Cannabis Research A-Z

Arch Mal Coeur Vaiss. 2006 Mar;99(3):242-6.

From Nature Clinical Practice Cardiovascular Medicine

Paul E. Szmitko; Subodh Verma

Posted: 03/17/2006; Nat Clin Pract Cardiovasc Med. 2006;3(3):116-117. © 2006 Nature Publishing Group

Obesity, particularly visceral adiposity, and its related metabolic and cardiovascular disorders, is a worldwide pandemic. The biological properties of one of the most widespread illicit drugs of abuse, marijuana, have been recruited for obesity management. By uncovering the cellular interactions of the cannabinoid Δ⁹-tetrahydrocannabinol (Δ⁹-THC)—the major active component of marijuana—researchers have identified new molecular pathways for treating cardiometabolic disease. Studies have demonstrated that modulation of the endocannabinoid system holds great therapeutic promise for the treatment of obesity, dyslipidemia, insulin resistance and atherosclerosis.

The endocannabinoid system contributes to the regulation of food intake, energy balance, inflammation, and lipid and glucose metabolism, and might therefore play a fundamental role in the development of obesity and atherosclerosis.

To date, two G-protein-coupled cannabinoid receptors that bind Δ⁹-THC with equal affinity have been identified: CB₁ and CB₂. The CB₁ receptor, believed to mediate the psychotropic effects of cannabis and to participate in the modulation of food intake and adipogenesis, is expressed at high levels by brain cells and by several peripheral tissues including the gastrointestinal tract, the adrenal gland, the heart and adipose tissue. CB₁ knockout mice exhibit a lean phenotype and appear to be resistant to diet-induced obesity and insulin resistance.

By contrast, CB₂ receptors are located primarily on blood cells and immune tissues, and stimulation of these receptors with Δ⁹-THC results in an immunosuppressive phenotype via the modulation of immune-cell cytokine production.^[5] This molecular system might have a role in the development of obesity, the metabolic syndrome and atherosclerosis, and its modulation might form the basis of new therapeutic strategies for these pathophysiologically linked conditions.

Using apolipoprotein E knockout mice Steffens et al. demonstrated that Δ⁹-THC can protect against the development of atherosclerosis.

CB₂ receptors were expressed in both human and mouse atherosclerotic lesions, but were absent in nondiseased arteries. Apolipoprotein E knockout mice fed a high cholesterol diet developed extensive atherosclerotic lesions in the aortic root; however, when 1 mg/kg Δ⁹-THC daily was added to the diet—a dose not associated with CB₁ activation and psychotropic effects—a significant reduction in the progression of atherosclerotic lesions was observed. Concomitant CB₂ receptor antagonist treatment abolished this observed anti-atherosclerotic effect. Even though Δ⁹-THC-fed mice continued to have elevated serum lipid levels, fewer inflammatory cells were recruited into atherosclerotic lesions, suggesting that Δ⁹-THC treatment had a beneficial effect on the inflammatory milieu. Indeed, Steffens and co-workers demonstrated that the immunosuppressive properties of Δ⁹-THC interfered with the adhesion, migration, proliferation and function of immune cells involved in atherosclerotic plaque formation.

These promising results do not imply that smoking marijuana is the key to a healthy heart. Too often there is failure to translate promising results observed in murine models to human patients. The effects of Δ⁹-THC on atherogenesis in man have not been studied, so whether this cannabinoid does more cardiovascular harm than good remains to be seen. The beneficial effects of Δ⁹-THC observed by Steffens et al. followed a U-shaped distribution with a very narrow therapeutic window, suggesting that the blood concentrations of Δ⁹-THC obtained from smoking marijuana would be too variable to provide sustained clinical benefit.^[1] Furthermore, it is unlikely that purified Δ⁹-THC extract or marijuana would be legalized for use as an adjunctive treatment of cardiovascular disease, since both compounds could serve as drugs of abuse. In addition, smoking marijuana increases carboxyhemoglobin levels, and Δ⁹-THC activation of CB₁ receptors induces a cardiovascular stress response; raising heart rate and blood pressure, decreasing the anginal threshold, and promoting acute coronary syndromes. Overall, smoking marijuana probably has a negative effect on the cardiovascular system. For these reasons, therapeutic strategies using the apparent anti-inflammatory properties of Δ⁹-THC will probably depend upon developing specific CB₂-receptor agonists, to prevent the onset of psychotropic effects.

Once thoroughly tested in animal models, translation to human trials could see the positive effects reported by Steffens et al. clinically realized.

Activation of the endocannabinoid system through the CB₁ receptor plays an important role in central and peripheral regulation of energy balance, body weight and food intake. Blockade of the CB₁ receptor appears to offer great promise in cardiometabolic risk reduction, and 1-year results from the RIO program are very encouraging.^[2] In this trial, 1,507 patients with a BMI of at least 30 kg/m², or at least 27 kg/m² or more with treated or untreated dyslipidemia, hypertension or both, received double-blind treatment with 5 mg rimonabant—a selective CB₁ receptor blocker—daily, 20 mg rimonabant daily, or placebo, in addition to a hypocaloric diet. Treatment with 20 mg rimonabant for 1 year significantly decreased total body weight and waist circumference, and produced a significant weight-independent effect on lipid parameters and several other cardiovascular risk factors. The beneficial changes to the lipid profile remained significant after adjusting for weight loss.

Furthermore, treatment resulted in a significant reduction in fasting plasma glucose, fasting plasma insulin, insulin resistance and the proportion of patients who fulfilled the criteria for the metabolic syndrome compared with placebo. To explain the observed weight-independent effect on both lipid and glycemic variables, Van Gaal et al. hypothesized that enhanced rimonabant-induced expression of adiponectin—a cytokine that has a role in the regulation of hyperglycemia, hyperinsulinemia and fatty acid oxidation and is reduced in obese individuals—could be responsible.

Thus, by improving adipocyte function, rimonabant might contribute to beneficial changes in other adipokines, such as C-reactive protein, reinforcing the link between obesity and atherosclerosis.Further investigation of in vivo effects of rimonabant are required to fully elucidate this mechanism, especially given the concern that CB₁ antagonists might raise blood pressure.^[8] Furthermore, rimonabant appears to be a useful agent for smoking cessation, yet another cardiac risk factor.

Thus, pharmacologic manipulation of cannabinoid-receptor signaling might combat the development of atherosclerosis through the treatment of obesity, the metabolic syndrome, vascular inflammation and smoking. The beneficial effects with rimonobant appear to be consistent in over 6,600 patients enrolled in the RIO program. Patients administered this drug enjoy sustained reductions in weight, BMI and visceral adiposity, and improvements in insulin sensitivity and dyslipidemia. More importantly, the beneficial effects to counter insulin resistance, improve dyslipidemia and increase adiponectin, are only partly explained by the reduction in weight, indicating a potential direct role for CB₁ in adipogenesis and lipid derangement.

The results of the RIO program and the study by Steffens et al. indicate that modulating the activity of the endocannabinoid system holds promise as an approach to treating obesity, dyslipidemia and atherogenesis.^[1,2] The CB₁ and CB₂ receptors might have opposing effects on atherogenesis: whereas central CB₁-receptor blockade offers hope for atherogenic risk reduction, peripheral CB₂-receptor stimulation in animals has powerful anti-atherosclerotic effects. It is possible that a strategy of CB₁-receptor antagonism and CB₂-receptor agonism might emerge as the most effective treatment across the spectrum of insulin resistance and vascular disease.

It is paradoxical that studying the effects of cannabis, an illicit drug that provides society with numerous social problems, could serve as the basis for novel therapeutic strategies to reduce cardiometabolic risk.

Correspondence: Subodh Verma, Division of Cardiac Surgery, St Michael's Hospital—8^th floor Bond Wing, 30 Bond Street, Toronto, ON M5B 1W8, Canada. Email: subodh.verma@sympatico.ca

February 16, 2006 - Ramat-Gan, Israel

Ramat-Gan, Israel: The administration of delta-9-THC protects heart muscle cells from injury during hypoxia (a deficiency in the levels of oxygen in the blood), according to preclinical trial data published in the February issue of the journal Molecular and Cellular Boichemistry.

Researchers at the Bar-Ilan University in Israel investigated the effect of THC on cultured heart cells during hypoxia. "The present study confirm[s] the ability of THC to confer cardioprotection on hypoxia-exposed cardiac cells in culture," authors concluded. Investigators defined" cardioprotection" as "delaying the onset of irreversible cell injury."

Authors also noted that THC appears to be non-toxic to heart cells.

"This research demonstrates that THC has beneficial effects on cardiac cells and supports the consideration of marijuana for specific medical uses," investigators concluded.

Previous research indicates that cannabinoids may also protect brain cells against alcohol-induced brain damage, stroke, and acute head trauma.

For more information, please contact Paul Armentano, NORML Senior Policy Analyst, at (202) 483-5500. Full text of the study," Delta-9-tetrahydrocannabinol protects cardiac cells from hypoxia via CB2 receptor activation and nitric oxide production," is available in the February issue of Molecular and Cellular Boichemistry.

    updated: Feb 16, 2006

August 10, 2006 - San Francisco, CA, USA

Heavy Cannabis Use Not Independently Associated With Cardiovascular Risks

San Francisco, CA: Heavy marijuana use is not independently associated with high blood pressure or other cardiovascular risk factors, according the findings of a 15-year longitudinal study published in the August issue of the American Journal of Cardiology.

Investigators at the Department of Epidemiology and Biostatistics at the University of California, San Francisco, assessed the association between marijuana use and caloric intake, body mass index (BMI) and cardiovascular risk factors in 3,617 young adults participating in the Coronary Artery Risk Development in Young Adults project (CARDIA). Though heavy self-reported use of cannabis was associated with higher caloric intake (3,365 calories per day in those who used cannabis >/= 1,800 days over a 15 year period versus 2,746 calories per day in non-users), marijuana use alone was not associated with higher levels of triglycerides, atherosclerosis, or blood pressure among respondents.

Investigators did note that the heavy use of cannabis and alcohol together was positively associated with cardiovascular risk factors.

A previous review of cannabis use and cardiotoxicity published earlier this year in the journal Forensic Science, Medicine and Pathology reported that moderate marijuana use likely poses little cardiovascular risk in humans.

In human trials, cannabis smoking is typically associated with a dose-dependent increase in heart rate and blood pressure in marijuana-naive subjects, though users often become completely tolerant to these effects over time. By contrast, cannabinoid administration in animals is typically associated with vasodilation, transient bradycardia and hypotension. The administration of synthetic cannabinoids has also been shown to lower blood pressure in animals and has not been associated with cardiotoxicity in humans.

In addition, recent studies demonstrate that anandamide and other endocannabinoids profoundly suppress cardiac contractility in hypertension and can normalize blood pressure.

For more information, please contact Paul Armentano, NORML Senior Policy Analyst, at (202) 483-5500. Full text of the study, Marijuana use, diet, body mass index, and cardiovascular risk, appears in the August issue of the American Journal of Cardiology. 

updated: Mar 20, 2011

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Answer, Says Study

April 6, 2005 -- The active ingredient in marijuana that produces changes in brain messages appears to fight atherosclerosis -- a hardening of the arteries.

But puffing pot probably won't help. The findings, reported in the journal Nature, "should not be taken to mean that smoking marijuana is beneficial for the heart," says Michael Roth, MD, a professor of medicine at UCLA medical school.

It takes a very specific amount of THC -- marijuana's key chemical -- to help the arteries. That dose is too low to produce mood-altering effects in the brain, according to the new study.

"It would be difficult to achieve such specific concentrations in the blood by smoking marijuana," Roth explains in a Nature editorial.

Smoking Pot: Bad for the Heart?

Smoking marijuana can speed up the pulse and raise blood pressure (followed by a sudden fall upon standing or walking), Roth notes.

"These effects lower the exercise threshold for chest pain [angina], and are an independent risk factor for heart attack and stroke," he writes. Inhaling marijuana smoke can also impair oxygen delivery via the blood, says Roth.

The best way to take advantage of THC's artery-protecting effects may be by developing new prescription drugs "rather than using marijuana or oral THC as medicines," he writes.

Testing THC on Mice

The new study was conducted on mice, not people. First, mice went on an 11-week fatty diet designed to clog their arteries. For the last six weeks of the diet, some mice also got an orally administered low dose of THC along with the high-fat food.

Afterward, the mice who had received THC had fewer signs of atherosclerosis. None of those mice died during treatment or showed unhealthy behavior, says the study.

The results may be due to THC's anti-inflammatory properties, write the researchers, who included François Mach, MD, of the cardiology division at University Hospital in Geneva, Switzerland. Inflammation has been shown to be associated with the development of atherosclerosis.

Tracing THC's Effects

The researchers took a closer look at THC. They knew the chemical has two receptors, called CB1 (mainly found in the brain) and CB2 (mostly found outside the brain).

When they used another drug to block CB2 receptors in the mice, THC couldn't protect the animals' arteries. As for the CB1 receptors, the THC dose used in the study was too low to affect them, so no "high" was created.

The study and editorial appear in Nature's April 7 edition.

Ashton JC, Smith PF

Curr Vasc Pharmacol 2007 Jul; 5(3):175-85.

Cannabinoid drugs exert their effects primarily through activation of cannabinoid CB1 and CB2 receptors. Both CB1 and CB2 receptors have been implicated in a number of cardiovascular processes, including vasodilation, cardiac protection, modulation of the baroreceptor reflex in the control of systolic blood pressure, and inhibition of endothelial inflammation and the progress of atherosclerosis in a murine model. These effects are mainly mediated through central and peripheral nervous system CB1 receptors, vascular CB1 receptors and immune cell CB2 receptors. Relevant cellular effects include: the inhibition of neurotransmitter release in the nucleus tractus solitarius and in peripheral adrenergic neurons; regulation of NOS activity in vascular beds; inhibition of vascular smooth muscle cell excitability; regulation of endothelial cell migration and proliferation; and effects on immune cell proliferation, activation, and inflammatory functions. We review the pre-clinical evidence for beneficial effects of cannabinoid drugs in a range of vascular and cardiovascular pathologies. We also discuss the clinically relevant potential of cannabinoids.

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Mendizábal VE, Adler-Graschinsky E

 Br J Pharmacol 2007 Apr 23.

In addition to their classical known effects, such as analgesia, impairment of cognition and learning and appetite enhancement, cannabinoids have also been related to the regulation of cardiovascular responses and implicated in cardiovascular pathology.

Elevated levels of endocannabinoids have been related to the extreme hypotension associated with various forms of shock as well as to the cardiovascular abnormalities that accompany cirrhosis. In contrast, cannabinoids have also been associated with beneficial effects on the cardiovascular system, such as a protective role in atherosclerosis progression and in cerebral and myocardial ischaemia. In addition, it has also been suggested that the pharmacological manipulation of the endocannabinoid system may offer a novel approach to antihypertensive therapy.

During the last decades, the tremendous increase in the understanding of the molecular basis of cannabinoid activity has encouraged many pharmaceutical companies to develop more potent synthetic cannabinoid analogues and antagonists, leading to an explosion of basic research and clinical trials. Consequently. not only the synthetic THC dronabinol (Marinol) and the synthetic THC analogue nabilone (Cesamet) have been approved in the United States, but also the standardized cannabis extract (Sativex) in Canada.

At least three strategies can be foreseen in the future clinical use of cannabinoid-based drugs: (a) the use of CB(1) receptor antagonists, such as the recently approved rimonabant (b) the use of CB(2)-selective agonists, and (c) the use of inhibitors of endocannabinoid degradation. In this context, the present review examines the effects of cannabinoids and of the pharmacological manipulation of the endocannabinoid system, in cardiovascular pathophysiology.British Journal of Pharmacology advance online publication, 23 April 2007; doi:10.1038/sj.bjp.0707261.

Br J Pharmacol

O'Sullivan SE, Randall MD, Gardiner SM

 Evidence suggests that Delta9-tetrahydrocannabinol (THC) may have antihypertensive effects and that the vasodilator effect of endocannabinoids is enhanced in rats made hypertensive by chronic NO synthase inhibition. Therefore, the aims of the present study were to investigate whether the in vitro and in vivo cardiovascular responses to THC are altered by Nomega-nitro-L-arginine methyl ester (L-NAME) treatment.

The vasorelaxant effects of THC were enhanced in small mesenteric arteries from L-NAME-treated rats. This enhanced response was not inhibited by cannabinoid CB1 receptor antagonism [1 microM N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; AM251]. Pretreating vessels with the transient receptor potential vanilloid receptor receptor agonist capsaicin at 10 microM for 1 h reduced vasorelaxation to THC to a greater extent in L-NAME-treated than control rats. Inhibition of cyclooxygenase with 10 microM indomethacin inhibited THC responses in arteries from L-NAME-treated rats but not from control rats. In conscious, chronically instrumented rats, 1 mg kg-1 i.v. THC caused a pressor effect, with vasoconstriction of the renal and mesenteric vascular beds, and hindquarters vasodilatation. Pretreatment with 3 mg kg-1 i.v. AM251 reduced the pressor and vasoconstrictor effects of THC, abolished the hindquarters vasodilatation, and revealed a bradycardic response. L-NAME-treated rats showed similar pressor and vasoconstrictor responses to THC, but with bradycardia, and reduced hindquarter vasodilatation. These data show that, in vitro, isolated arteries of L-NAME-treated rats show enhanced vasorelaxant responses to THC through an increased sensory nerve component and stimulation of prostanoids. However, in vivo,

THC causes a CB1 receptor-mediated pressor effect with hindquarters vasodilatation. There was no evidence of enhanced vasodilator effects of THC in L-NAME-treated animals in vivo.

Heart failure is a serious possible consequence of a heart attack or other diseases that damage the heart. It occurs when the heart loses its ability to pump enough blood through the body. Often it develops slowly over years, as the heart gradually loses its pumping ability.

In rats heart failure develops within 12 weeks after a big cardiac infarction. Scientists of the University of Wurzburg in Germany found out that daily application of the synthetic cannabinoid HU-210 after the infarction prevented the drop of blood pressure (left-ventricular systolic pressure) and dysfunction of the arteries (endothelial dysfunction). However, the cannabinoid also increased the filling pressure in the left chamber of the heart (left-ventricular end-diastolic pressure), which may be negative in the long run.

HU-210 activates CB1 receptors as does THC. CB1 receptors are not only found in the brain where they cause the characteristic psychic effects, but also in the heart and many other organs. Dr. Jens Wagner and colleagues treated another group of rats with a selective blocker of the CB1 receptor which reduced the pumping ability of the heart after cardiac infarction.

Researchers concluded that taken together with other results their studies show that endocannabinoids produced by the body itsself excert a protective effect after a heart attack. A commentary by the British Journal of Pharmacology says that "cannabinoids and endocannabinoid systems may therefore present useful targets for therapy following myocardial infarction."

(Sources: Wagner JA, et a. Br J Pharmacol 2003 Apr;138(7):1251-8; Hiley CR, Ford WR. Br J Pharmacol 2003 Apr;138(7):1183-4; press release of the University of Wurzburg of 11 April 2003)

According to research published in the American Journal of Cardiology the use of cannabis is not associated with development of risk factors for cardiovascular diseases such as heart attack and stroke. While acute cannabis use is associated with increased appetite and changes in blood pressure, a long-term study (the CARDIA study) with 3,617 participants from the United States found no effect of regular cannabis use on blood pressure and blood lipids.

Participants who had used cannabis on more than 1,800 days had a higher daily caloric intake, a higher alcohol intake and slightly higher blood pressure and somewhat higher triglycerid levels in blood, but no higher weight and no higher overall lipid and glucose levels than the average of the other participants. Closer analysis revealed that alcohol was responsible for the somewhat higher blood pressure and triglycerid levels. Researchers concluded that cannabis use "was not independently associated with cardiovascular risk factors, [but] it was associated with other unhealthy behaviours, such as high caloric diet, tobacco smoking, and other illicit drug use."

The CARDIA study is examining how heart disease develops in adults. It began in 1986 with a group of 5115 black and white men and women aged 18-30 years. The participants were selected so that there would be approximately the same number of people in subgroups of race, gender and education from four cities in the United States. These same participants were asked to participate in follow-up examinations during 1987-1988 (Year 2), 1990-1991 (Year 5), 1992-1993 (Year 7), 1995-1996 (Year 10), and 2000-2001 (Year 15).

(Source: Rodondi N, Pletcher MJ, Liu K, Hulley SB, Sidney S. Marijuana Use, Diet, Body Mass Index, and Cardiovascular Risk Factors (from the CARDIA Study). Am J Cardiol 2006;98(4):478-484.)

Israelian researchers at the Bar-Ilan University in Ramat-Gan demonstrated that THC protects heart cells (cardiomyocytes) against the damage caused by hypoxia (reduced oxygen concentration in the blood) in experimental studies. Pre-treatment of cultures of cardiomyocytes with THC for 24 hours prevented leakage of LDH induced by hypoxia. Leakage of LDH (lactate dehydrogenase) from cells is a sign of cell damage.

This protective effects of THC was mediated by the CB2 receptor. CB2 receptor activation by THC induced the production of nitric oxide (NO). Nitric oxide signals the smooth muscles of blood vessels to relax, thus dilating the artery and increasing blood flow. This underlies the action of nitroglycerin and other drugs used in the treatment of heart disease, since these compounds are converted to nitric oxide in the body.

Researchers noted that THC also "probably pre-trains the cardiomyocytes to hypoxic conditions." They concluded that their research "demonstrates that THC has beneficial effects on cardiac cells and supports the consideration of marijuana for specific medical uses."

(Source: Shmist YA, Goncharov I, Eichler M, Shneyvays V, Isaac A, Vogel Z, Shainberg A. Delta-9-tetrahydrocannabinol protects cardiac cells from hypoxia via CB2 receptor activation and nitric oxide production. Mol Cell Biochem 2006;283(1-2):75-83)

April 06, 2005

The study is in this week's edition of the journal Nature.  You can get the full text of the article for $30 if you aren't a subscriber, or you can just read the handy news release:

A compound derived from the cannabis plant protects blood vessels from dangerous clogging, a study of mice has shown. The discovery could lead to new drugs to ward off heart disease and stroke.

The compound, called delta-9-tetrahydrocannabinol (THC), combats the blood-vessel disease atherosclerosis in mice. This disease occurs when damage to blood vessels, by nicotine from cigarettes, for example, causes an immune response that leads to the formation of fatty deposits in arteries.

These deposits form because the immune cells can linger too long, recruiting others and leading to an inflamed blockage that snares fatty molecules. The disease is the leading cause of heart disease and stroke in the developed world.

THC seems to tone down this immune response, report François Mach of the University Hospital Geneva, Switzerland and his colleagues. The compound binds to a protein called CB2 that is present on the surfaces of certain immune cells.

In addition to CB2, there is another receptor called CB1.  Simply put, when THC binds to that one, you get high.  Anyway, the researchers in this study proved that THC had to bind to CB2 for it to slow atherosclerosis.  It didn't have any effect when it bound to CB1 (except possibly get the mice stoned).

The news release goes on to point out that:

The benefits for atherosclerosis occurred only at a certain dosage, Mach adds. At higher and lower doses, THC has no therapeutic effect on blood vessels, he says. He notes the similarly moderated effects of alcohol on heart disease, adding that a single glass of Bordeaux may reduce risk while overindulgence can increase it.

The team also emphasises that the THC dose required to protect blood vessels is lower, relative to body weight, than that which would produce the mind-altering altering effects of cannabis in humans. "This paper has nothing to do with smoking marijuana," Mach stresses.

The researchers speculate that perhaps cannabinoids could be used in conjunction with statins, which lower blood cholesterol levels.

Obviously, the effects of THC are complex.  However, the volume of literature that indicates the medical benefits of marijuana is obviously growing.  Someday, hopefully, lawmakers in all states will be convinced that marijuana should be decriminalized for medical use.

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. The effect taken together is analogous to a car changing down a gear.

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

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 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. Animal studies are conflicting, the effect in dogs appears opposite to that in humans. 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.

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."

Blood Pressure:

Early studies on rats bred for high blood pressure[xviii] found that THC reduced levels of blood pressure, and that tolerance developed to this effect.

Mechoulam 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"

Hanus et al[ 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."

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"

Jarai & Kunos 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 alreport "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 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 found that, in anaesthetised rats "Intravenously administered delta9-THC evoked ... bradycardia, and hypotension"

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)"

Cerebrovascular Effects:

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"

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.

Strokes and Neuroprotectivity:

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 report a case history of a patient suffering a stroke following a heavy bout of cannabis smoking.

Alvaro et al 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 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 stressed the likely role of alcohol or other drugs in the etiology of such strokes.

Mouzak et al 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."

However, it is clear that cannabinoids have a variety of cerebrovascular effects, increasing the blood supply to the brain, 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, Jobreported 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 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."

Panikashvili et al 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."

Belayev et al 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."

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 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"

Summary - Cardiovascular effects of Cannabis:

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

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.

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

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.

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.

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Biol Psychiatry. 1992 Jul 15;32(2):164-9.

 Mathew RJ, Wilson WH, Humphreys DF, Lowe JV, Wiethe KE.

Department of Psychiatry, Duke University Medical Center, Durham, North Carolina 27710.

Durst R, Danenberg H, Gallily R, Mechoulam R, Meir K, Grad E, Beeri R, Pugatsch T, Tarsish E, Lotan C

Cardiac Echo Lab, Massachusetts General Hospital, Blake 2, Rm. 255, 55 Fruit St., Boston, MA 02114. rdurst@partners.org).

Cannabidiol (CBD) is a major, nonpsychoactive Cannabis constituent with anti-inflammatory activity mediated by enhancing adenosine signaling. Inasmuch as adenosine receptors are promising pharmaceutical targets for ischemic heart diseases, we tested the effect of CBD on ischemic rat hearts.

For the in vivo studies, the left anterior descending coronary artery was transiently ligated for 30 min, and the rats were treated for 7 days with CBD (5 mg/kg ip) or vehicle. Cardiac function was studied by echocardiography. Infarcts were examined morphometrically and histologically. For ex vivo evaluation, CBD was administered 24 and 1 h before the animals were killed, and hearts were harvested for physiological measurements. In vivo studies showed preservation of shortening fraction in CBD-treated animals: from 48 +/- 8 to 39 +/- 8% and from 44 +/- 5 to 32 +/- 9% in CBD-treated and control rats, respectively (n = 14, P < 0.05). Infarct size was reduced by 66% in CBD-treated animals, despite nearly identical areas at risk (9.6 +/- 3.9 and 28.2 +/- 7.0% in CBD and controls, respectively, P < 0.001) and granulation tissue proportion as assessed qualitatively. Infarcts in CBD-treated animals were associated with reduced myocardial inflammation and reduced IL-6 levels (254 +/- 22 and 2,812 +/- 500 pg/ml in CBD and control rats, respectively, P < 0.01)

In isolated hearts, no significant difference in infarct size, left ventricular developed pressures during ischemia and reperfusion, or coronary flow could be detected between CBD-treated and control hearts. Our study shows that CBD induces a substantial in vivo cardioprotective effect from ischemia that is not observed ex vivo. Inasmuch as CBD has previously been administered to humans without causing side effects, it may represent a promising novel treatment for myocardial ischemia.

Published 6 December 2007 in Am J Physiol Heart Circ Physiol, 293(6): H3602-7.
Full-text of this article is available online (may require subscription).

Rudź R, Baranowska U, Malinowska B

 Postepy Hig Med Dosw (Online) 2008.:174-84.

Cannabinoids, substances derived from Cannabis sativa, have been used by humans as therapeutic agents for thousands of years. They act through the cannabinoid CB(1), CB(2), vanilloid TRPV1, and the as yet undefined putative endothelial cannabinoid receptors. Intensive research on the influence of cannabinoids on the cardiovascular system has been conducted since the 1990s after the discovery that cannabinoids are involved in hypotension connected with septic, cardiogenic, and hemorrhagic shock. One cannot exclude the future possibility of using cannabinoids as new therapeutic agents in diseases of the cardiovascular system.

In the present paper the mechanisms of cannabinoids on heart failure are described. In the acute phase of myocardial infarction, cannabinoids protect the endothelium of coronary vessels and decrease the heart's necrotic area and the risk of arrhythmia. Cannabinoids also act in the chronic phase of myocardial infarction in the process of the heart remodeling. However, the present knowledge of the effects of cannabinoids on the acute and chronic phases of myocardial infarction and the possibility of using these agents in cardiovascular disease therapy is still insufficient.

Prague Med Rep. 2009;110(1):5-12.

  Hemp seed is an ancient superfood that has a rich history of culinary enjoyment, as well as use by cultures as a traditional medicine to enhance health and well-being. Over the past few years, this nutritious and eco-friendly seed has been gaining more attention from nutrition and health experts – and deservedly so. Scientists in Canada, a country where hemp agriculture is thriving and experiencing a rebirth, recently performed research to study hemp seed’s role in maintaining heart health. The title of the abstract from their research sums things up well, “Cholesterol Induced Stimulation of Platelet Aggregation is Prevented by a Hempseed-Enriched Diet.”

In somewhat technical terms, the authors of the scientific paper establish that “Hypercholesterolemia indirectly increases the risk for myocardial infarction by enhancing the ability of platelets to aggregate.” Their research, published in the April 2008 edition of the Canadian Journal of Physiology and Pharmacology*, investigated whether hempseed, a rich source of polyunsaturated fatty acids (PUFAs), inhibits platelet aggregation under normal and hypercholesterolemic conditions. “The results of this study demonstrate that when hempseed is added to a cholesterol-enriched diet, cholesterol-induced platelet aggregation returns to control levels,” noted the authors

The Abstract of the research highlights the elevated concentration of Gamma Linolenic Acid (GLA) in the test subjects, and notes that the heart health benefits may be attributable to the increased levels of GLA. Hemp is a plentiful and rare plant food source of the “super” omega-6 EFA gamma-linolenic acid (GLA). “GLA can be difficult to obtain in the diet,” notes Meghan Atkinson CN, a nutrition consultant based in Los Angeles, California. There are only 4 significant natural sources of GLA: Hemp Seed, Evening Primrose, Borage, and Black Courant. “Of these, hemp seed is the only whole food source that has a wide variety of culinary functions,” notes Atkinson.

In addition to GLA, nutrition experts tout hemp due to its balanced and high concentration of Omega-3 and Omega-6 Essential Fatty Acids, strong digestible protein profile, plentiful fiber, and abundance of vitamins and minerals. Hemp foods offer the richest vegetable source of the Omega 3 & 6 Essential Fatty Acids, and hemp’s overall protein content is comparable to soy beans without containing hormone inhibitors, and is higher than that found in nuts, other seeds, meats, dairy products, fish and poultry.

Hemp Foods Feature Gourmet Flavor and Versatility

Manitoba Harvest hemp food products have a sweet nutty flavor and add a boost of nutrition and taste to a wide variety of delicious recipes. There are many forms of healthy hemp foods to choose from. For example, Hemp Seed Oil is a wonderful base for salad dressings and can be added to juices, smoothies, soups and sauces to create a rich creamy texture. Shelled Hemp Seed is delicious sprinkled over salad, cereal, yogurt and soup or as a healthy snack right from the bag. Hemp Seed Butter is a creamy and satisfying spread for sandwiches, breads, bagels, crackers, fruit and croissants or it can be combined with herbs to create delicious sauces, spreads and dips. There is no better way to start the day than with a fruit smoothie packed with the nutritional benefits of Hemp Protein Powder with Fiber.

Last year, Manitoba Harvest launched Hemp Bliss (the first and only line of organic non-dairy hempmilks), which earned the 2007 Best New Food Product Award at Natural Products Expo East. This tasty and nutritious dairy milk alternative provides 1,200 mg of Omega-3 essential fatty acids (EFAs), 5 grams of highly digestible protein and 250 mg of powerful Gamma Linolenic Acid (GLA) per serving. A Hemp Bliss recipe is listed below.

Manitoba Harvest - An Award Winning Hemp Foods Pioneer

Founded in 1998, Manitoba Harvest’s mission is to create the healthiest hemp foods, to educate the public about healthy lifestyle choices and to support sustainable agriculture. Manitoba Harvest was honored with the 2006 Socially Responsible Business Award at Natural Products Expo East for their work pioneering sustainable organic hemp agriculture in North America. The company just announced new Organic Dark Chocolate and Organic Vanilla Hemp Protein Powders. In addition, Manitoba Harvest produces an award-winning line of Hemp Bliss organic hempmilk, organic cold-pressed Hemp Seed Oil, Shelled Hemp Seed, Hemp Seed Butter and Hemp Protein Powder and Hemp Protein & Fiber Powder. Their products are distributed to thousands of stores in the U.S., Canada, Europe and Japan and are also sold as bulk ingredients to food and cosmetic manufacturers.

News Hawk- Ganjarden http://www.420Magazine.com
Source: NPI Center
Contact: NPI Center
Copyright: 2008 NPI Center

Am J Cardiol.  2006; 98(4):478-84 (ISSN: 0002-9149)

Rodondi N; Pletcher MJ; Liu K; Hulley SB; Sidney S;  
The Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA. nicolas.rodondi@hospvd.ch

Marijuana use has been associated with increased appetite, high caloric diet, acute increase in blood pressure, and decreases in high-density lipoprotein cholesterol and triglycerides. Marijuana is the most commonly used illicit drug in the United States, but its long-term effects on body mass index (BMI) and cardiovascular risk factors are unknown. Using 15 years of longitudinal data from 3,617 black and white young adults participating in the Coronary Artery Risk Development in Young Adults (CARDIA) study, we assessed whether marijuana use was associated with caloric intake, BMI, and cardiovascular risk factors.

Of the 3,617 participants, 1,365 (38%) reported ever using marijuana. Marijuana use was associated with male gender, tobacco smoking, and other illicit drug use. More extensive marijuana use was associated with a higher caloric intake (2,746 kcal/day in never users to 3,365 kcal/day in those who used marijuana for > or = 1,800 days over 15 years) and alcohol intake (3.6 to 10.8 drinks/week), systolic blood pressure (112.7 to 116.5 mm Hg), and triglyceride levels (84 to 100 mg/dl or 0.95 to 1.13 mmol/L, all p values for trend < 0.001), but not with higher BMI and lipid and glucose levels. In multivariate analysis, the associations between marijuana use and systolic blood pressure and triglycerides disappeared, having been mainly confounded by greater alcohol use in marijuana users. In conclusion, although marijuana use was not independently associated with cardiovascular risk factors, it was associated with other unhealthy behaviors, such as high caloric diet, tobacco smoking, and other illicit drug use, which all have long-term detrimental effects on health.