**3. Cannabis**

Because of its accessibility and legality of use in many countries, cannabis, also known as "marijuana" or "hashish," is the most consumed drug in Tunisia and all over the world [1, 2]. Cardiovascular complications of cannabis use rose from 1.1 to 3.6% between 2006 and 2010 among 9936 abusers according to the French Addictovigilance Network, most of them presenting with an acute coronary syndrome, while two patients had cardiac arrhythmia [35]. Due to its widespread use and of possible harmful cardiovascular impact reported in many case and series reports, cardiologists should be sensitized to detect its potential dangerous effects and be able to prevent and manage them properly.

Cannabis is rapidly absorbed through the lungs and less so with ingestion. The effects of the drug can last up to 6 hours with the onset of arrhythmias beginning anywhere from within a few minutes to a few hours of smoking and with a peak at 30 minutes [36].

Delta-9-tétrahydrocannabinol (Δ-9-THC), the active agent of cannabis, exercises its action via the cannabinoid system with its two receptors CB1 and CB2. This system induces modifications of the regulation of the autonomic nervous system leading to cardiovascular consequences and of central nervous system resulting in psychoneurological effects [37, 38].

Finally, we should note that the burden of this problem is possibly underestimated given euphoric and neuropsychological effects of marijuana that may cover palpitations, possible occurrence of unnoticed short episodes of AF and because of social and legal reasons leading most users of illicit drugs to avoid seeking medical attention [43]. AF onset in young patients without structural heart disease should pay attention to an eventual illicit drug abuse. Its identification is very important because drug cessation will protect against AF recurrences.

**Figure 3.** ECG showing a ventricular tachycardia at 170 beats/min with left bundle branch block pattern and left QRS

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In contrast, at higher doses, parasympathetic activity is increased causing bradycardia and

Bradyarrhythmias such as sinus bradycardia and higher-degree atrioventricular block have been reported. And, these conduction disturbances were reversible 72 hours after drug ces-

The most described parasympathetic complication of cannabis abuse is vasovagal and postural syncope leading in some cases to sinus asystole. In a randomized controlled trial where 29 volunteers had participated, the effects of THC infusion and marijuana smoking when reclining and standing were studied. Both THC and marijuana-induced postural dizziness, with 28% reporting severe symptoms immediately after drug administration. The severe dizziness group showed the most marked postural drop in cerebral blood velocity and blood pressure and showed a drop in pulse rate after an initial increase during standing [45, 46].

The risk of myocardial infarction (MI) is 4.8-fold increased in the first hour following marijuana use [47]. Urgent coronary angiography practiced in these victims of cannabis-induced MI may show angiographically normal coronary arteries supposing a spastic mechanism or an increased myocardial oxygen demand due to increased sympathetic activity. Coronary

**3.2. Increase in parasympathetic activity**

axis in a 39-year-old man with a history of chronic cannabis use.

hypotension [36].

**3.3. Acute coronary syndrome**

sation [44].

Most published reports have focused on incidents of acute coronary syndromes and acute cerebrovascular and peripheral vascular events. However, an increasing number of case reports indicate an association between cannabis use and cardiac arrhythmias mainly atrial fibrillation (AF) and ventricular arrhythmias (**Figure 3**) [39]. Management and reversibility of these arrhythmias are similar to those induced by cocaine abuse and will not be re-explained in this chapter.

In fact, cannabis has a biphasic effect on the autonomic nervous system.

#### **3.1. Increase in sympathetic activity**

At low to moderate doses, THC leads to an increase in sympathetic activity causing sinus tachycardia with a rise of 20–100% of the heart rate, premature ventricular beats associated with increased cardiac output and hypertension [36]. The concept of sympathetic activation is supported by studies demonstrating an increased urinary excretion of epinephrine after THC use [40].

Atrial fibrillation is another complication of acute cannabis intoxication. A recent study focused on causes of atrial fibrillation in young people ≤45 years old. Among 88 patients, 22 of them, the atrial fibrillation was directly related to alcohol (86.4%), cannabis (13.6%), or cocaine abuse (4.5%) [41]. In a systematic review published in 2008, six reported cases were analyzed. In all instances, AF was of recent onset occurring shortly after marijuana smoking in young subjects. No patient had a structural heart disease, and only one had a precipitating factor (hypertension); all patients had a favorable outcome with no recurrence after cessation of marijuana smoking [42]. Of note, adrenergic stimulation and disturbances in atrial coronary or microvascular flow associated with marijuana smoking may facilitate AF development and perpetuation possibly because of increased pulmonary vein ectopy, enhanced atrial electrical remodeling, and increased dispersion of refractoriness [42]. It should also be stressed that although this adverse event seems to be quite "benign" in young healthy subjects, it is apparently more "malignant" in older patients having other risk factors for thromboembolism.

**Figure 3.** ECG showing a ventricular tachycardia at 170 beats/min with left bundle branch block pattern and left QRS axis in a 39-year-old man with a history of chronic cannabis use.

Finally, we should note that the burden of this problem is possibly underestimated given euphoric and neuropsychological effects of marijuana that may cover palpitations, possible occurrence of unnoticed short episodes of AF and because of social and legal reasons leading most users of illicit drugs to avoid seeking medical attention [43]. AF onset in young patients without structural heart disease should pay attention to an eventual illicit drug abuse. Its identification is very important because drug cessation will protect against AF recurrences.

#### **3.2. Increase in parasympathetic activity**

**3. Cannabis**

182 Cardiac Arrhythmias

Because of its accessibility and legality of use in many countries, cannabis, also known as "marijuana" or "hashish," is the most consumed drug in Tunisia and all over the world [1, 2]. Cardiovascular complications of cannabis use rose from 1.1 to 3.6% between 2006 and 2010 among 9936 abusers according to the French Addictovigilance Network, most of them presenting with an acute coronary syndrome, while two patients had cardiac arrhythmia [35]. Due to its widespread use and of possible harmful cardiovascular impact reported in many case and series reports, cardiologists should be sensitized to detect its potential dangerous

Cannabis is rapidly absorbed through the lungs and less so with ingestion. The effects of the drug can last up to 6 hours with the onset of arrhythmias beginning anywhere from within a

Delta-9-tétrahydrocannabinol (Δ-9-THC), the active agent of cannabis, exercises its action via the cannabinoid system with its two receptors CB1 and CB2. This system induces modifications of the regulation of the autonomic nervous system leading to cardiovascular consequences and of central nervous system resulting in psychoneurological effects [37, 38].

Most published reports have focused on incidents of acute coronary syndromes and acute cerebrovascular and peripheral vascular events. However, an increasing number of case reports indicate an association between cannabis use and cardiac arrhythmias mainly atrial fibrillation (AF) and ventricular arrhythmias (**Figure 3**) [39]. Management and reversibility of these arrhythmias are similar to those induced by cocaine abuse and will not be re-explained in this chapter.

At low to moderate doses, THC leads to an increase in sympathetic activity causing sinus tachycardia with a rise of 20–100% of the heart rate, premature ventricular beats associated with increased cardiac output and hypertension [36]. The concept of sympathetic activation is supported by

Atrial fibrillation is another complication of acute cannabis intoxication. A recent study focused on causes of atrial fibrillation in young people ≤45 years old. Among 88 patients, 22 of them, the atrial fibrillation was directly related to alcohol (86.4%), cannabis (13.6%), or cocaine abuse (4.5%) [41]. In a systematic review published in 2008, six reported cases were analyzed. In all instances, AF was of recent onset occurring shortly after marijuana smoking in young subjects. No patient had a structural heart disease, and only one had a precipitating factor (hypertension); all patients had a favorable outcome with no recurrence after cessation of marijuana smoking [42]. Of note, adrenergic stimulation and disturbances in atrial coronary or microvascular flow associated with marijuana smoking may facilitate AF development and perpetuation possibly because of increased pulmonary vein ectopy, enhanced atrial electrical remodeling, and increased dispersion of refractoriness [42]. It should also be stressed that although this adverse event seems to be quite "benign" in young healthy subjects, it is apparently more "malignant" in older patients having other risk factors for thromboembolism.

studies demonstrating an increased urinary excretion of epinephrine after THC use [40].

effects and be able to prevent and manage them properly.

few minutes to a few hours of smoking and with a peak at 30 minutes [36].

In fact, cannabis has a biphasic effect on the autonomic nervous system.

**3.1. Increase in sympathetic activity**

In contrast, at higher doses, parasympathetic activity is increased causing bradycardia and hypotension [36].

Bradyarrhythmias such as sinus bradycardia and higher-degree atrioventricular block have been reported. And, these conduction disturbances were reversible 72 hours after drug cessation [44].

The most described parasympathetic complication of cannabis abuse is vasovagal and postural syncope leading in some cases to sinus asystole. In a randomized controlled trial where 29 volunteers had participated, the effects of THC infusion and marijuana smoking when reclining and standing were studied. Both THC and marijuana-induced postural dizziness, with 28% reporting severe symptoms immediately after drug administration. The severe dizziness group showed the most marked postural drop in cerebral blood velocity and blood pressure and showed a drop in pulse rate after an initial increase during standing [45, 46].

#### **3.3. Acute coronary syndrome**

The risk of myocardial infarction (MI) is 4.8-fold increased in the first hour following marijuana use [47]. Urgent coronary angiography practiced in these victims of cannabis-induced MI may show angiographically normal coronary arteries supposing a spastic mechanism or an increased myocardial oxygen demand due to increased sympathetic activity. Coronary arteries may also be very thrombotic with or without atherosclerotic plaque rupture. Finally, a no-flow or slow-flow with normal appearing epicardial vessels was reported as well [48]. Ventricular tachycardia and sudden cardiac death were reported as a complication of cannabis-induced MI [49].

ectopy and tachycardia were all reported. ECGs of 511 opioid addicts were analyzed. The main anomalies detected were sinus bradycardia, type-1 atrioventricular block, wandering atrial pacemaker, supraventricular and ventricular ectopic beats, and QT prolongation [58].

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Methadone is another synthetic opioid used for the treatment of opioid addiction and for its analgesic effect. Methadone is responsible for QT prolongation and occurrence of torsade de pointes (TdP) especially when QT interval exceeds 500 ms. TdP should always be suspected in patients receiving methadone and presenting with syncope [59, 60]. Correction of predisposing factors as hypokalemia and hypomagnesemia is recommended, in case of prolonged QT and TdP. Magnesium perfusion is proposed, even in case of normal serum magnesium

Lysergic acid diethylamide (LSD) and psilocybin "magic mushrooms" are commonly used hallucinogenic agents in developed countries. LSD is about 100 times more potent than psilocybin. Their mechanisms of action are complex and include agonist, partial agonist, and antagonist effects at various serotonin, dopaminergic, and adrenergic receptors. The adrenergic effects are usually mild and do not produce the profound sympathetic storms that can occur after taking cocaine, amphetamine, or ecstasy. Besides common sinus tachycardia, cardiovascular complications are rarely serious, although occasional instances of supraventricu-

Inhalant abuse is the intentional inhalation of chemical vapors by sniffing, snorting, bagging, or huffing the substance to attain a euphoric effect. Spray paints, shoe polish, dust-off spray, glue, and lighter fluids are some products commonly abused by people. Glue sniffing has become a widespread form of inhalant abuse, usually among in adolescents and

Studies have indicated that about 20% of children in middle and high schools have experimented with inhalant substances [63]. These products are cheap, easily accessible at home, school, and workplace, and they are legal for all age groups (e.g., glue). Many common household products containing halogenated hydrocarbon like 1,1-difluoroethane (DFE) (known as Freon 152A used in refrigeration, dust-off spray, and airbrush painting) and toluene (used in

Halogenated hydrocarbon abuse can cause a fatal malignant arrhythmia, termed "sudden sniffing death." Cardiotoxic effects have been described in human and in animal models [64]. Avella et al. [65] have demonstrated different levels in DFE tissues in the brain and heart, but the DFE level in the heart remained higher than the brain tissue after approximately

concentration. Alternative drugs can be used when corrected QT exceeds 500 ms [59].

lar tachyarrhythmias and myocardial infarction have been reported [61, 62].

**6. Lysergic acid diethylamide and psilocybin**

glues) are abused by inhalation for euphoric effects [64].

**7. Inhalent abuse**

young adults.

#### **3.4. Sodium channel blockade**

A Brugada-like effect was reported to be associated to cannabis intoxication as described with cocaine abuse [50–52]. This ECG pattern is believed to be related to a partial sodium channel antagonist activity. The ST segment normalizes once the acute intoxication is resolved.
