.2 Bloom et al[xxxviii] found different areas of the brain to have different blood-flow responses to THC · "Changes in regional cerebral blood flow were observed in 16 of the 37 areas measured." Stein et al[xxxix] in the rat, an O"Leary et al[xl] in human recreational users, also found wide variations in cerebrovascular response in different brain regions.

4 Strokes and Neuroprotectivity:

4.1 There are a number of case studies describing patients who have suffered strokes following or during cannabis use, some, but not all,of these cases can be explained by use of other drugs (alcohol or stimulants). Cooles & Michaud[xli] report a case history of a patient suffering a stroke following a heavy bout of cannabis smoking. Alvaro et al[xlii] reported another case history "of a young man and heavy cannabis smoker who suffered posterior cerebral artery infarction during his first episode of coital headache"In a further case history, Lawson & Rees[xliii] reported "A 22-year-old man with a five-year history of drug and alcohol abuse presented with a left hemiparesis preceded by three transient ischaemic attacks, two of which occurred whilst smoking cannabis" although in response, McCarrom & Thomas[xliv] stressed the likely role of alcohol or other drugs in the etiology of such strokes. Mouzak et al[xlv] described "Three male patients (mean age 24.6 years) who were heavy cannabis smokers presented with transient ischemic attacks (TIA) shortly after cannabis abuse... The urine analysis was positive for cannabis metabolites. There were no other abnormal findings in the rest of the meticulous and thorough study of all 3 patients, which leads to the conclusion that cannabis was the only risk factor responsible for the observed TIA, contradictory to other studies, which support that cannabis is a 'safe' drug."

4.2 However, it is clear that cannabinoids have a variety of cerebrovascular effects, increasing the blood supply to the brain[xlvi], and can protect against potentially fatal brain cell death following a stroke by reducing tumour necrosis factor, which causes self-destruction in exposed cells. The use of cannabinoids for treatment of brain damage arising from strokes is reaching an advanced stage of the licensing process, Job[xlvii] reported in 2000 "Dexanabinol is a non-psychotropic cannabinoid NMDA receptor antagonist under development by Pharmos Corp for the potential treatment of cerebral ischemia... cardiac failure, head injury and multiple sclerosis (MS)... it is in phase III trials for traumatic brain injury... Pharmos estimates that the worldwide market for dexanabinol in the treatment of severe head trauma may reach $1 billion per year" Leker et al[xlviii] investigated the effect of dexanabinol, a synthetic cannabinoid which is a NMDA antagonist, with antioxidant and anti-tumour necrosis factor alpha properties, on the levels of brain damage (infarct) following experimentally induced ischaemic strokes in rats, finding "Dexanabinol significantly decreased infarct volumes. It also significantly lowered TNFalpha levels in the ipsilateral hemisphere although not to the level of sham operated rats... In conclusion, dexanabinol may be a pluripotent cerebroprotective agent."

4.3 Panikashvili et al[xlix] reported "Traumatic brain injury triggers the accumulation of harmful mediators that may lead to secondary damage. Protective mechanisms to attenuate damage are also set in motion. 2-Arachidonoyl glycerol (2-AG) is an endogenous cannabinoid... after injury to the mouse brain, 2-AG may have a neuroprotective role in which the cannabinoid system is involved. After closed head injury (CHI) in mice, the level of endogenous 2-AG was significantly elevated. We administered synthetic 2-AG to mice after CHI and found significant reduction of brain oedema, better clinical recovery, reduced infarct volume and reduced hippocampal cell death compared with controls. When 2-AG was administered together with additional inactive 2-acyl-glycerols that are normally present in the brain, functional recovery was significantly enhanced. The beneficial effect of 2-AG was dose-dependently attenuated by SR-141761A, an antagonist of the CB1 cannabinoid receptor."

4.4 Belayev et al[l] found the synthetic cannabinoid HU-211 to be "an effective drug in protecting against the effects of focal ischemia-induced (blood-brain barrier) disruption in the rat and suggest that the drug may be an effective treatment against the ischemic cell death and BBB disruption that can occur clinically following a stroke or cardiac arrest." Nagayama et al[li] noted "R(+)-WIN 55212-2, a synthetic cannabinoid agonist, decreased hippocampal neuronal loss after transient global cerebral ischemia and reduced infarct volume after permanent focal cerebral ischemia induced by middle cerebral artery occlusion in rats. The less active enantiomer S(-)-WIN 55212-3 was ineffective, and the protective effect ... was blocked by (a) specific central cannabinoid (CB1) cannabinoid receptor antagonist . R(+)-WIN 55212-2 also protected cultured cerebral cortical neurons from in vitro hypoxia and glucose deprivation, but in contrast to the receptor-mediated neuroprotection observed in vivo, this in vitro effect was not stereoselective and was insensitive to CB1 and CB2 receptor antagonists" concluding "Cannabinoids may have therapeutic potential in disorders resulting from cerebral ischemia, including stroke, and may protect neurons from injury through a variety of mechanisms."

4.5 In a 1999 review of advances in cannabinoid research, Mechoulam[lii] noted "A synthetic cannabinoid, HU-211, is in advanced clinical tests against brain damage caused by closed head injury. It may prove to be valuable against stroke and other neurological diseases" Guzman et al[liii] observed "One of the most exciting and promising areas of current cannabinoid research is the ability of these compounds to control the cell survival/death decision. Thus cannabinoids may induce proliferation, growth arrest, or apoptosis in a number of cells, including neurons, lymphocytes, and various transformed neural and nonneural cells." Jin et al[liv] concluded "These findings are consistent with a neuroprotective role for endogenous cannabinoid signaling pathways and with a potential therapeutic role in stroke for drugs that activate CB1 receptors"

5 Summary · Cardiovascular effects of Cannabis:

5.1 Cannabis increases heart rate in na•ve users although tolerance develops to this effect.

5.2 Cannabinoids can also reduce blood pressure via arteriollar dilatation in a variety of tissues, although the effect on blood flow varies at a local level, with some organs or brain regions experiencing vasoconstriction, others vasodilation.

5.3 In the withdrawal phase following cessation of chronic use, cerebral blood flow may be significantly reduced.

5.4 Cannabis use has been implicated as a causative factor in a small number of patients suffering strokes or transient ischaemic attacks, and may represent a risk factor to susceptible individuals.

5.5 However cannabinoids, in particular CB1-receptor agonists, have been shown to protect against nerve cell death following stroke, and dexanabinol at an advanced stage of the licensing process as a drug to be administered to victims of stroke or closed-head injuries to minimise the long-term brain damage caused by such events, and to improve survival and recovery prospects.