By Debra L. Beck

Is everyone toking on marijuana these days whether recreationally or for its touted (and often unproven) medical benefits? Maybe not everybody, but given that cannabis is approved for medicinal use in 23 states, recreational use in two states, and may be ready to roll in another five, it's a fair guess that many more of your patients are lighting up than you might suspect. (California is thought to be the big fatty, given that it could tilt marijuana legalization in the US and elsewhere, and that battle is set for 2016.)

While marijuana has long enjoyed a reputation for being an innocuous drug, offering its users feelings of euphoria, well-being, detachment, relaxation, and, of course, increased appetite, an increasing body of research hints that some of its effects may not be so benign. Keep in mind, cannabis research is challenging since it remains illegal in most countries and research-grade samples are difficult to obtain – which may be a moot point given that research-grade plants in the US are thought to be very low potency and inferior quality.

Of greatest interest to the cardiology community: evidence that inhaled cannabis has adverse cardiovascular consequences. Couple that with its increasing use and decriminalization, we're not just blowing smoke to say that if you haven't already seen a pot-related acute coronary syndrome (ACS), you might in the very near future.

"It is important that cardiologists be made aware of the potential for marijuana-associated adverse cardiovascular effects that may begin to occur in the population with greater frequency given the current wave of decriminalization," said Robert A. Kloner, MD, in an interview with CardioSource WorldNews. Dr. Kloner, from the Heart Institute at Good Samaritan Hospital in Los Angeles, has been at the forefront of research on the cardiovascular effects of illicit drugs and published a review on the adverse cardiovascular, cerebrovascular, and peripheral vascular effects of marijuana inhalation earlier this year.¹

Unfortunately, like everyone else, the cardiology community has done vanishingly little bench or clinical research on the cardiovascular effects of inhaled marijuana. Although there have been several case reports and small case series published over the last 40 years, much of what we know about the physiological effects of smoking pot comes from basic psychological research on marijuana, if only because investigators monitored vital signs during experiments.

The Plural of Anecdote Still Isn't Data...

Given the dearth of data, we have to get information where we can. In terms of the adverse cardiovascular (CV) consequences of smoking Mary Jane, the anecdotal information looks pretty damning. (Speaking of anecdotes, the slang use of Mary Jane for marijuana actually has its roots in biology: the female cannabis plant holds much more active THC than the male.)

There appears to be a temporal relationship between marijuana smoke inhalation and myocardial infarction (MI). Back in 2001, Mittleman et al. addressed this relationship by interviewing 3,882 patients with acute MI an average of 4 days after symptom onset.² In the relatively small number of patients who reported smoking marijuana before symptom onset, there was a 4.8-fold elevated risk of MI over baseline in the 60 minutes after marijuana use. Similarly, a 4.2-fold increased risk of mortality was seen in regular marijuana users compared with nonusers following MI.³

Besides myocardial infarction, marijuana use has been temporally related to cardiac arrhythmias, sudden cardiac death, cardiomyopathy, stroke, transient ischemic attack, and arteritis.¹

This past April, Emilie Juoanjus, PharmD, PhD, and colleagues at the Centres d'Evaluation et d'Information sur la Pharmacodependance-Addictovigilance in France, presented a large case series that offers a little more insight into the link between marijuana use and serious CV complications.⁴

In France, serious cases of abuse and dependence associated with the use of psychoactive substances must by law be reported to the national system of the French Addictovigilance Network. The Network is comprised of 13 regional centers created in the early 1990s to offer reliable reports of abuse and pharmacodependence associated with drugs of abuse. Jouanjus et al. identified all cannabis-related cardiovascular complications reported to the Network from 2006 to 2010.

In total, just 1.8% of all cannabis-related reports were CV complications (35 of 1,979 events). That group of patients was mostly male (85.7%), and the mean age was 34.3 (± 9) years. Details of cardiovascular history and risk factors could be determined for 16 of 35 cases (46%); researchers found that nine subjects had a personal CV history and seven a family history. In patients in whom body mass index was assessed (31%), 54% were of normal weight, 36% were overweight, and only one was obese.

There were 22 cardiac complications (20 ACS and two heart rate disorders), 10 extracardiac peripheral complications (lower limb or juvenile arteriopathies and Buerger-like diseases), and three extracardiac cerebral complications (acute cerebral angiopathy, transient cortical blindness, and spasm of cerebral artery).

In nine of 35 cases (26%), the event led to death. None of those who died made it to the hospital, but were rather found dead or unconscious, with cannabis use indicated by toxicology or bystander report.

While the numbers were small, they appear to be growing: the percentage of cannabis-related cardiovascular complications (of all cannabis-related reports) increased from 1.1% in 2006 to 3.6% in 2010 (five cases in 2006, increasing to 11 cases in 2010).

Concluded Joaunjus et al.: "Despite the known underreporting, the rate of cannabis-related cardiovascular complications reported steadily rose during the past 5 years...The majority consisted of acute coronary syndromes and peripheral arteriopathies," consistent with previous findings and strengthening the conclusion that "cannabis use may be responsible for serious complications, in particular on the cardiovascular system.

"Given that cannabis is perceived to be harmless by the general public and that legalization of its use is debated, data concerning its danger must be widely disseminated," wrote the authors.

In an accompanying editorial, Shereif Rezkalla, MD, and Dr. Kloner expressed concern over this signal of increased events and the associated high death rate, particularly as they seemed to cluster in "very young patients with no other risk factors."⁵

While the exact mechanism of these events is unknown, no-reflow or cerebral artery spasm have been implicated as possible causes, noted Dr. Kloner. Still, the perception that marijuana is safe is "deep-seated in the public and even amongst some health professionals."

Instead, he advocates that to better understand the cardiovascular risks of marijuana before wider legalization efforts light up throughout the US, we might want to consider adopting a mandatory reporting system similar to that used in France.

"There is definitely a need for more serious research in this area—basic science research, observational studies, and controlled studies looking at the acute and chronic effects of marijuana on the structure and function of the heart and the vasculature—because there hasn't been much done," he stressed.

Don't Ask, Don't Tell in the ED

Ground zero for determining the adverse cardiovascular consequences of inhaled marijuana is likely the emergency department, but only if ED staff actually ask about it.

Yes, in an emergency you can't ask about everything. "I work in one of the busiest EDs in California and you have to move patients through, so if they come in with chest pain, you're not going to ask about their foot fungus," said Thomas F. Minahan, DO, in an interview with CardioSource WorldNews. "If there truly is an increase in infarct with smoking pot, we as ED physicians are missing it as a risk factor."

Dr. Minahan is an ED physician and the program director for the Emergency Medicine Residency Program at Arrowhead Regional Medical Center in Colton, CA, the second busiest ED in California, with an annual volume of 130,000 visits. He has both a professional and personal interest in marijuana (see Not Just a Rocky Mountain High).

"When I go to the bedside and think about drugs and coronary disease, I'm thinking about methamphetamines and cocaine," he said. "With marijuana, there is this perception that you can't have a respiratory arrest from it, and I don't think most ED docs think of it as having an association with cardiovascular events, so I don't think most of us even think to ask about it."

In terms of substance abuse, alcohol "outdoes" any other substance by far as a cause for ED visits, said Dr. Minahan, with methamphetamine-related issues also being prevalent. While he does see patients who are stoned, that's not usually what brings them into the ED. He added that most of his patients are far more willing to admit to marijuana use than cocaine or methamphetamine use. "And if they say they smoke it once a week, it's probably more like once a day."

Both Drs. Kloner and Minahan acknowledge that the ED would offer fertile ground to do research into possible cardiovascular effects of inhaled marijuana. Both have also tried to undertake marijuana-related research but it's gone up in smoke because, they say, it's an uphill slog from an administrative, financial, and regulatory perspective, in large part due to the fact that marijuana remains a Schedule 1 drug under the U.S. Controlled Substances Act.

The act categorizes substances as Schedule 1 if they have a high potential for abuse and no accepted medical use. Heroin and LSD are also classified as Schedule 1, while cocaine, methamphetamine, and prescription painkillers are classified as Schedule 2, a less restrictive classification. In June 2014, it was announced that the Food and Drug Administration was reviewing the scheduling on marijuana at the request of the Drug Enforcement Agency.⁶ The FDA reviewed marijuana's status for the DEA in 2001 and again in 2006 and recommended it remain Schedule 1.

"If Congress would move it out of Schedule 1, it would get a ton of study," said Dr. Minahan.

Potency and Acute Physiologic Effects

Even if we had more information about the effects of marijuana, would the research reflect current trends? The problem: today's pot is not the same marijuana the hippies and hipsters were smoking in the 1960s and 70s.

THC, or Δ9-tetrahydrocannabinol, is the main psychoactive component in marijuana. Cannabidiol (CBD) is one of at least 85 active cannabinoids in cannabis and is considered to have a wider scope of medical applications than THC. The THC content in cannabis cigarettes has risen exponentially over the last 3 decades and the use of more potent forms of cannabis has also increased.

Studies done in the 1970s showed an increase in heart rate after smoking marijuana, from an average of 66 bpm to 89 bpm. Systolic blood pressure also increased slightly, 5 to 10 mm Hg, but – and yes, it is a big but – the THC concentration of the marijuana used then was about 3%. The average now is approaching 20%. Many Baby Boomers reject out-of-hand the whole notion that pot is more potent today; they really need enlightenment before they light up: a quick perusal of a website that offers home delivery of cannabis product to Canadian users with "approved" medical need shows the ready availability of THC-potent marijuana ranging from 7% to 23%. Put that in your pipe and – well, actually don't.

"The pot dealers are extremely open about selectively breeding plants to high THC content," said Cynthia Kuhn, PhD, of the Duke Institute for Brain Sciences, Duke University. Indeed, there are competitions to see who can grow the highest THC content product, advertised (no kidding!) as "Lab Tested, Stoner Approved."⁷ A recent winning strain, called A-Dub, boasts a THC concentration of 27.72% and is produced by the "Southern California Patients Association." (Still, not kidding.)

"If people were having tachycardia with lower THC pot, imagine the response to the much more potent stuff they're using now," said Dr. Kuhn. "I don't think cardiologists have really thought of this as a risk factor and yet they think of things like caffeine as a risk factor, which can also produce mild tachycardia in some people."

The acute physiologic, subjective, and psychomotor effects of lower and higher THC marijuana was tested among recreational users by a group from the National Institute for Public Health and the Environment in The Netherlands.^8,9 Twenty men smoked four combined tobacco and cannabis products (commonly used in Europe) containing zero, 29.3, 49.1, and 69.4 mg of THC on 4 exposure days. The highest THC dose was equivalent to 23% THC marijuana.

Heart rate increased significantly with increasing THC dose (p < 0.001), and in 26 out of 54 non-placebo exposures (45%), the participant's heart rate exceeded 140 bpm. Three subjects were obliged to stop smoking temporarily because their heart rate exceeded the maximum protocol-set limit of 170 bpm.

With the most potent THC cannabis cigarette, heart rate accelerations up to 121% above baseline (from 76 to 168 bpm) were seen. After the initial increase, which occurred in the first 12 minutes of smoking, heart rate decreased slowly for several hours after smoking. At 8 hours post-smoking, 14 of 20 participants still had increased heart rates relative to baseline.

Blood pressure was not significantly affected with higher versus lower THC cigarettes. However, in 13 out of 58 non-placebo exposures (22%), participants were placed in a supine position (during or just after smoking) due to symptoms of hypotension. Two subjects had to stop smoking temporarily because their diastolic blood pressures were approaching the lower limit of 55 mm Hg.

Not surprisingly, the most potent marijuana also increased the "high" feeling; but it also increased palpitations, impaired memory and concentration, and feelings of sedation. Sedation also lasted longer, increasing 5.7-fold at 8 hours post-pot for the highest THC dose compared to placebo. Response times were slowed and motor control worse, too, and both linearly, with increasing THC doses.

"Smokers tended to breathe deeper during the early puffs that resulted in quick effects on heart rate and blood pressure," wrote Hunault et al. They added that the nicotine in the joints might have increased the heart rate response and decreased the blood pressure response, but that the effects of higher THC doses were clearly seen even in participants already accustomed to smoking more potent marijuana/tobacco cigarettes.

Dr. Kuhn doesn't expect the risk level for the average person smoking pot occasionally to be very high, but worries more about people who are smoking large amounts of very high potency pot as well as recreational use in individuals with CV risk factors.

Those two groups may be joining in joint rolling more than we think. "One of the demographics of this country in which pot use is rising are the over 65 group because baby boomers are retiring—this is my interpretation—and we were the first generation to smoke pot in college," she said. "Most, on average, stopped as they got older, but as people have (retired), the use of illicit drugs rises a bit and the aging cohort have more CV risk factors. That's a worry to cardiologists in terms of guiding their patients."

"So it's not the smoking gun—so to speak—of terrible potentially lethal toxicity but it's a concern that's really been understudied," she said.

High Times for Big Marijuana

Worldwide, marijuana is the most widely produced and used illicit drug.¹⁰ In 2013, 39% of American college students indicated they'd used an illicit drug in the preceding year—up from 34% in 2006. Most of this rise is attributed to increasing use of marijuana.

Perhaps more importantly, daily or near-daily use of marijuana has also risen during the same period (from 3.5% to 5.1% among college students) and the perceived risk of regular use has decreased across all age cohorts, from 18 to 30 years of age.

To boot, a broad new survey released in August showed that fully 58% of American adults support marijuana legalization.¹¹ Besides the nearly one-half of all states that have passed medical-marijuana laws and the two—Colorado and Washington— that have legalized recreational use of marijuana, several more states have decriminalized possession of pot and/or are considering legalization for medicinal or recreational uses. And, if legalized across the country, proponents may not be half-baked when they contend that the annual tax revenue would amount to $3 billion.

Let's see: increasing use, decreasing perceived harmfulness of regular use, increasing support for legalization, and decriminalization spreading quickly across the country...what might be down the road for the US regarding marijuana?

Dr. Kuhn thinks the grand experiment has already begun.

"As I keep telling people when I talk about the consequences of legalization of pot use, we are kind of doing the experiment in Colorado and Washington right now."

References

1. Thomas G, Kloner RA, Rezkalla S. Am J Cardiol. 2014;113:187-90.
2. Mittleman MA, Lewis RA, Maclure M, Sherwood JB, Muller JE. Circulation. 2001;103:2805-9.
3. Mukamal KJ, Maclure M, Muller JE, Mittleman MA. Am Heart J. 2008;155:465-70.
4. Jouanjus E, Lapeyre-Mestre M, Micallef J; The French Association of the Regional Abuse and Dependence Monitoring Centres (CEIP-A) Working Group on Cannabis Complications. J Am Heart Assoc. 2014 Apr 23;3:e000638 doi: 10.1161/JAHA.113.000638.
5. Rezkalla S, Kloner RA. J Am Heart Assoc. 2014 Apr23;3:e000904 doi: 10.1161/JAHA.114.000904.
6. "Marijuana considered for looser restrictions by the U.S. FDA. Anna Edney. June 20, 2014. http://www.bloomberg.com/news/2014-06-20/drug-regulators-study-easing-u-s-marijuana-restrictions.html. Accessed on September 29, 2014.
7. "The Strongest Strains on Earth: 2014" http://www.hightimes.com/ss2013. Accessed on September 18, 2014.
8. Hunault CC, Mensinga TT, de Vries I, et al. Psychopharmacology 2008; 201: 171-81. Hunault CC, Mensinga TT, Bocker KB, et al. Psychopharmacology. 2009;204:85-94.
9. Hunault CC, Bocker KB, Stellato RK, Kenemans JL, de Vries I, Meulenbelt J. Psychopharmacology. 2014;epublished May 31.
10. United Nations Office on Drugs and Crime Discussion Paper. Cannabis: A Short Review. Available at: http://www.unodc.org/documents/drug-prevention-and-treatment/cannabis_review.pdf. Accessed on September 18, 2014.
11. CivicScience Insight Report. http://civicscience.com/wp-content/uploads/2014/09/Insight-Report-Marijuana-Legalization-Supporters-Sept-2014.pdf. Accessed on September 19, 2014.

Keywords: Appetite, Ischemic Attack, Transient, Overweight, Risk Factors, Lower Extremity, Los Angeles, Marijuana Abuse, Cerebral Arteries, Mandatory Reporting, France, Illicit Drugs, California, Cardiomyopathies, Euphoria, Cannabis, Death, Sudden, Cardiac, Arrhythmias, Cardiac, Arteritis, Spasm, Myocardial Infarction, Stroke, Blindness, Cortical, Cardiovascular System, Vasospasm, Intracranial, Heart Rate, Smoking, Body Mass Index, Marijuana Smoking

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