Pharmacology Consult

Synthetic marijuana poses risk for cardiotoxicity

In conjunction with the growth in legally accessibly marijuana in many regions of the United States, a significant increase in marijuana-like synthetic compounds, or synthetic cannabinoids, has also occurred in the past 5 to 10 years.

This spike in usage is likely multifactorial and may relate to the relative ease of access and the hundreds of available products currently on the market. However, the key attributable factors appear to be the inability to detect synthetic marijuana compounds on standard urine drug screens and the overwhelming public opinion that synthetic products are safer than more traditional forms of marijuana.

Michael J. Scalese

In contrast to the latter common perception, a large rise in adverse effects is being observed after acute ingestion of one of the many available synthetic formulations. In fact, it is estimated that more than 7,000 cases of intoxication secondary to synthetic marijuana requiring medical attention have occurred annually in the past few years.

Dangers to the CV system

Most cases of acute intoxication have not resulted in significant damage requiring medical intervention. However, such cases are on the rise and may impact a variety of organ systems, including the CV, neurologic, gastrointestinal, pulmonary, cerebrovascular, renal and ophthalmologic systems. Some of the most severe and life-threatening reactions have engrossed the CV system and have been the focus of many case reports and/or case series in recent years. Understanding the physiology and pharmacology of these synthetic compounds will allow preemptive screening and mitigation of potential adverse reactions.

Like marijuana, synthetic compound interact with cannabinoid receptors and are primarily responsible for the psychoactive and toxic effects. Specifically, tetrahydrocannabinol (THC) and synthetic compounds exert their activity through two primary binding sites within the endocannabinoid pathway resulting in diverse activity based on the receptors’ location. Cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 (CB2R) are membrane-based, G protein-coupled receptors with very different physiological effects and a wide distribution in the body. For example, CB2R is most commonly expressed in the immune system in association with immune-derived cells in circulation. As a result, CB2R stimulation may be cardioprotective through anti-inflammatory properties and is currently the target for some investigational therapies.

Most synthetic THC has a higher binding affinity for CB1R than CB2R, thereby negating any potential benefit with a more predominating adverse stimulus. CB1R is one of the most abundant G protein-coupled receptors in the human brain and is responsible for eliciting the psychoactive effects of THC. A lower yet very functional concentration of CB1R has also been located in peripheral tissues that mediate cardiac, vascular and neurotoxicity. To date, receptors have been discovered in myocytes, vascular smooth muscle and endothelial cells, circulating blood cells and platelets, and afferent vagal neurons innervating various conduits in the CV system. Activation of CB1R with varying degrees of potency is linked to a variety of negative CV outcomes (Figure). The most common sequelae are ischemia resulting from thromboembolic or vasospastic mechanisms. The adverse pathways are not mutually exclusive and may be activated in varying combinations depending on the compounds present in any given product. The resulting effects may employ a variety of clinical presentations and pathophysiological complications.

More than 60 case reports have been published to date describing negative CV effects temporally linked to ingestion of synthetic marijuana compounds. The observed reactions range in severity from minor and requiring observation to those requiring emergent patient stabilization or intervention. There is little consistency in patient characteristics across case reports and adverse cardiac effects appear to occur independent of underlying CVD. In fact, many reports describe relatively healthy individuals in the second or third decade of life.

Risks underreported

Even with the recent increase in reporting, the risks may be significantly underreported due to the difficulty in identifying synthetic marijuana as a contributing factor. None of these compounds return a positive result on standard urine drug screens and require specialty testing for detection. This can make objective identification very difficult and may explain for recent popularity.

The lack of ability to objectively evaluate recent use of synthetic marijuana highlights the importance of the subjective information obtained from the patient at presentation. While patient honesty may not be the most reliable, a focused patient interview is likely the most advantageous way to obtain relevant information.

Spending time discussing the use of illicit substances with patients at admission and educating them on their risks before discharge is of utmost importance. Doing so can help ascertain otherwise identifiable illicit drug use and help prevent future adverse CV events.

Disclosure: Scalese reports no relevant financial disclosures.

In conjunction with the growth in legally accessibly marijuana in many regions of the United States, a significant increase in marijuana-like synthetic compounds, or synthetic cannabinoids, has also occurred in the past 5 to 10 years.

This spike in usage is likely multifactorial and may relate to the relative ease of access and the hundreds of available products currently on the market. However, the key attributable factors appear to be the inability to detect synthetic marijuana compounds on standard urine drug screens and the overwhelming public opinion that synthetic products are safer than more traditional forms of marijuana.

Michael J. Scalese

In contrast to the latter common perception, a large rise in adverse effects is being observed after acute ingestion of one of the many available synthetic formulations. In fact, it is estimated that more than 7,000 cases of intoxication secondary to synthetic marijuana requiring medical attention have occurred annually in the past few years.

Dangers to the CV system

Most cases of acute intoxication have not resulted in significant damage requiring medical intervention. However, such cases are on the rise and may impact a variety of organ systems, including the CV, neurologic, gastrointestinal, pulmonary, cerebrovascular, renal and ophthalmologic systems. Some of the most severe and life-threatening reactions have engrossed the CV system and have been the focus of many case reports and/or case series in recent years. Understanding the physiology and pharmacology of these synthetic compounds will allow preemptive screening and mitigation of potential adverse reactions.

Like marijuana, synthetic compound interact with cannabinoid receptors and are primarily responsible for the psychoactive and toxic effects. Specifically, tetrahydrocannabinol (THC) and synthetic compounds exert their activity through two primary binding sites within the endocannabinoid pathway resulting in diverse activity based on the receptors’ location. Cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 (CB2R) are membrane-based, G protein-coupled receptors with very different physiological effects and a wide distribution in the body. For example, CB2R is most commonly expressed in the immune system in association with immune-derived cells in circulation. As a result, CB2R stimulation may be cardioprotective through anti-inflammatory properties and is currently the target for some investigational therapies.

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Most synthetic THC has a higher binding affinity for CB1R than CB2R, thereby negating any potential benefit with a more predominating adverse stimulus. CB1R is one of the most abundant G protein-coupled receptors in the human brain and is responsible for eliciting the psychoactive effects of THC. A lower yet very functional concentration of CB1R has also been located in peripheral tissues that mediate cardiac, vascular and neurotoxicity. To date, receptors have been discovered in myocytes, vascular smooth muscle and endothelial cells, circulating blood cells and platelets, and afferent vagal neurons innervating various conduits in the CV system. Activation of CB1R with varying degrees of potency is linked to a variety of negative CV outcomes (Figure). The most common sequelae are ischemia resulting from thromboembolic or vasospastic mechanisms. The adverse pathways are not mutually exclusive and may be activated in varying combinations depending on the compounds present in any given product. The resulting effects may employ a variety of clinical presentations and pathophysiological complications.

More than 60 case reports have been published to date describing negative CV effects temporally linked to ingestion of synthetic marijuana compounds. The observed reactions range in severity from minor and requiring observation to those requiring emergent patient stabilization or intervention. There is little consistency in patient characteristics across case reports and adverse cardiac effects appear to occur independent of underlying CVD. In fact, many reports describe relatively healthy individuals in the second or third decade of life.

Risks underreported

Even with the recent increase in reporting, the risks may be significantly underreported due to the difficulty in identifying synthetic marijuana as a contributing factor. None of these compounds return a positive result on standard urine drug screens and require specialty testing for detection. This can make objective identification very difficult and may explain for recent popularity.

The lack of ability to objectively evaluate recent use of synthetic marijuana highlights the importance of the subjective information obtained from the patient at presentation. While patient honesty may not be the most reliable, a focused patient interview is likely the most advantageous way to obtain relevant information.

Spending time discussing the use of illicit substances with patients at admission and educating them on their risks before discharge is of utmost importance. Doing so can help ascertain otherwise identifiable illicit drug use and help prevent future adverse CV events.

Disclosure: Scalese reports no relevant financial disclosures.