David Streem, MD

Most people assume that electronic cigarettes (e-cigarettes) are safer than conventional tobacco products. Nevertheless, we should not encourage addicted smokers to try “vaping” as an alternative to nicotine replacement therapy, and we should discourage never-smokers from taking up vaping as vigorously as we try to discourage them from taking up smoking.

This article examines the prevailing assumptions and the evidence regarding the safety of e-cigarettes and traditional nicotine replacement therapy.

SMOKING IS DECLINING BUT FAR FROM GONE

While smoking rates have been declining over the past 50 years, the burden of disease attributable to tobacco use remains high. In the United States, it is estimated that nearly 6 million of those currently under the age of 18 will die of tobacco-related illnesses.¹ In the 50 years since the US surgeon general first reported on the health concerns related to tobacco, smoking has claimed the lives of nearly 21 million Americans¹ and continues to kill more than 400,000 every year.²

Even though the risks of smoking are well known, smoking remains one of the most difficult habits to quit. Indeed, about half of all smokers attempt to quit each year, but very few succeed.³

NICOTINE REPLACEMENT: GUM, PATCHES…E-CIGARETTES?

Smoking continues to kill more than 400,000 Americans every year

Nicotine replacement therapy was born out of the thought that, though nicotine is responsible for tobacco’s addictive quality, most tobacco-related disease is attributable to the 7,000 other substances found in tobacco smoke.⁴ Nicotine polacrilex gum was approved by the US Food and Drug Administration (FDA) in 1984, and nicotine transdermal film was approved in 1991.⁵

Nicotine replacement therapy, in the form of patches and gum, has been shown to improve the odds of successfully quitting smoking by a factor of nearly 1.5 to 2.⁶ Nicotine patches and gum were initially prescription medications but became available over the counter in 1996.⁷ They quickly became first-line agents for smoking cessation, and their over-the-counter availability softened any potential concerns about the possible deleterious health consequences of nicotine itself.

E-cigarettes—devices that generate a nicotine vapor that can be inhaled in a fashion that mimics the experience of smoking—were introduced in China in 2004.⁸ By 2012, sales of these devices in the United States had reached $500 million and in 2013 were expected to top $1 billion.^9,10

E-cigarette manufacturers make no therapeutic claims about their products, thus allowing them to escape regulation by the FDA as nicotine replacement therapy. A recent FDA proposal, however, is likely to change their “protected” status.¹¹ Despite the lack of regulation up to this point, patients generally assume that e-cigarettes are just another form of nicotine replacement therapy, even though they contain substances other than nicotine.

WHAT’S IN E-CIGARETTES?

Nicotine, which is bad in itself

E-cigarettes contain nicotine in varying amounts (some cartridges contain none at all). Though nicotine replacement therapy is less harmful than tobacco, nicotine by itself is associated with its own health problems, notably cancer, cardiovascular disease, birth defects (possibly), and poisoning.

Carcinogenesis. Nicotine plays a direct role in carcinogenesis through a variety of mechanisms, including increasing the activity of tumor growth-promoting transcription factors, decreasing apoptosis, and increasing angiogenesis in tumors.¹² Additionally, specific types of nicotinic acetylcholine receptors— eg, alpha 7 receptors, which are stimulated by nicotine—are found in many malignant tumors and are thought to play a role in tumor progression.¹² Blockade of alpha 7 nicotinic acetylcholine receptors has been shown to decrease the growth of certain cancers.¹²

However, these findings were from in vitro studies, and the concerns they raised have not been reflected in in vivo studies. Despite having been on the market for 30 years, nicotine replacement therapy has as yet not been associated with any “real world” increase in cancer risk.

Smoking is one of the leading risk factors for cervical cancer, and nicotine itself may play a contributing role. Nicotine has been shown to increase cellular proliferation in cervical cancer.¹³ Some evidence suggests that it may also play a role in the lymphogenic metastasis of cervical cancer.¹³

Cardiovascular disease. Nicotine has been linked to cardiovascular disease. It directly affects the heart’s rate and rhythm via nicotinic acetylcholine receptors in the peripheral autonomic nervous system. It impairs endothelial-dependent dilation of blood vessels in response to nitric oxide, and this inhibition in the coronary arteries may contribute to smoking-related heart disease.^14,15 Nicotine has also been shown to raise serum cholesterol levels, increase clot formation, and contribute to plaque formation by increasing vascular smooth muscle.¹⁴

Possible teratogenic effect. There is some theoretical concern regarding exposure to nicotine in utero, as nicotinic acetylcholine receptors develop before neurons, and nicotine may therefore interfere with the natural influence of acetylcholine on the development of this system.¹⁴

Consuming one vial of e-cigarette fluid could be fatal

Direct toxicity. Nicotine is toxic at high levels. The overdose potential associated with nicotine is particularly worrisome with e-cigarettes, as the nicotine solution they use is typically supplied in 5-mL, 10-mL, or 20-mL vials that range in concentration from 8.5 to 22.2 mg of nicotine per mL.¹⁶ The fatal single dose range of nicotine has been reported at 30 to 60 mg in adults and 10 mg in children and can be achieved by oral, intravenous, or transdermal absorption,¹⁶ so one vial, if consumed orally, could be fatal.

The number of calls to US poison control centers regarding e-cigarettes has increased, closely paralleling their rise in popularity. In 2010, there were only 30 e-cigarette related calls to poison control centers; in 2011 the number increased to 269, and in 2012 it had reached 459 and included one fatality that was deemed a suicide.^17–19 Even though such toxic nicotine overdoses are rare, physicians should exercise caution and avoid recommending e-cigarettes to individuals with mental confusion, psychotic disorders, or suicidality, who might consume an entire vial.

Possible positive effects? Smoking is one of the worst things that people can do to their body, but the picture is complicated by a few possible positive effects. In the brain, although smoking increases the risk of Alzheimer disease, it is associated with a lower risk of Parkinson disease. In the bowel, it increases the risk of Crohn disease but may decrease the risk of ulcerative colitis. Gahring and Rogers²⁰ pointed out that neuronal nicotinic receptors are present in nonneuronal cells throughout the body and proposed that expression of these receptors may play a role in mediating the consequences of nicotine use, both good and bad. The lesson may be that nicotine is very active in the body, its effects are complicated and still incompletely understood, and therefore we should not encourage people to inhale nicotine products ad lib.

Additives

E-cigarettes typically contain propylene glycol, flavorings, and glycerine. One study that analyzed the additive contents of e-cigarettes found that propylene glycol accounted for 66% of the fluid, glycerine 24%, and flavorings less than 0.1%.²¹ Propylene glycol is the substance typically used in theater fog machines and is used to generate the vapor in e-cigarettes. Other substances such as tobacco-specific nitrosamines and diethylene glycol have also been found in e-cigarettes in small amounts.²²

Propylene glycol, ‘generally recognized as safe’

Propylene glycol has been used in theater fog machines for years—think Phantom of the Opera. It is also widely used as a solvent in many consumer products and pharmaceuticals. The FDA classified it as “generally recognized as safe” on the basis of one study conducted in rats and monkeys over 60 years ago.²³ As other authors have noted, however, a major manufacturer of propylene glycol recommends that exposure to propylene glycol mist be avoided.^24,25 Potential concern over propylene glycol mist was heightened when it was discovered that of all industries, the entertainment business ranked first in terms of work-related asthma symptoms and had the fifth-highest rate of wheezing.^26,27

Studies conducted over the last several decades have raised numerous health concerns about the safety of propylene glycol (Table 1).^26,28–36 The studies of propylene glycol fog are particularly important, as they most closely resemble the route of exposure in e-cigarette users.

Wieslander et al²⁸ exposed 27 volunteers to propylene glycol mist for 1 minute in an aircraft simulator under training conditions. Exposures were high, ranging from 176 to 851 mg/m³ (mean = 309 mg/m³). Four volunteers who developed a cough exhibited evidence of airway obstruction as indicated by a 5% decrease in forced expiratory volume in 1 second (FEV₁), while the rest did not exhibit any change in FEV₁.

Moline et al²⁹ conducted a non-peer-reviewed study for the Actors Equity Association and the League of American Theaters and Producers of 439 actors exposed to theater fog. They found statistically significant evidence of throat and vocal cord inflammation with prolonged peak exposure to glycols and recommended that actors not be exposed to glycol concentrations exceeding 40 mg/m³.

Varughese et al²⁶ conducted a study in 101 volunteers at 19 sites. The mean concentration of glycol-based fog was much lower than that in the studies by Wieslander et al²⁸ and Moline et al,²⁹ at 0.49 mg/m³ (the maximum was 3.22 mg/m³). The investigators concluded that glycol-based fog was associated with deleterious respiratory effects and that employees’ exposure should be limited.

The health issues related to propylene glycol are unique to e-cigarettes compared with nicotine replacement therapy. Unfortunately, the most applicable data available are from studies of persons exposed to theater fog, which involved periodic exposure and likely do not emulate the deep inhalation, multiple times daily, of propylene glycol by e-cigarette smokers. A 2014 review of the chemistry of contaminants in e-cigarettes³⁷ concluded that estimated levels of propylene glycol exposure in e-cigarette users come close to the threshold limit value set by the American Conference of Governmental Industrial Hygienists, and should merit concern.

These studies and real-life experience in the theater, while limited in scope, should give physicians pause and should cause increased awareness of the possibility of e-cigarette-induced pulmonary and upper airway complications. If such complications should occur, discontinuation of vaping should be advised.

Contaminants

The issue of adulterants is common to both e-cigarettes and nicotine replacement therapy. Several unlisted substances have been found in analyzed samples of e-cigarette fluid, including tobacco-specific nitrosamines (TSNAs), diethylene glycol (found in only one e-cigarette cartridge), cotinine, anabasine, myosmine, and beta-nicotyrine.²² The tobacco-specific nitrosamines N´-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N-nitrosoanabasine, and nitrosoanatabine have been found in five e-cigarette cartridge samples from two manufacturers in amounts similar to those found in nicotine replacement products.²²

Goniewicz et al³⁸ tested the vapor generated by 12 e-cigarette brands and found trace amounts of TSNAs. NNN was present in the vapor of eight of the samples in concentrations ranging from 0.8 to 4.3 ng per 150 puffs, and NNK in the vapor of nine of the samples in concentrations ranging from 1.1 to 28.3 ng per 150 puffs. Neither NNN nor NNK was found in blank samples nor with the Nicorette inhalator tested in the same study.³⁸

Because TNSAs can be formed from nicotine and its metabolites, there is also concern that cancer-causing nitrosamines may be formed from nicotine after it is absorbed into the body (ie, endogenously). While endogenous formation of NNK from nicotine has never been demonstrated, endogenous formation of NNN has been seen in some nicotine patch users.³⁹ The presence of these nitrosamines has raised concern that e-cigarettes and nicotine replacement therapy may have carcinogenic potential. The amounts of tobacco-specific nitrosamines found in e-cigarettes are also found in some nicotine replacement products.⁴⁰

Investigators have examined a possible connection between e-cigarettes and potentially carcinogenic carbonyl compounds, including formaldehyde, acetaldehyde, and acrolein. Formaldehyde (a known carcinogen) and acetaldehyde (a potential carcinogen) have been detected in e-cigarette cartridges and vapor.^38,41–43 Acrolein, a mucosal irritant, has been found in e-cigarette vapor.^38,43 Goniewicz et al³⁸ suggested that acrolein may be formed by the heating of the glycerin contained in the e-cigarette solution.

An extensive review of the studies of possible contaminant exposures (including polycylic aromatic hydrocarbons, TSNAs, volatile organic compounds, diethylene glycol, and inorganic compounds) with e-cigarette use according to occupational hygiene standards concluded that there was no cause for concern about increased health risk.³⁷ The study by Goniewicz et al also concluded that using e-cigarettes instead of traditional cigarettes may significantly reduce exposure to some tobacco-specific toxins.³⁸

E-CIGARETTES VS NICOTINE REPLACEMENT

Traditional nicotine replacement therapy products are regulated by the FDA and therefore standardized in terms of their contents. E-cigarettes, on the other hand, are unregulated vehicles for supplying nicotine, and may pose other health risks. One such risk is related to exposure to propylene glycol, which has never been studied under conditions (in terms of mode of delivery, frequency of dosing, and total duration of exposure) that approximate the exposure associated with e-cigarettes. Furthermore, the high concentration of nicotine in e-cigarette fluid poses a real risk of toxicity and potentially fatal overdose.

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine if used in a harm-reduction strategy as a maintenance medication. Whether the ongoing nicotine addiction makes it more likely that individuals would switch back and forth between nicotine replacement and tobacco-based products is not clear. Also not known is whether e-cigarettes may serve as the “gateway drug” by which teens enter into nicotine addiction, but we believe that the potential exists, as these products are potentially more appealing in terms of the lack of pungent smell, the perception of safety, and the variety of flavors of e-cigarettes.

The efficacy of nicotine replacement therapy in improving smoking cessation has been reviewed extensively elsewhere³⁷ and is beyond the scope of this article. E-cigarettes may be appealing to many cigarette smokers because they deliver smokeless nicotine, and they more closely emulate the actual experience of smoking compared with traditional nicotine replacement therapy. Though some evidence suggests that e-cigarettes may be modestly effective in helping tobacco smokers quit nicotine, they are not FDA-approved for smoking cessation and are not marketed for that indication.⁴⁴ Medical practitioners should see them for what they are: a new nicotine product with a novel delivery system that is not approved as treatment. Because of the inherent risks involved with e-cigarettes, medical practitioners are best advised to remain neutral on the relative value of e-cigarettes and should continue to motivate patients to discontinue nicotine use altogether.

Most people assume that electronic cigarettes (e-cigarettes) are safer than conventional tobacco products. Nevertheless, we should not encourage addicted smokers to try “vaping” as an alternative to nicotine replacement therapy, and we should discourage never-smokers from taking up vaping as vigorously as we try to discourage them from taking up smoking.

This article examines the prevailing assumptions and the evidence regarding the safety of e-cigarettes and traditional nicotine replacement therapy.

SMOKING IS DECLINING BUT FAR FROM GONE

While smoking rates have been declining over the past 50 years, the burden of disease attributable to tobacco use remains high. In the United States, it is estimated that nearly 6 million of those currently under the age of 18 will die of tobacco-related illnesses.¹ In the 50 years since the US surgeon general first reported on the health concerns related to tobacco, smoking has claimed the lives of nearly 21 million Americans¹ and continues to kill more than 400,000 every year.²

Even though the risks of smoking are well known, smoking remains one of the most difficult habits to quit. Indeed, about half of all smokers attempt to quit each year, but very few succeed.³

NICOTINE REPLACEMENT: GUM, PATCHES…E-CIGARETTES?

Smoking continues to kill more than 400,000 Americans every year

Nicotine replacement therapy was born out of the thought that, though nicotine is responsible for tobacco’s addictive quality, most tobacco-related disease is attributable to the 7,000 other substances found in tobacco smoke.⁴ Nicotine polacrilex gum was approved by the US Food and Drug Administration (FDA) in 1984, and nicotine transdermal film was approved in 1991.⁵

Nicotine replacement therapy, in the form of patches and gum, has been shown to improve the odds of successfully quitting smoking by a factor of nearly 1.5 to 2.⁶ Nicotine patches and gum were initially prescription medications but became available over the counter in 1996.⁷ They quickly became first-line agents for smoking cessation, and their over-the-counter availability softened any potential concerns about the possible deleterious health consequences of nicotine itself.

E-cigarettes—devices that generate a nicotine vapor that can be inhaled in a fashion that mimics the experience of smoking—were introduced in China in 2004.⁸ By 2012, sales of these devices in the United States had reached $500 million and in 2013 were expected to top $1 billion.^9,10

E-cigarette manufacturers make no therapeutic claims about their products, thus allowing them to escape regulation by the FDA as nicotine replacement therapy. A recent FDA proposal, however, is likely to change their “protected” status.¹¹ Despite the lack of regulation up to this point, patients generally assume that e-cigarettes are just another form of nicotine replacement therapy, even though they contain substances other than nicotine.

WHAT’S IN E-CIGARETTES?

Nicotine, which is bad in itself

E-cigarettes contain nicotine in varying amounts (some cartridges contain none at all). Though nicotine replacement therapy is less harmful than tobacco, nicotine by itself is associated with its own health problems, notably cancer, cardiovascular disease, birth defects (possibly), and poisoning.

Carcinogenesis. Nicotine plays a direct role in carcinogenesis through a variety of mechanisms, including increasing the activity of tumor growth-promoting transcription factors, decreasing apoptosis, and increasing angiogenesis in tumors.¹² Additionally, specific types of nicotinic acetylcholine receptors— eg, alpha 7 receptors, which are stimulated by nicotine—are found in many malignant tumors and are thought to play a role in tumor progression.¹² Blockade of alpha 7 nicotinic acetylcholine receptors has been shown to decrease the growth of certain cancers.¹²

However, these findings were from in vitro studies, and the concerns they raised have not been reflected in in vivo studies. Despite having been on the market for 30 years, nicotine replacement therapy has as yet not been associated with any “real world” increase in cancer risk.

Smoking is one of the leading risk factors for cervical cancer, and nicotine itself may play a contributing role. Nicotine has been shown to increase cellular proliferation in cervical cancer.¹³ Some evidence suggests that it may also play a role in the lymphogenic metastasis of cervical cancer.¹³

Cardiovascular disease. Nicotine has been linked to cardiovascular disease. It directly affects the heart’s rate and rhythm via nicotinic acetylcholine receptors in the peripheral autonomic nervous system. It impairs endothelial-dependent dilation of blood vessels in response to nitric oxide, and this inhibition in the coronary arteries may contribute to smoking-related heart disease.^14,15 Nicotine has also been shown to raise serum cholesterol levels, increase clot formation, and contribute to plaque formation by increasing vascular smooth muscle.¹⁴

Possible teratogenic effect. There is some theoretical concern regarding exposure to nicotine in utero, as nicotinic acetylcholine receptors develop before neurons, and nicotine may therefore interfere with the natural influence of acetylcholine on the development of this system.¹⁴

Consuming one vial of e-cigarette fluid could be fatal

Direct toxicity. Nicotine is toxic at high levels. The overdose potential associated with nicotine is particularly worrisome with e-cigarettes, as the nicotine solution they use is typically supplied in 5-mL, 10-mL, or 20-mL vials that range in concentration from 8.5 to 22.2 mg of nicotine per mL.¹⁶ The fatal single dose range of nicotine has been reported at 30 to 60 mg in adults and 10 mg in children and can be achieved by oral, intravenous, or transdermal absorption,¹⁶ so one vial, if consumed orally, could be fatal.

The number of calls to US poison control centers regarding e-cigarettes has increased, closely paralleling their rise in popularity. In 2010, there were only 30 e-cigarette related calls to poison control centers; in 2011 the number increased to 269, and in 2012 it had reached 459 and included one fatality that was deemed a suicide.^17–19 Even though such toxic nicotine overdoses are rare, physicians should exercise caution and avoid recommending e-cigarettes to individuals with mental confusion, psychotic disorders, or suicidality, who might consume an entire vial.

Possible positive effects? Smoking is one of the worst things that people can do to their body, but the picture is complicated by a few possible positive effects. In the brain, although smoking increases the risk of Alzheimer disease, it is associated with a lower risk of Parkinson disease. In the bowel, it increases the risk of Crohn disease but may decrease the risk of ulcerative colitis. Gahring and Rogers²⁰ pointed out that neuronal nicotinic receptors are present in nonneuronal cells throughout the body and proposed that expression of these receptors may play a role in mediating the consequences of nicotine use, both good and bad. The lesson may be that nicotine is very active in the body, its effects are complicated and still incompletely understood, and therefore we should not encourage people to inhale nicotine products ad lib.

Additives

E-cigarettes typically contain propylene glycol, flavorings, and glycerine. One study that analyzed the additive contents of e-cigarettes found that propylene glycol accounted for 66% of the fluid, glycerine 24%, and flavorings less than 0.1%.²¹ Propylene glycol is the substance typically used in theater fog machines and is used to generate the vapor in e-cigarettes. Other substances such as tobacco-specific nitrosamines and diethylene glycol have also been found in e-cigarettes in small amounts.²²

Propylene glycol, ‘generally recognized as safe’

Propylene glycol has been used in theater fog machines for years—think Phantom of the Opera. It is also widely used as a solvent in many consumer products and pharmaceuticals. The FDA classified it as “generally recognized as safe” on the basis of one study conducted in rats and monkeys over 60 years ago.²³ As other authors have noted, however, a major manufacturer of propylene glycol recommends that exposure to propylene glycol mist be avoided.^24,25 Potential concern over propylene glycol mist was heightened when it was discovered that of all industries, the entertainment business ranked first in terms of work-related asthma symptoms and had the fifth-highest rate of wheezing.^26,27

Studies conducted over the last several decades have raised numerous health concerns about the safety of propylene glycol (Table 1).^26,28–36 The studies of propylene glycol fog are particularly important, as they most closely resemble the route of exposure in e-cigarette users.

Wieslander et al²⁸ exposed 27 volunteers to propylene glycol mist for 1 minute in an aircraft simulator under training conditions. Exposures were high, ranging from 176 to 851 mg/m³ (mean = 309 mg/m³). Four volunteers who developed a cough exhibited evidence of airway obstruction as indicated by a 5% decrease in forced expiratory volume in 1 second (FEV₁), while the rest did not exhibit any change in FEV₁.

Moline et al²⁹ conducted a non-peer-reviewed study for the Actors Equity Association and the League of American Theaters and Producers of 439 actors exposed to theater fog. They found statistically significant evidence of throat and vocal cord inflammation with prolonged peak exposure to glycols and recommended that actors not be exposed to glycol concentrations exceeding 40 mg/m³.

Varughese et al²⁶ conducted a study in 101 volunteers at 19 sites. The mean concentration of glycol-based fog was much lower than that in the studies by Wieslander et al²⁸ and Moline et al,²⁹ at 0.49 mg/m³ (the maximum was 3.22 mg/m³). The investigators concluded that glycol-based fog was associated with deleterious respiratory effects and that employees’ exposure should be limited.

The health issues related to propylene glycol are unique to e-cigarettes compared with nicotine replacement therapy. Unfortunately, the most applicable data available are from studies of persons exposed to theater fog, which involved periodic exposure and likely do not emulate the deep inhalation, multiple times daily, of propylene glycol by e-cigarette smokers. A 2014 review of the chemistry of contaminants in e-cigarettes³⁷ concluded that estimated levels of propylene glycol exposure in e-cigarette users come close to the threshold limit value set by the American Conference of Governmental Industrial Hygienists, and should merit concern.

These studies and real-life experience in the theater, while limited in scope, should give physicians pause and should cause increased awareness of the possibility of e-cigarette-induced pulmonary and upper airway complications. If such complications should occur, discontinuation of vaping should be advised.

Contaminants

The issue of adulterants is common to both e-cigarettes and nicotine replacement therapy. Several unlisted substances have been found in analyzed samples of e-cigarette fluid, including tobacco-specific nitrosamines (TSNAs), diethylene glycol (found in only one e-cigarette cartridge), cotinine, anabasine, myosmine, and beta-nicotyrine.²² The tobacco-specific nitrosamines N´-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N-nitrosoanabasine, and nitrosoanatabine have been found in five e-cigarette cartridge samples from two manufacturers in amounts similar to those found in nicotine replacement products.²²

Goniewicz et al³⁸ tested the vapor generated by 12 e-cigarette brands and found trace amounts of TSNAs. NNN was present in the vapor of eight of the samples in concentrations ranging from 0.8 to 4.3 ng per 150 puffs, and NNK in the vapor of nine of the samples in concentrations ranging from 1.1 to 28.3 ng per 150 puffs. Neither NNN nor NNK was found in blank samples nor with the Nicorette inhalator tested in the same study.³⁸

Because TNSAs can be formed from nicotine and its metabolites, there is also concern that cancer-causing nitrosamines may be formed from nicotine after it is absorbed into the body (ie, endogenously). While endogenous formation of NNK from nicotine has never been demonstrated, endogenous formation of NNN has been seen in some nicotine patch users.³⁹ The presence of these nitrosamines has raised concern that e-cigarettes and nicotine replacement therapy may have carcinogenic potential. The amounts of tobacco-specific nitrosamines found in e-cigarettes are also found in some nicotine replacement products.⁴⁰

Investigators have examined a possible connection between e-cigarettes and potentially carcinogenic carbonyl compounds, including formaldehyde, acetaldehyde, and acrolein. Formaldehyde (a known carcinogen) and acetaldehyde (a potential carcinogen) have been detected in e-cigarette cartridges and vapor.^38,41–43 Acrolein, a mucosal irritant, has been found in e-cigarette vapor.^38,43 Goniewicz et al³⁸ suggested that acrolein may be formed by the heating of the glycerin contained in the e-cigarette solution.

An extensive review of the studies of possible contaminant exposures (including polycylic aromatic hydrocarbons, TSNAs, volatile organic compounds, diethylene glycol, and inorganic compounds) with e-cigarette use according to occupational hygiene standards concluded that there was no cause for concern about increased health risk.³⁷ The study by Goniewicz et al also concluded that using e-cigarettes instead of traditional cigarettes may significantly reduce exposure to some tobacco-specific toxins.³⁸

E-CIGARETTES VS NICOTINE REPLACEMENT

Traditional nicotine replacement therapy products are regulated by the FDA and therefore standardized in terms of their contents. E-cigarettes, on the other hand, are unregulated vehicles for supplying nicotine, and may pose other health risks. One such risk is related to exposure to propylene glycol, which has never been studied under conditions (in terms of mode of delivery, frequency of dosing, and total duration of exposure) that approximate the exposure associated with e-cigarettes. Furthermore, the high concentration of nicotine in e-cigarette fluid poses a real risk of toxicity and potentially fatal overdose.

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine if used in a harm-reduction strategy as a maintenance medication. Whether the ongoing nicotine addiction makes it more likely that individuals would switch back and forth between nicotine replacement and tobacco-based products is not clear. Also not known is whether e-cigarettes may serve as the “gateway drug” by which teens enter into nicotine addiction, but we believe that the potential exists, as these products are potentially more appealing in terms of the lack of pungent smell, the perception of safety, and the variety of flavors of e-cigarettes.

The efficacy of nicotine replacement therapy in improving smoking cessation has been reviewed extensively elsewhere³⁷ and is beyond the scope of this article. E-cigarettes may be appealing to many cigarette smokers because they deliver smokeless nicotine, and they more closely emulate the actual experience of smoking compared with traditional nicotine replacement therapy. Though some evidence suggests that e-cigarettes may be modestly effective in helping tobacco smokers quit nicotine, they are not FDA-approved for smoking cessation and are not marketed for that indication.⁴⁴ Medical practitioners should see them for what they are: a new nicotine product with a novel delivery system that is not approved as treatment. Because of the inherent risks involved with e-cigarettes, medical practitioners are best advised to remain neutral on the relative value of e-cigarettes and should continue to motivate patients to discontinue nicotine use altogether.

Most people assume that electronic cigarettes (e-cigarettes) are safer than conventional tobacco products. Nevertheless, we should not encourage addicted smokers to try “vaping” as an alternative to nicotine replacement therapy, and we should discourage never-smokers from taking up vaping as vigorously as we try to discourage them from taking up smoking.

This article examines the prevailing assumptions and the evidence regarding the safety of e-cigarettes and traditional nicotine replacement therapy.

SMOKING IS DECLINING BUT FAR FROM GONE

While smoking rates have been declining over the past 50 years, the burden of disease attributable to tobacco use remains high. In the United States, it is estimated that nearly 6 million of those currently under the age of 18 will die of tobacco-related illnesses.¹ In the 50 years since the US surgeon general first reported on the health concerns related to tobacco, smoking has claimed the lives of nearly 21 million Americans¹ and continues to kill more than 400,000 every year.²

Even though the risks of smoking are well known, smoking remains one of the most difficult habits to quit. Indeed, about half of all smokers attempt to quit each year, but very few succeed.³

NICOTINE REPLACEMENT: GUM, PATCHES…E-CIGARETTES?

Smoking continues to kill more than 400,000 Americans every year

Nicotine replacement therapy was born out of the thought that, though nicotine is responsible for tobacco’s addictive quality, most tobacco-related disease is attributable to the 7,000 other substances found in tobacco smoke.⁴ Nicotine polacrilex gum was approved by the US Food and Drug Administration (FDA) in 1984, and nicotine transdermal film was approved in 1991.⁵

Nicotine replacement therapy, in the form of patches and gum, has been shown to improve the odds of successfully quitting smoking by a factor of nearly 1.5 to 2.⁶ Nicotine patches and gum were initially prescription medications but became available over the counter in 1996.⁷ They quickly became first-line agents for smoking cessation, and their over-the-counter availability softened any potential concerns about the possible deleterious health consequences of nicotine itself.

E-cigarettes—devices that generate a nicotine vapor that can be inhaled in a fashion that mimics the experience of smoking—were introduced in China in 2004.⁸ By 2012, sales of these devices in the United States had reached $500 million and in 2013 were expected to top $1 billion.^9,10

E-cigarette manufacturers make no therapeutic claims about their products, thus allowing them to escape regulation by the FDA as nicotine replacement therapy. A recent FDA proposal, however, is likely to change their “protected” status.¹¹ Despite the lack of regulation up to this point, patients generally assume that e-cigarettes are just another form of nicotine replacement therapy, even though they contain substances other than nicotine.

WHAT’S IN E-CIGARETTES?

Nicotine, which is bad in itself

E-cigarettes contain nicotine in varying amounts (some cartridges contain none at all). Though nicotine replacement therapy is less harmful than tobacco, nicotine by itself is associated with its own health problems, notably cancer, cardiovascular disease, birth defects (possibly), and poisoning.

Carcinogenesis. Nicotine plays a direct role in carcinogenesis through a variety of mechanisms, including increasing the activity of tumor growth-promoting transcription factors, decreasing apoptosis, and increasing angiogenesis in tumors.¹² Additionally, specific types of nicotinic acetylcholine receptors— eg, alpha 7 receptors, which are stimulated by nicotine—are found in many malignant tumors and are thought to play a role in tumor progression.¹² Blockade of alpha 7 nicotinic acetylcholine receptors has been shown to decrease the growth of certain cancers.¹²

However, these findings were from in vitro studies, and the concerns they raised have not been reflected in in vivo studies. Despite having been on the market for 30 years, nicotine replacement therapy has as yet not been associated with any “real world” increase in cancer risk.

Smoking is one of the leading risk factors for cervical cancer, and nicotine itself may play a contributing role. Nicotine has been shown to increase cellular proliferation in cervical cancer.¹³ Some evidence suggests that it may also play a role in the lymphogenic metastasis of cervical cancer.¹³

Cardiovascular disease. Nicotine has been linked to cardiovascular disease. It directly affects the heart’s rate and rhythm via nicotinic acetylcholine receptors in the peripheral autonomic nervous system. It impairs endothelial-dependent dilation of blood vessels in response to nitric oxide, and this inhibition in the coronary arteries may contribute to smoking-related heart disease.^14,15 Nicotine has also been shown to raise serum cholesterol levels, increase clot formation, and contribute to plaque formation by increasing vascular smooth muscle.¹⁴

Possible teratogenic effect. There is some theoretical concern regarding exposure to nicotine in utero, as nicotinic acetylcholine receptors develop before neurons, and nicotine may therefore interfere with the natural influence of acetylcholine on the development of this system.¹⁴

Consuming one vial of e-cigarette fluid could be fatal

Direct toxicity. Nicotine is toxic at high levels. The overdose potential associated with nicotine is particularly worrisome with e-cigarettes, as the nicotine solution they use is typically supplied in 5-mL, 10-mL, or 20-mL vials that range in concentration from 8.5 to 22.2 mg of nicotine per mL.¹⁶ The fatal single dose range of nicotine has been reported at 30 to 60 mg in adults and 10 mg in children and can be achieved by oral, intravenous, or transdermal absorption,¹⁶ so one vial, if consumed orally, could be fatal.

The number of calls to US poison control centers regarding e-cigarettes has increased, closely paralleling their rise in popularity. In 2010, there were only 30 e-cigarette related calls to poison control centers; in 2011 the number increased to 269, and in 2012 it had reached 459 and included one fatality that was deemed a suicide.^17–19 Even though such toxic nicotine overdoses are rare, physicians should exercise caution and avoid recommending e-cigarettes to individuals with mental confusion, psychotic disorders, or suicidality, who might consume an entire vial.

Possible positive effects? Smoking is one of the worst things that people can do to their body, but the picture is complicated by a few possible positive effects. In the brain, although smoking increases the risk of Alzheimer disease, it is associated with a lower risk of Parkinson disease. In the bowel, it increases the risk of Crohn disease but may decrease the risk of ulcerative colitis. Gahring and Rogers²⁰ pointed out that neuronal nicotinic receptors are present in nonneuronal cells throughout the body and proposed that expression of these receptors may play a role in mediating the consequences of nicotine use, both good and bad. The lesson may be that nicotine is very active in the body, its effects are complicated and still incompletely understood, and therefore we should not encourage people to inhale nicotine products ad lib.

Additives

E-cigarettes typically contain propylene glycol, flavorings, and glycerine. One study that analyzed the additive contents of e-cigarettes found that propylene glycol accounted for 66% of the fluid, glycerine 24%, and flavorings less than 0.1%.²¹ Propylene glycol is the substance typically used in theater fog machines and is used to generate the vapor in e-cigarettes. Other substances such as tobacco-specific nitrosamines and diethylene glycol have also been found in e-cigarettes in small amounts.²²

Propylene glycol, ‘generally recognized as safe’

Propylene glycol has been used in theater fog machines for years—think Phantom of the Opera. It is also widely used as a solvent in many consumer products and pharmaceuticals. The FDA classified it as “generally recognized as safe” on the basis of one study conducted in rats and monkeys over 60 years ago.²³ As other authors have noted, however, a major manufacturer of propylene glycol recommends that exposure to propylene glycol mist be avoided.^24,25 Potential concern over propylene glycol mist was heightened when it was discovered that of all industries, the entertainment business ranked first in terms of work-related asthma symptoms and had the fifth-highest rate of wheezing.^26,27

Studies conducted over the last several decades have raised numerous health concerns about the safety of propylene glycol (Table 1).^26,28–36 The studies of propylene glycol fog are particularly important, as they most closely resemble the route of exposure in e-cigarette users.

Wieslander et al²⁸ exposed 27 volunteers to propylene glycol mist for 1 minute in an aircraft simulator under training conditions. Exposures were high, ranging from 176 to 851 mg/m³ (mean = 309 mg/m³). Four volunteers who developed a cough exhibited evidence of airway obstruction as indicated by a 5% decrease in forced expiratory volume in 1 second (FEV₁), while the rest did not exhibit any change in FEV₁.

Moline et al²⁹ conducted a non-peer-reviewed study for the Actors Equity Association and the League of American Theaters and Producers of 439 actors exposed to theater fog. They found statistically significant evidence of throat and vocal cord inflammation with prolonged peak exposure to glycols and recommended that actors not be exposed to glycol concentrations exceeding 40 mg/m³.

Varughese et al²⁶ conducted a study in 101 volunteers at 19 sites. The mean concentration of glycol-based fog was much lower than that in the studies by Wieslander et al²⁸ and Moline et al,²⁹ at 0.49 mg/m³ (the maximum was 3.22 mg/m³). The investigators concluded that glycol-based fog was associated with deleterious respiratory effects and that employees’ exposure should be limited.

The health issues related to propylene glycol are unique to e-cigarettes compared with nicotine replacement therapy. Unfortunately, the most applicable data available are from studies of persons exposed to theater fog, which involved periodic exposure and likely do not emulate the deep inhalation, multiple times daily, of propylene glycol by e-cigarette smokers. A 2014 review of the chemistry of contaminants in e-cigarettes³⁷ concluded that estimated levels of propylene glycol exposure in e-cigarette users come close to the threshold limit value set by the American Conference of Governmental Industrial Hygienists, and should merit concern.

These studies and real-life experience in the theater, while limited in scope, should give physicians pause and should cause increased awareness of the possibility of e-cigarette-induced pulmonary and upper airway complications. If such complications should occur, discontinuation of vaping should be advised.

Contaminants

The issue of adulterants is common to both e-cigarettes and nicotine replacement therapy. Several unlisted substances have been found in analyzed samples of e-cigarette fluid, including tobacco-specific nitrosamines (TSNAs), diethylene glycol (found in only one e-cigarette cartridge), cotinine, anabasine, myosmine, and beta-nicotyrine.²² The tobacco-specific nitrosamines N´-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N-nitrosoanabasine, and nitrosoanatabine have been found in five e-cigarette cartridge samples from two manufacturers in amounts similar to those found in nicotine replacement products.²²

Goniewicz et al³⁸ tested the vapor generated by 12 e-cigarette brands and found trace amounts of TSNAs. NNN was present in the vapor of eight of the samples in concentrations ranging from 0.8 to 4.3 ng per 150 puffs, and NNK in the vapor of nine of the samples in concentrations ranging from 1.1 to 28.3 ng per 150 puffs. Neither NNN nor NNK was found in blank samples nor with the Nicorette inhalator tested in the same study.³⁸

Because TNSAs can be formed from nicotine and its metabolites, there is also concern that cancer-causing nitrosamines may be formed from nicotine after it is absorbed into the body (ie, endogenously). While endogenous formation of NNK from nicotine has never been demonstrated, endogenous formation of NNN has been seen in some nicotine patch users.³⁹ The presence of these nitrosamines has raised concern that e-cigarettes and nicotine replacement therapy may have carcinogenic potential. The amounts of tobacco-specific nitrosamines found in e-cigarettes are also found in some nicotine replacement products.⁴⁰

Investigators have examined a possible connection between e-cigarettes and potentially carcinogenic carbonyl compounds, including formaldehyde, acetaldehyde, and acrolein. Formaldehyde (a known carcinogen) and acetaldehyde (a potential carcinogen) have been detected in e-cigarette cartridges and vapor.^38,41–43 Acrolein, a mucosal irritant, has been found in e-cigarette vapor.^38,43 Goniewicz et al³⁸ suggested that acrolein may be formed by the heating of the glycerin contained in the e-cigarette solution.

An extensive review of the studies of possible contaminant exposures (including polycylic aromatic hydrocarbons, TSNAs, volatile organic compounds, diethylene glycol, and inorganic compounds) with e-cigarette use according to occupational hygiene standards concluded that there was no cause for concern about increased health risk.³⁷ The study by Goniewicz et al also concluded that using e-cigarettes instead of traditional cigarettes may significantly reduce exposure to some tobacco-specific toxins.³⁸

E-CIGARETTES VS NICOTINE REPLACEMENT

Traditional nicotine replacement therapy products are regulated by the FDA and therefore standardized in terms of their contents. E-cigarettes, on the other hand, are unregulated vehicles for supplying nicotine, and may pose other health risks. One such risk is related to exposure to propylene glycol, which has never been studied under conditions (in terms of mode of delivery, frequency of dosing, and total duration of exposure) that approximate the exposure associated with e-cigarettes. Furthermore, the high concentration of nicotine in e-cigarette fluid poses a real risk of toxicity and potentially fatal overdose.

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine if used in a harm-reduction strategy as a maintenance medication. Whether the ongoing nicotine addiction makes it more likely that individuals would switch back and forth between nicotine replacement and tobacco-based products is not clear. Also not known is whether e-cigarettes may serve as the “gateway drug” by which teens enter into nicotine addiction, but we believe that the potential exists, as these products are potentially more appealing in terms of the lack of pungent smell, the perception of safety, and the variety of flavors of e-cigarettes.

The efficacy of nicotine replacement therapy in improving smoking cessation has been reviewed extensively elsewhere³⁷ and is beyond the scope of this article. E-cigarettes may be appealing to many cigarette smokers because they deliver smokeless nicotine, and they more closely emulate the actual experience of smoking compared with traditional nicotine replacement therapy. Though some evidence suggests that e-cigarettes may be modestly effective in helping tobacco smokers quit nicotine, they are not FDA-approved for smoking cessation and are not marketed for that indication.⁴⁴ Medical practitioners should see them for what they are: a new nicotine product with a novel delivery system that is not approved as treatment. Because of the inherent risks involved with e-cigarettes, medical practitioners are best advised to remain neutral on the relative value of e-cigarettes and should continue to motivate patients to discontinue nicotine use altogether.

Over the past year, it has been hard to avoid news reports involving people getting high on “bath salts” and “incense” (also known as “Spice” or “K2”). Addiction treatment professionals have been overwhelmed by questions regarding why one would want to “snort bath salts” or “smoke incense.”

These substances are not what they appear to be. They are sold as bath salts and incense and are labeled “not for human consumption” simply to avoid regulation by the US Food and Drug Administration (FDA). In reality, they are powerful psychoactive drugs, with effects that mimic those of more commonly abused drugs such as amphetamines and marijuana. Until recently, they were legally available over the counter at quick-marts, head shops, and on the Internet. Because they are relatively new, they may not be detectable on routine urine drug screens, and users may be unaware of the specific chemicals contained in them.

These drugs, which we have collectively termed synthetic legal intoxicating drugs (SLIDs), are increasing dramatically in use.^1–3 A survey of youths at a rave party indicated that 21% had used one of them on at least one occasion.⁴ The general impression held by the drug-using public is that SLIDs are relatively cheap, are not detected on standard urine drug screens, can produce a powerful high, and, until recently, were readily available through legitimate sources.

Physicians need to be aware of SLIDs in order to recognize and manage the intoxication syndromes associated with these substances when encountered in clinical practice, and in order to educate patients about their potential dangers.

SYNTHETIC CANNABINOIDS MARKETED AS INCENSE

Herbal incense products that could be smoked as an alternative to marijuana started appearing on the Internet in Europe in 2004. By 2008, when such products first appeared in the United States, their use in Europe was already widespread.

Initially, consumers were led to believe that such herbal smoking blends were safe, legal alternatives to marijuana, and that it was the proprietary blend of herbs that was responsible for the “natural” high. Spice, a specific brand name, was originally trademarked in England as incense and also as an herbal smoking product.⁵

Legal authorities, however, suspected that these herbal blends were adulterated with synthetic substances. In December 2008, the first such substance was found when Austrian authorities isolated a synthetic cannabinoid, JWH-018, from an herbal incense product.⁶ By the end of 2009, five other synthetic cannabinoids—CP-47,497, HU-210, JWH-073, JWH-250, and JWH-398—had been isolated from various herbal incense samples around the world.⁷

The synthetic cannabinoids in herbal incense products are not derived from the hemp plant (Cannabis sativa), but are synthesized in laboratories and are formulated to interact with the endogenous cannabinoid receptors in the brain to produce psychoactive effects.

Synthetic cannabinoids are full agonists; natural THC is only a partial agonist

Two types of cannabinoid receptors have been discovered in humans: CB1 and CB2. Both types are found in the central nervous system, and CB2 is also found extensively in the periphery. CB1 is the receptor responsible for the psychoactive effects of cannabinoids, including altered consciousness, euphoria, relaxation, perceptual disturbances, intensified sensory experiences, cognitive impairment, and increased reaction time.⁶ The physiologic role of CB2 remains uncertain.

The major psychoactive cannabinoid in naturally occurring marijuana is delta-9-tetrahydrocannabinol (THC). The so-called classic cannabinoids, such as HU-210, are analogues of THC and are based on its chemical structure. The rest of the synthetic cannabinoids commonly found in incense products differ in chemical structure from naturally occurring cannabinoids such as THC, but have activity at the CB1 receptor and are thus psychoactive.

Of clinical relevance is that THC is only a partial agonist at the CB1 receptor, while all synthetic cannabinoids commonly found in incense products are full agonists at CB1.⁷ This difference is important because partial agonists bind to receptors but stimulate them only partially and therefore exhibit a plateau effect in terms of dose vs clinical response. In contrast, full agonists have no ceiling on the dose-response relationship and therefore have a greater potential for overdose and severe toxic effects.

Despite uncertainties, use is widespread

Most of the synthetic cannabinoids in herbal incense products were developed for research purposes, and there are almost no reliable scientific data on their effects in humans. Of additional concern is that no research has been conducted on their pyrolytic effects, ie, how these chemicals are transformed when they are burned, such as when consumers smoke them. Furthermore, herbal incense products often vary in their active substances and concentrations, so consumers really do not know what they are getting.

Despite the many uncertainties, the use of these products is widespread. Data submitted to the US Drug Enforcement Administration (DEA) from a major toxicology laboratory indicated that from July through November of 2010, 3,700 samples tested positive for either JWH-018 or JWH-073. This report also indicated that 30% to 35% of specimens submitted by juvenile probation departments were positive for synthetic cannabinoids.⁸

MEDICAL CONCERNS OVER SYNTHETIC CANNABINOIDS

Amid the mysteries surrounding synthetic cannabinoids, one thing is clear: users are increasingly seeking medical attention. In 2010, there were 2,906 calls to poison control centers across the United States pertaining to “synthetic marijuana”; in 2011 there were 6,959 calls, and in January 2012, 639 such calls had been placed.⁹

The duration of the intoxicating effects of synthetic cannabinoids is generally longer than that of THC, but this seems to be variable. JWH-018, for instance, seems to have a shorter duration of action, at around 1 to 2 hours, while a longer, 5- to 6-hour intoxicating effect has been observed with CP-47,497.^7,12

Serious adverse effects

Although the prevalence of serious adverse effects associated with the use of synthetic cannabinoids is not known, a number of serious complications have been recognized.

Seizures. One case of seizure has been reported in association with the use of synthetic cannabinoids, specifically JWH-018.¹² This case involved a previously healthy 48-year-old man who had ingested a powder that was subsequently confirmed to be JWH-018, which he mixed with alcohol. Of further concern in this case is that this individual developed a refractory supraventricular tachycardia that required cardioversion on the first hospital day.

The authors speculated that the seizure may have been due to a dose-response mechanism that resulted in either the release of presynaptic excitatory neurotransmitters or the decreased release of inhibitory neurotransmitters. They further postulated that the supraventricular tachycardia could have been caused by one of two mechanisms previously reported in association with CB1 agonists: an increase in circulating catecholamines or heightened oxidative demands on the myocardium.¹²

Psychosis. The occurrence of psychotic symptoms such as hallucinations and paranoid delusions in association with synthetic cannabinoids is not surprising, given the well-documented link between marijuana use and psychosis.^13,14

A case report of a 25-year-old patient with a 7-year history of recurrent psychosis that was initially triggered by cannabis use indicated that the use of 3 g of herbal incense on three occasions was associated with worsening of previous psychotic symptoms and the emergence of command and paranoid types of auditory hallucination.¹⁰

Semistructured interviews of 15 patients in a forensic rehabilitative service, all of whom had a history of psychotic illness, showed that 69% experienced symptoms consistent with psychotic relapse after smoking an herbal incense product containing JWH-018.¹⁵

It is possible that psychotic symptoms may be more prominent with synthetic cannabinoids than with natural marijuana because not only are synthetic cannabinoids more potent and work as full agonists, but, unlike marijuana, they do not contain cannabidiol, which is thought to have antipsychotic efficacy.^10,16 However, the risk of psychotic symptoms in association with synthetic cannabinoid usage in otherwise healthy people is unknown.

Regulation lags behind

Growing concern over the perceived dangers posed by synthetic cannabinoids has led to a ban on some of the more common ones contained in herbal incense preparations. On March 1, 2011, the US DEA temporarily placed five synthetic cannabinoids (JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol) under schedule I (banned substances).

Such a ban, however, may be futile because there are an estimated 100 synthetic cannabinoids that have yet to enter the market, and when one is banned, a new one is likely to be introduced immediately as a replacement.⁸

SYNTHETIC STIMULANTS MARKETED AS BATH SALTS

Like the herbal incense products, “bath salts” may likewise not be what they appear to be. They too may be labeled “not for human consumption” in an effort to bypass laws governing mind-altering substances.

Several pharmacologically active substances have been marketed as bath salts. Two of the more common ingredients are 3,4-methylenedioxypyrovalerone (MDPV) and 4-methylcathinone (mephedrone).

MDPV is a dopamine and norepineph-rine reuptake inhibitor that acts as a powerful stimulant. It has no FDA-approved medical use, but it is an analogue of the stimulant pyrovalerone, which was once used to treat chronic fatigue.¹⁷

MDPV seems to be the most common substance found in bath salt products in the United States. A sample of this substance was first seized on the streets by German authorities in 2007. A study in Finland conducted from August 2009 to September 2010 estimated that 5.7% of all arrests for driving under the influence (DUI) unrelated to alcohol consumption involved MDPV intoxication.¹⁷ In 2009, the National Forensic Laboratory Information System of the US DEA had seized only two samples of MDPV, but by 2010 that had increased to 161.¹⁸

Mephedrone is derived from phenethylamine and is closely related to cathinone, the active ingredient in the African khat plant (Catha edulis).¹⁹ Khat has a history of abuse, and the chemical structure of cathinone and its derivatives is similar to that of amphetamine.

Mephedrone, a powerful stimulant, is suspected of working as a monoamine reuptake inhibitor, and it may also directly induce the presynaptic release of monoamines.²⁰ The net effect is an increase in serotonin, norepineph-rine, and dopamine levels at neuronal synapses.

Mephedrone was first described in 1929 by chemist Saem de Burnaga Sanchez, and it remained an obscure research chemical for many years.²¹ It was formally recognized as a drug of abuse in Europe in 2007, and by 2009 it was the sixth most frequently used such drug in Europe.^8,22

Although MDPV and mephedrone are the most common psychoactive ingredients in bath salts, many other synthetic drugs have been found on the market.

A temporary ban

On September 7, 2011, the US government made it illegal to possess or sell any substance containing MDPV, mephedrone, or methy-lone. This temporary restriction was to remain in effect for 1 year to give the DEA time to collect data to support a move to permanently control these substances.³

Like synthetic cannabinoids, however, synthetic stimulants are very difficult to regulate because they are a large group of substances. As soon as one substance is outlawed, another synthetic stimulant will likely take its place.

MEDICAL CONCERNS REGARDING SYNTHETIC STIMULANTS

The medical and psychiatric sequelae that are associated with the use of bath salts have sent an increasing number of people to emergency rooms. The number of bath-salt-related calls to US poison control centers increased dramatically from 303 in 2010 to 4,720 by August 31, 2011. Most of these calls were related to tachycardia, agitation, hallucinations, extreme paranoia, delusions, and elevations in blood pressure.³

A report of 35 cases of people who had used bath salts and who had reported to Michigan emergency rooms between November 13, 2010, and March 31, 2011, indicated that agitation was present in 66%, tachycardia in 63%, delusions and hallucinations in 40%, seizure or tremor in 29%, hypertension in 23%, drowsiness in 23%, paranoia in 20%, and mydriasis in 20%; one patient was dead on arrival. Of the 34 patients who were alive on arrival, 17 (50%) were hospitalized, 15 were released, and 2 left against medical advice. In the patients in this study, 63% had injected the drug, 26% snorted it, and 11% ingested it orally.² Toxicology results obtained during an autopsy on the one person who died revealed a high level of MDPV, and the coroner ruled that MDPV toxicity was the primary cause of death.²

Though the pharmacokinetic properties of mephedrone are unknown, James et al²⁴ noted that an interesting feature is that its clinical effects seem to persist for more than 24 hours after the last exposure to the drug, which would not be expected based on the rapid elimination of other similar cathinones.

Sympathomimetic toxicity. Many of the symptoms listed in Table 2 are consistent with a sympathomimetic syndrome. In a case series reported by Regan et al,²⁶ most of the 57 patients exhibited cardiovascular findings consistent with sympathomimetic toxicity.

In the study by James et al,²⁴ one of the patients with chest pain had electrocardiographic changes consistent with acute myocardial infarction. Though it is not possible to conclude from a single case that mephedrone poses a risk of myocardial infarction, such a risk has been reported with khat.²⁸ More research is needed to determine whether mephedrone poses a risk of cardiac events when used by people with or without an underlying cardiac condition.

Seizure also seems to be a relatively common feature associated with mephedrone use in case series of emergency room presentations. The US Centers for Disease Control and Prevention l² reported that of 35 patients who had used bath salts, 40% experienced seizures or “tremors.” A recent case series²⁷ of 15 patients presenting to an emergency department after mephedrone use reported that 20% had experienced seizures. In the study by James et al,²⁴ four patients (3% of the total group) experienced seizures after using mephedrone. It should be noted that, aside from people presenting to emergency rooms, seizures are rarely reported in the wider population of mephedrone users.

Psychotic symptoms are also quite common in users of synthetic stimulants who present to emergency rooms, occurring, as previously stated, in 14% to 40% of cases.^2,24

In a small case series, Penders and Gestring²⁹ pointed out some common features in three patients who had used MDPV and had presented with psychosis: sleep problems, inattention, vivid hallucinations of intruders, fearfulness, and inability to remember many of the events surrounding their drug use. The authors concluded that the psychotic syndrome present in their three patients was indicative of a short-term delirium rather than a substance-induced psychosis based on the presence of attention deficits and memory problems. The patients in this series responded well to brief hospitalization and antipsychotic medications.

As with seizure, extreme presentations such as psychosis are infrequently mentioned except in people requiring treatment at a hospital. There are simply no data regarding the prevalence of psychotic symptoms in the larger group of all synthetic stimulant users.

SUSPECT SLID INTOXICATION IN ‘PSYCHIATRIC’ PATIENTS

Despite the temporary ban on the more common substances found in Spice and bath salts, it is premature for the medical community to breath a sigh of relief. Producers of these products are already likely bringing to market new ones containing similar but as yet nonbanned substances. Furthermore, such bans will do little to affect Internet commerce; rather than go to a head shop, consumers will order the products online.

Doctors in urgent care centers, emergency rooms, and on general medical floors should pay close attention to any patient without a known psychiatric history who is acting in a bizarre fashion. Most SLID-intoxicated patients will present with anxiety, agitation, and psychosis. Rather than assume that they are psychiatric patients, one should consider the possibility of SLID intoxication and pay close attention to the possible medical sequelae associated with SLID use, such as elevated blood pressure, tachycardia, and seizure.

Benzodiazepines, especially lorazepam (Ativan), have been the agents most commonly used to treat both agitation and seizures associated with SLID intoxication.

Antipsychotics should be used judiciously because of their propensity to lower the seizure threshold, and patients with synthetic stimulant toxicity are already at increased risk of seizure.

A psychiatric consult should be considered in the event of any suspected toxicity or for any patient whose behavior is difficult to manage.

Restraints may be needed in some circumstances when agitation cannot be controlled with benzodiazepines alone, to ensure safety for the patient as well as that of others in the emergency department.

Routine laboratory tests should be part of the workup of patients suspected of being under the influence of SLIDs. These include a complete blood cell count, complete metabolic panel, and urine toxicology (Table 3).^23,25 A routine urine toxicology study will likely be negative, but either the patient or collateral information may give you a general idea of what the patient used, in which case the sample could be sent out for special tests for the more common substances found in herbal incense or bath salt products.

Electroencephalography may be indicated if there is any question as to whether the patient may have suffered a seizure. There should be a low threshold to order electrocardiography, especially in the case of synthetic stimulant intoxication.

Serial cardiac enzymes may be warranted if a patient with synthetic-stimulant intoxicated has chest pain.

Education, addiction treatment. Much is unknown about the risk of SLIDs, but given the adverse events reported in the literature, it seems likely that those with underlying cardiac or psychiatric issues may be at higher risk for the most serious drug-related consequences. With regard to synthetic stimulants, Winstock et al²⁰ recommend a harm-reduction approach involving educating patients about avoiding the development of tolerance, not engaging in polydrug use, not injecting, and paying special attention to remaining cool and well hydrated.

Experience shows that once SLID patients get through their acute crisis and are no longer psychotic, they tend to be forthright in divulging what they used to get high. At that point, consideration should be given to consulting an addiction treatment specialist for further evaluation of the patient’s drug use history and for formulation of a treatment plan to help ensure that the patient doesn’t return to using these drugs.

SLIDs POSE A REAL CHALLENGE

SLIDs present a real challenge to law enforcement, governments, the public, and the addiction treatment community. There is currently no way to routinely test for these substances. Furthermore, any tests that are developed or laws that are enacted will be easily evaded, as there are many more synthetic substances waiting in the wings to be released.

Don’t be lulled into thinking that SLIDs are gone with the recent bans against some of the more common substances. More SLIDs are coming, and more morbidity should be expected in medical settings.

Doctors in emergency departments and other settings need to be prepared for the agitated and often psychotic presentation of SLID-intoxicated patients and should be ready with benzodiazepines, restraints, and a calm and reassuring manner. And for patients who present with psychotic symptoms, medical staff should also be ready to consider involuntary short-term commitment to an inpatient psychiatric unit.

Once they recover, patients need to be educated about the dangers of substances such as SLIDs that, because of their novelty, may be perceived as less dangerous alternatives to traditional illicit drugs.

Over the past year, it has been hard to avoid news reports involving people getting high on “bath salts” and “incense” (also known as “Spice” or “K2”). Addiction treatment professionals have been overwhelmed by questions regarding why one would want to “snort bath salts” or “smoke incense.”

These substances are not what they appear to be. They are sold as bath salts and incense and are labeled “not for human consumption” simply to avoid regulation by the US Food and Drug Administration (FDA). In reality, they are powerful psychoactive drugs, with effects that mimic those of more commonly abused drugs such as amphetamines and marijuana. Until recently, they were legally available over the counter at quick-marts, head shops, and on the Internet. Because they are relatively new, they may not be detectable on routine urine drug screens, and users may be unaware of the specific chemicals contained in them.

These drugs, which we have collectively termed synthetic legal intoxicating drugs (SLIDs), are increasing dramatically in use.^1–3 A survey of youths at a rave party indicated that 21% had used one of them on at least one occasion.⁴ The general impression held by the drug-using public is that SLIDs are relatively cheap, are not detected on standard urine drug screens, can produce a powerful high, and, until recently, were readily available through legitimate sources.

Physicians need to be aware of SLIDs in order to recognize and manage the intoxication syndromes associated with these substances when encountered in clinical practice, and in order to educate patients about their potential dangers.

SYNTHETIC CANNABINOIDS MARKETED AS INCENSE

Herbal incense products that could be smoked as an alternative to marijuana started appearing on the Internet in Europe in 2004. By 2008, when such products first appeared in the United States, their use in Europe was already widespread.

Initially, consumers were led to believe that such herbal smoking blends were safe, legal alternatives to marijuana, and that it was the proprietary blend of herbs that was responsible for the “natural” high. Spice, a specific brand name, was originally trademarked in England as incense and also as an herbal smoking product.⁵

Legal authorities, however, suspected that these herbal blends were adulterated with synthetic substances. In December 2008, the first such substance was found when Austrian authorities isolated a synthetic cannabinoid, JWH-018, from an herbal incense product.⁶ By the end of 2009, five other synthetic cannabinoids—CP-47,497, HU-210, JWH-073, JWH-250, and JWH-398—had been isolated from various herbal incense samples around the world.⁷

The synthetic cannabinoids in herbal incense products are not derived from the hemp plant (Cannabis sativa), but are synthesized in laboratories and are formulated to interact with the endogenous cannabinoid receptors in the brain to produce psychoactive effects.

Synthetic cannabinoids are full agonists; natural THC is only a partial agonist

Two types of cannabinoid receptors have been discovered in humans: CB1 and CB2. Both types are found in the central nervous system, and CB2 is also found extensively in the periphery. CB1 is the receptor responsible for the psychoactive effects of cannabinoids, including altered consciousness, euphoria, relaxation, perceptual disturbances, intensified sensory experiences, cognitive impairment, and increased reaction time.⁶ The physiologic role of CB2 remains uncertain.

The major psychoactive cannabinoid in naturally occurring marijuana is delta-9-tetrahydrocannabinol (THC). The so-called classic cannabinoids, such as HU-210, are analogues of THC and are based on its chemical structure. The rest of the synthetic cannabinoids commonly found in incense products differ in chemical structure from naturally occurring cannabinoids such as THC, but have activity at the CB1 receptor and are thus psychoactive.

Of clinical relevance is that THC is only a partial agonist at the CB1 receptor, while all synthetic cannabinoids commonly found in incense products are full agonists at CB1.⁷ This difference is important because partial agonists bind to receptors but stimulate them only partially and therefore exhibit a plateau effect in terms of dose vs clinical response. In contrast, full agonists have no ceiling on the dose-response relationship and therefore have a greater potential for overdose and severe toxic effects.

Despite uncertainties, use is widespread

Most of the synthetic cannabinoids in herbal incense products were developed for research purposes, and there are almost no reliable scientific data on their effects in humans. Of additional concern is that no research has been conducted on their pyrolytic effects, ie, how these chemicals are transformed when they are burned, such as when consumers smoke them. Furthermore, herbal incense products often vary in their active substances and concentrations, so consumers really do not know what they are getting.

Despite the many uncertainties, the use of these products is widespread. Data submitted to the US Drug Enforcement Administration (DEA) from a major toxicology laboratory indicated that from July through November of 2010, 3,700 samples tested positive for either JWH-018 or JWH-073. This report also indicated that 30% to 35% of specimens submitted by juvenile probation departments were positive for synthetic cannabinoids.⁸

MEDICAL CONCERNS OVER SYNTHETIC CANNABINOIDS

Amid the mysteries surrounding synthetic cannabinoids, one thing is clear: users are increasingly seeking medical attention. In 2010, there were 2,906 calls to poison control centers across the United States pertaining to “synthetic marijuana”; in 2011 there were 6,959 calls, and in January 2012, 639 such calls had been placed.⁹

The duration of the intoxicating effects of synthetic cannabinoids is generally longer than that of THC, but this seems to be variable. JWH-018, for instance, seems to have a shorter duration of action, at around 1 to 2 hours, while a longer, 5- to 6-hour intoxicating effect has been observed with CP-47,497.^7,12

Serious adverse effects

Although the prevalence of serious adverse effects associated with the use of synthetic cannabinoids is not known, a number of serious complications have been recognized.

Seizures. One case of seizure has been reported in association with the use of synthetic cannabinoids, specifically JWH-018.¹² This case involved a previously healthy 48-year-old man who had ingested a powder that was subsequently confirmed to be JWH-018, which he mixed with alcohol. Of further concern in this case is that this individual developed a refractory supraventricular tachycardia that required cardioversion on the first hospital day.

The authors speculated that the seizure may have been due to a dose-response mechanism that resulted in either the release of presynaptic excitatory neurotransmitters or the decreased release of inhibitory neurotransmitters. They further postulated that the supraventricular tachycardia could have been caused by one of two mechanisms previously reported in association with CB1 agonists: an increase in circulating catecholamines or heightened oxidative demands on the myocardium.¹²

Psychosis. The occurrence of psychotic symptoms such as hallucinations and paranoid delusions in association with synthetic cannabinoids is not surprising, given the well-documented link between marijuana use and psychosis.^13,14

A case report of a 25-year-old patient with a 7-year history of recurrent psychosis that was initially triggered by cannabis use indicated that the use of 3 g of herbal incense on three occasions was associated with worsening of previous psychotic symptoms and the emergence of command and paranoid types of auditory hallucination.¹⁰

Semistructured interviews of 15 patients in a forensic rehabilitative service, all of whom had a history of psychotic illness, showed that 69% experienced symptoms consistent with psychotic relapse after smoking an herbal incense product containing JWH-018.¹⁵

It is possible that psychotic symptoms may be more prominent with synthetic cannabinoids than with natural marijuana because not only are synthetic cannabinoids more potent and work as full agonists, but, unlike marijuana, they do not contain cannabidiol, which is thought to have antipsychotic efficacy.^10,16 However, the risk of psychotic symptoms in association with synthetic cannabinoid usage in otherwise healthy people is unknown.

Regulation lags behind

Growing concern over the perceived dangers posed by synthetic cannabinoids has led to a ban on some of the more common ones contained in herbal incense preparations. On March 1, 2011, the US DEA temporarily placed five synthetic cannabinoids (JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol) under schedule I (banned substances).

Such a ban, however, may be futile because there are an estimated 100 synthetic cannabinoids that have yet to enter the market, and when one is banned, a new one is likely to be introduced immediately as a replacement.⁸

SYNTHETIC STIMULANTS MARKETED AS BATH SALTS

Like the herbal incense products, “bath salts” may likewise not be what they appear to be. They too may be labeled “not for human consumption” in an effort to bypass laws governing mind-altering substances.

Several pharmacologically active substances have been marketed as bath salts. Two of the more common ingredients are 3,4-methylenedioxypyrovalerone (MDPV) and 4-methylcathinone (mephedrone).

MDPV is a dopamine and norepineph-rine reuptake inhibitor that acts as a powerful stimulant. It has no FDA-approved medical use, but it is an analogue of the stimulant pyrovalerone, which was once used to treat chronic fatigue.¹⁷

MDPV seems to be the most common substance found in bath salt products in the United States. A sample of this substance was first seized on the streets by German authorities in 2007. A study in Finland conducted from August 2009 to September 2010 estimated that 5.7% of all arrests for driving under the influence (DUI) unrelated to alcohol consumption involved MDPV intoxication.¹⁷ In 2009, the National Forensic Laboratory Information System of the US DEA had seized only two samples of MDPV, but by 2010 that had increased to 161.¹⁸

Mephedrone is derived from phenethylamine and is closely related to cathinone, the active ingredient in the African khat plant (Catha edulis).¹⁹ Khat has a history of abuse, and the chemical structure of cathinone and its derivatives is similar to that of amphetamine.

Mephedrone, a powerful stimulant, is suspected of working as a monoamine reuptake inhibitor, and it may also directly induce the presynaptic release of monoamines.²⁰ The net effect is an increase in serotonin, norepineph-rine, and dopamine levels at neuronal synapses.

Mephedrone was first described in 1929 by chemist Saem de Burnaga Sanchez, and it remained an obscure research chemical for many years.²¹ It was formally recognized as a drug of abuse in Europe in 2007, and by 2009 it was the sixth most frequently used such drug in Europe.^8,22

Although MDPV and mephedrone are the most common psychoactive ingredients in bath salts, many other synthetic drugs have been found on the market.

A temporary ban

On September 7, 2011, the US government made it illegal to possess or sell any substance containing MDPV, mephedrone, or methy-lone. This temporary restriction was to remain in effect for 1 year to give the DEA time to collect data to support a move to permanently control these substances.³

Like synthetic cannabinoids, however, synthetic stimulants are very difficult to regulate because they are a large group of substances. As soon as one substance is outlawed, another synthetic stimulant will likely take its place.

MEDICAL CONCERNS REGARDING SYNTHETIC STIMULANTS

The medical and psychiatric sequelae that are associated with the use of bath salts have sent an increasing number of people to emergency rooms. The number of bath-salt-related calls to US poison control centers increased dramatically from 303 in 2010 to 4,720 by August 31, 2011. Most of these calls were related to tachycardia, agitation, hallucinations, extreme paranoia, delusions, and elevations in blood pressure.³

A report of 35 cases of people who had used bath salts and who had reported to Michigan emergency rooms between November 13, 2010, and March 31, 2011, indicated that agitation was present in 66%, tachycardia in 63%, delusions and hallucinations in 40%, seizure or tremor in 29%, hypertension in 23%, drowsiness in 23%, paranoia in 20%, and mydriasis in 20%; one patient was dead on arrival. Of the 34 patients who were alive on arrival, 17 (50%) were hospitalized, 15 were released, and 2 left against medical advice. In the patients in this study, 63% had injected the drug, 26% snorted it, and 11% ingested it orally.² Toxicology results obtained during an autopsy on the one person who died revealed a high level of MDPV, and the coroner ruled that MDPV toxicity was the primary cause of death.²

Though the pharmacokinetic properties of mephedrone are unknown, James et al²⁴ noted that an interesting feature is that its clinical effects seem to persist for more than 24 hours after the last exposure to the drug, which would not be expected based on the rapid elimination of other similar cathinones.

Sympathomimetic toxicity. Many of the symptoms listed in Table 2 are consistent with a sympathomimetic syndrome. In a case series reported by Regan et al,²⁶ most of the 57 patients exhibited cardiovascular findings consistent with sympathomimetic toxicity.

In the study by James et al,²⁴ one of the patients with chest pain had electrocardiographic changes consistent with acute myocardial infarction. Though it is not possible to conclude from a single case that mephedrone poses a risk of myocardial infarction, such a risk has been reported with khat.²⁸ More research is needed to determine whether mephedrone poses a risk of cardiac events when used by people with or without an underlying cardiac condition.

Seizure also seems to be a relatively common feature associated with mephedrone use in case series of emergency room presentations. The US Centers for Disease Control and Prevention l² reported that of 35 patients who had used bath salts, 40% experienced seizures or “tremors.” A recent case series²⁷ of 15 patients presenting to an emergency department after mephedrone use reported that 20% had experienced seizures. In the study by James et al,²⁴ four patients (3% of the total group) experienced seizures after using mephedrone. It should be noted that, aside from people presenting to emergency rooms, seizures are rarely reported in the wider population of mephedrone users.

Psychotic symptoms are also quite common in users of synthetic stimulants who present to emergency rooms, occurring, as previously stated, in 14% to 40% of cases.^2,24

In a small case series, Penders and Gestring²⁹ pointed out some common features in three patients who had used MDPV and had presented with psychosis: sleep problems, inattention, vivid hallucinations of intruders, fearfulness, and inability to remember many of the events surrounding their drug use. The authors concluded that the psychotic syndrome present in their three patients was indicative of a short-term delirium rather than a substance-induced psychosis based on the presence of attention deficits and memory problems. The patients in this series responded well to brief hospitalization and antipsychotic medications.

As with seizure, extreme presentations such as psychosis are infrequently mentioned except in people requiring treatment at a hospital. There are simply no data regarding the prevalence of psychotic symptoms in the larger group of all synthetic stimulant users.

SUSPECT SLID INTOXICATION IN ‘PSYCHIATRIC’ PATIENTS

Despite the temporary ban on the more common substances found in Spice and bath salts, it is premature for the medical community to breath a sigh of relief. Producers of these products are already likely bringing to market new ones containing similar but as yet nonbanned substances. Furthermore, such bans will do little to affect Internet commerce; rather than go to a head shop, consumers will order the products online.

Doctors in urgent care centers, emergency rooms, and on general medical floors should pay close attention to any patient without a known psychiatric history who is acting in a bizarre fashion. Most SLID-intoxicated patients will present with anxiety, agitation, and psychosis. Rather than assume that they are psychiatric patients, one should consider the possibility of SLID intoxication and pay close attention to the possible medical sequelae associated with SLID use, such as elevated blood pressure, tachycardia, and seizure.

Benzodiazepines, especially lorazepam (Ativan), have been the agents most commonly used to treat both agitation and seizures associated with SLID intoxication.

Antipsychotics should be used judiciously because of their propensity to lower the seizure threshold, and patients with synthetic stimulant toxicity are already at increased risk of seizure.

A psychiatric consult should be considered in the event of any suspected toxicity or for any patient whose behavior is difficult to manage.

Restraints may be needed in some circumstances when agitation cannot be controlled with benzodiazepines alone, to ensure safety for the patient as well as that of others in the emergency department.

Routine laboratory tests should be part of the workup of patients suspected of being under the influence of SLIDs. These include a complete blood cell count, complete metabolic panel, and urine toxicology (Table 3).^23,25 A routine urine toxicology study will likely be negative, but either the patient or collateral information may give you a general idea of what the patient used, in which case the sample could be sent out for special tests for the more common substances found in herbal incense or bath salt products.

Electroencephalography may be indicated if there is any question as to whether the patient may have suffered a seizure. There should be a low threshold to order electrocardiography, especially in the case of synthetic stimulant intoxication.

Serial cardiac enzymes may be warranted if a patient with synthetic-stimulant intoxicated has chest pain.

Education, addiction treatment. Much is unknown about the risk of SLIDs, but given the adverse events reported in the literature, it seems likely that those with underlying cardiac or psychiatric issues may be at higher risk for the most serious drug-related consequences. With regard to synthetic stimulants, Winstock et al²⁰ recommend a harm-reduction approach involving educating patients about avoiding the development of tolerance, not engaging in polydrug use, not injecting, and paying special attention to remaining cool and well hydrated.

Experience shows that once SLID patients get through their acute crisis and are no longer psychotic, they tend to be forthright in divulging what they used to get high. At that point, consideration should be given to consulting an addiction treatment specialist for further evaluation of the patient’s drug use history and for formulation of a treatment plan to help ensure that the patient doesn’t return to using these drugs.

SLIDs POSE A REAL CHALLENGE

SLIDs present a real challenge to law enforcement, governments, the public, and the addiction treatment community. There is currently no way to routinely test for these substances. Furthermore, any tests that are developed or laws that are enacted will be easily evaded, as there are many more synthetic substances waiting in the wings to be released.

Don’t be lulled into thinking that SLIDs are gone with the recent bans against some of the more common substances. More SLIDs are coming, and more morbidity should be expected in medical settings.

Doctors in emergency departments and other settings need to be prepared for the agitated and often psychotic presentation of SLID-intoxicated patients and should be ready with benzodiazepines, restraints, and a calm and reassuring manner. And for patients who present with psychotic symptoms, medical staff should also be ready to consider involuntary short-term commitment to an inpatient psychiatric unit.

Once they recover, patients need to be educated about the dangers of substances such as SLIDs that, because of their novelty, may be perceived as less dangerous alternatives to traditional illicit drugs.

Over the past year, it has been hard to avoid news reports involving people getting high on “bath salts” and “incense” (also known as “Spice” or “K2”). Addiction treatment professionals have been overwhelmed by questions regarding why one would want to “snort bath salts” or “smoke incense.”

These substances are not what they appear to be. They are sold as bath salts and incense and are labeled “not for human consumption” simply to avoid regulation by the US Food and Drug Administration (FDA). In reality, they are powerful psychoactive drugs, with effects that mimic those of more commonly abused drugs such as amphetamines and marijuana. Until recently, they were legally available over the counter at quick-marts, head shops, and on the Internet. Because they are relatively new, they may not be detectable on routine urine drug screens, and users may be unaware of the specific chemicals contained in them.

These drugs, which we have collectively termed synthetic legal intoxicating drugs (SLIDs), are increasing dramatically in use.^1–3 A survey of youths at a rave party indicated that 21% had used one of them on at least one occasion.⁴ The general impression held by the drug-using public is that SLIDs are relatively cheap, are not detected on standard urine drug screens, can produce a powerful high, and, until recently, were readily available through legitimate sources.

Physicians need to be aware of SLIDs in order to recognize and manage the intoxication syndromes associated with these substances when encountered in clinical practice, and in order to educate patients about their potential dangers.

SYNTHETIC CANNABINOIDS MARKETED AS INCENSE

Herbal incense products that could be smoked as an alternative to marijuana started appearing on the Internet in Europe in 2004. By 2008, when such products first appeared in the United States, their use in Europe was already widespread.

Initially, consumers were led to believe that such herbal smoking blends were safe, legal alternatives to marijuana, and that it was the proprietary blend of herbs that was responsible for the “natural” high. Spice, a specific brand name, was originally trademarked in England as incense and also as an herbal smoking product.⁵

Legal authorities, however, suspected that these herbal blends were adulterated with synthetic substances. In December 2008, the first such substance was found when Austrian authorities isolated a synthetic cannabinoid, JWH-018, from an herbal incense product.⁶ By the end of 2009, five other synthetic cannabinoids—CP-47,497, HU-210, JWH-073, JWH-250, and JWH-398—had been isolated from various herbal incense samples around the world.⁷

The synthetic cannabinoids in herbal incense products are not derived from the hemp plant (Cannabis sativa), but are synthesized in laboratories and are formulated to interact with the endogenous cannabinoid receptors in the brain to produce psychoactive effects.

Synthetic cannabinoids are full agonists; natural THC is only a partial agonist

Two types of cannabinoid receptors have been discovered in humans: CB1 and CB2. Both types are found in the central nervous system, and CB2 is also found extensively in the periphery. CB1 is the receptor responsible for the psychoactive effects of cannabinoids, including altered consciousness, euphoria, relaxation, perceptual disturbances, intensified sensory experiences, cognitive impairment, and increased reaction time.⁶ The physiologic role of CB2 remains uncertain.

The major psychoactive cannabinoid in naturally occurring marijuana is delta-9-tetrahydrocannabinol (THC). The so-called classic cannabinoids, such as HU-210, are analogues of THC and are based on its chemical structure. The rest of the synthetic cannabinoids commonly found in incense products differ in chemical structure from naturally occurring cannabinoids such as THC, but have activity at the CB1 receptor and are thus psychoactive.

Of clinical relevance is that THC is only a partial agonist at the CB1 receptor, while all synthetic cannabinoids commonly found in incense products are full agonists at CB1.⁷ This difference is important because partial agonists bind to receptors but stimulate them only partially and therefore exhibit a plateau effect in terms of dose vs clinical response. In contrast, full agonists have no ceiling on the dose-response relationship and therefore have a greater potential for overdose and severe toxic effects.

Despite uncertainties, use is widespread

Most of the synthetic cannabinoids in herbal incense products were developed for research purposes, and there are almost no reliable scientific data on their effects in humans. Of additional concern is that no research has been conducted on their pyrolytic effects, ie, how these chemicals are transformed when they are burned, such as when consumers smoke them. Furthermore, herbal incense products often vary in their active substances and concentrations, so consumers really do not know what they are getting.

Despite the many uncertainties, the use of these products is widespread. Data submitted to the US Drug Enforcement Administration (DEA) from a major toxicology laboratory indicated that from July through November of 2010, 3,700 samples tested positive for either JWH-018 or JWH-073. This report also indicated that 30% to 35% of specimens submitted by juvenile probation departments were positive for synthetic cannabinoids.⁸

MEDICAL CONCERNS OVER SYNTHETIC CANNABINOIDS

Amid the mysteries surrounding synthetic cannabinoids, one thing is clear: users are increasingly seeking medical attention. In 2010, there were 2,906 calls to poison control centers across the United States pertaining to “synthetic marijuana”; in 2011 there were 6,959 calls, and in January 2012, 639 such calls had been placed.⁹

The duration of the intoxicating effects of synthetic cannabinoids is generally longer than that of THC, but this seems to be variable. JWH-018, for instance, seems to have a shorter duration of action, at around 1 to 2 hours, while a longer, 5- to 6-hour intoxicating effect has been observed with CP-47,497.^7,12

Serious adverse effects

Although the prevalence of serious adverse effects associated with the use of synthetic cannabinoids is not known, a number of serious complications have been recognized.

Seizures. One case of seizure has been reported in association with the use of synthetic cannabinoids, specifically JWH-018.¹² This case involved a previously healthy 48-year-old man who had ingested a powder that was subsequently confirmed to be JWH-018, which he mixed with alcohol. Of further concern in this case is that this individual developed a refractory supraventricular tachycardia that required cardioversion on the first hospital day.

The authors speculated that the seizure may have been due to a dose-response mechanism that resulted in either the release of presynaptic excitatory neurotransmitters or the decreased release of inhibitory neurotransmitters. They further postulated that the supraventricular tachycardia could have been caused by one of two mechanisms previously reported in association with CB1 agonists: an increase in circulating catecholamines or heightened oxidative demands on the myocardium.¹²

Psychosis. The occurrence of psychotic symptoms such as hallucinations and paranoid delusions in association with synthetic cannabinoids is not surprising, given the well-documented link between marijuana use and psychosis.^13,14

A case report of a 25-year-old patient with a 7-year history of recurrent psychosis that was initially triggered by cannabis use indicated that the use of 3 g of herbal incense on three occasions was associated with worsening of previous psychotic symptoms and the emergence of command and paranoid types of auditory hallucination.¹⁰

Semistructured interviews of 15 patients in a forensic rehabilitative service, all of whom had a history of psychotic illness, showed that 69% experienced symptoms consistent with psychotic relapse after smoking an herbal incense product containing JWH-018.¹⁵

It is possible that psychotic symptoms may be more prominent with synthetic cannabinoids than with natural marijuana because not only are synthetic cannabinoids more potent and work as full agonists, but, unlike marijuana, they do not contain cannabidiol, which is thought to have antipsychotic efficacy.^10,16 However, the risk of psychotic symptoms in association with synthetic cannabinoid usage in otherwise healthy people is unknown.

Regulation lags behind

Growing concern over the perceived dangers posed by synthetic cannabinoids has led to a ban on some of the more common ones contained in herbal incense preparations. On March 1, 2011, the US DEA temporarily placed five synthetic cannabinoids (JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol) under schedule I (banned substances).

Such a ban, however, may be futile because there are an estimated 100 synthetic cannabinoids that have yet to enter the market, and when one is banned, a new one is likely to be introduced immediately as a replacement.⁸

SYNTHETIC STIMULANTS MARKETED AS BATH SALTS

Like the herbal incense products, “bath salts” may likewise not be what they appear to be. They too may be labeled “not for human consumption” in an effort to bypass laws governing mind-altering substances.

Several pharmacologically active substances have been marketed as bath salts. Two of the more common ingredients are 3,4-methylenedioxypyrovalerone (MDPV) and 4-methylcathinone (mephedrone).

MDPV is a dopamine and norepineph-rine reuptake inhibitor that acts as a powerful stimulant. It has no FDA-approved medical use, but it is an analogue of the stimulant pyrovalerone, which was once used to treat chronic fatigue.¹⁷

MDPV seems to be the most common substance found in bath salt products in the United States. A sample of this substance was first seized on the streets by German authorities in 2007. A study in Finland conducted from August 2009 to September 2010 estimated that 5.7% of all arrests for driving under the influence (DUI) unrelated to alcohol consumption involved MDPV intoxication.¹⁷ In 2009, the National Forensic Laboratory Information System of the US DEA had seized only two samples of MDPV, but by 2010 that had increased to 161.¹⁸

Mephedrone is derived from phenethylamine and is closely related to cathinone, the active ingredient in the African khat plant (Catha edulis).¹⁹ Khat has a history of abuse, and the chemical structure of cathinone and its derivatives is similar to that of amphetamine.

Mephedrone, a powerful stimulant, is suspected of working as a monoamine reuptake inhibitor, and it may also directly induce the presynaptic release of monoamines.²⁰ The net effect is an increase in serotonin, norepineph-rine, and dopamine levels at neuronal synapses.

Mephedrone was first described in 1929 by chemist Saem de Burnaga Sanchez, and it remained an obscure research chemical for many years.²¹ It was formally recognized as a drug of abuse in Europe in 2007, and by 2009 it was the sixth most frequently used such drug in Europe.^8,22

Although MDPV and mephedrone are the most common psychoactive ingredients in bath salts, many other synthetic drugs have been found on the market.

A temporary ban

On September 7, 2011, the US government made it illegal to possess or sell any substance containing MDPV, mephedrone, or methy-lone. This temporary restriction was to remain in effect for 1 year to give the DEA time to collect data to support a move to permanently control these substances.³

Like synthetic cannabinoids, however, synthetic stimulants are very difficult to regulate because they are a large group of substances. As soon as one substance is outlawed, another synthetic stimulant will likely take its place.

MEDICAL CONCERNS REGARDING SYNTHETIC STIMULANTS

The medical and psychiatric sequelae that are associated with the use of bath salts have sent an increasing number of people to emergency rooms. The number of bath-salt-related calls to US poison control centers increased dramatically from 303 in 2010 to 4,720 by August 31, 2011. Most of these calls were related to tachycardia, agitation, hallucinations, extreme paranoia, delusions, and elevations in blood pressure.³

A report of 35 cases of people who had used bath salts and who had reported to Michigan emergency rooms between November 13, 2010, and March 31, 2011, indicated that agitation was present in 66%, tachycardia in 63%, delusions and hallucinations in 40%, seizure or tremor in 29%, hypertension in 23%, drowsiness in 23%, paranoia in 20%, and mydriasis in 20%; one patient was dead on arrival. Of the 34 patients who were alive on arrival, 17 (50%) were hospitalized, 15 were released, and 2 left against medical advice. In the patients in this study, 63% had injected the drug, 26% snorted it, and 11% ingested it orally.² Toxicology results obtained during an autopsy on the one person who died revealed a high level of MDPV, and the coroner ruled that MDPV toxicity was the primary cause of death.²

Though the pharmacokinetic properties of mephedrone are unknown, James et al²⁴ noted that an interesting feature is that its clinical effects seem to persist for more than 24 hours after the last exposure to the drug, which would not be expected based on the rapid elimination of other similar cathinones.

Sympathomimetic toxicity. Many of the symptoms listed in Table 2 are consistent with a sympathomimetic syndrome. In a case series reported by Regan et al,²⁶ most of the 57 patients exhibited cardiovascular findings consistent with sympathomimetic toxicity.

In the study by James et al,²⁴ one of the patients with chest pain had electrocardiographic changes consistent with acute myocardial infarction. Though it is not possible to conclude from a single case that mephedrone poses a risk of myocardial infarction, such a risk has been reported with khat.²⁸ More research is needed to determine whether mephedrone poses a risk of cardiac events when used by people with or without an underlying cardiac condition.

Seizure also seems to be a relatively common feature associated with mephedrone use in case series of emergency room presentations. The US Centers for Disease Control and Prevention l² reported that of 35 patients who had used bath salts, 40% experienced seizures or “tremors.” A recent case series²⁷ of 15 patients presenting to an emergency department after mephedrone use reported that 20% had experienced seizures. In the study by James et al,²⁴ four patients (3% of the total group) experienced seizures after using mephedrone. It should be noted that, aside from people presenting to emergency rooms, seizures are rarely reported in the wider population of mephedrone users.

Psychotic symptoms are also quite common in users of synthetic stimulants who present to emergency rooms, occurring, as previously stated, in 14% to 40% of cases.^2,24

In a small case series, Penders and Gestring²⁹ pointed out some common features in three patients who had used MDPV and had presented with psychosis: sleep problems, inattention, vivid hallucinations of intruders, fearfulness, and inability to remember many of the events surrounding their drug use. The authors concluded that the psychotic syndrome present in their three patients was indicative of a short-term delirium rather than a substance-induced psychosis based on the presence of attention deficits and memory problems. The patients in this series responded well to brief hospitalization and antipsychotic medications.

As with seizure, extreme presentations such as psychosis are infrequently mentioned except in people requiring treatment at a hospital. There are simply no data regarding the prevalence of psychotic symptoms in the larger group of all synthetic stimulant users.

SUSPECT SLID INTOXICATION IN ‘PSYCHIATRIC’ PATIENTS

Despite the temporary ban on the more common substances found in Spice and bath salts, it is premature for the medical community to breath a sigh of relief. Producers of these products are already likely bringing to market new ones containing similar but as yet nonbanned substances. Furthermore, such bans will do little to affect Internet commerce; rather than go to a head shop, consumers will order the products online.

Doctors in urgent care centers, emergency rooms, and on general medical floors should pay close attention to any patient without a known psychiatric history who is acting in a bizarre fashion. Most SLID-intoxicated patients will present with anxiety, agitation, and psychosis. Rather than assume that they are psychiatric patients, one should consider the possibility of SLID intoxication and pay close attention to the possible medical sequelae associated with SLID use, such as elevated blood pressure, tachycardia, and seizure.

Benzodiazepines, especially lorazepam (Ativan), have been the agents most commonly used to treat both agitation and seizures associated with SLID intoxication.

Antipsychotics should be used judiciously because of their propensity to lower the seizure threshold, and patients with synthetic stimulant toxicity are already at increased risk of seizure.

A psychiatric consult should be considered in the event of any suspected toxicity or for any patient whose behavior is difficult to manage.

Restraints may be needed in some circumstances when agitation cannot be controlled with benzodiazepines alone, to ensure safety for the patient as well as that of others in the emergency department.

Routine laboratory tests should be part of the workup of patients suspected of being under the influence of SLIDs. These include a complete blood cell count, complete metabolic panel, and urine toxicology (Table 3).^23,25 A routine urine toxicology study will likely be negative, but either the patient or collateral information may give you a general idea of what the patient used, in which case the sample could be sent out for special tests for the more common substances found in herbal incense or bath salt products.

Electroencephalography may be indicated if there is any question as to whether the patient may have suffered a seizure. There should be a low threshold to order electrocardiography, especially in the case of synthetic stimulant intoxication.

Serial cardiac enzymes may be warranted if a patient with synthetic-stimulant intoxicated has chest pain.

Education, addiction treatment. Much is unknown about the risk of SLIDs, but given the adverse events reported in the literature, it seems likely that those with underlying cardiac or psychiatric issues may be at higher risk for the most serious drug-related consequences. With regard to synthetic stimulants, Winstock et al²⁰ recommend a harm-reduction approach involving educating patients about avoiding the development of tolerance, not engaging in polydrug use, not injecting, and paying special attention to remaining cool and well hydrated.

Experience shows that once SLID patients get through their acute crisis and are no longer psychotic, they tend to be forthright in divulging what they used to get high. At that point, consideration should be given to consulting an addiction treatment specialist for further evaluation of the patient’s drug use history and for formulation of a treatment plan to help ensure that the patient doesn’t return to using these drugs.

SLIDs POSE A REAL CHALLENGE

SLIDs present a real challenge to law enforcement, governments, the public, and the addiction treatment community. There is currently no way to routinely test for these substances. Furthermore, any tests that are developed or laws that are enacted will be easily evaded, as there are many more synthetic substances waiting in the wings to be released.

Don’t be lulled into thinking that SLIDs are gone with the recent bans against some of the more common substances. More SLIDs are coming, and more morbidity should be expected in medical settings.

Doctors in emergency departments and other settings need to be prepared for the agitated and often psychotic presentation of SLID-intoxicated patients and should be ready with benzodiazepines, restraints, and a calm and reassuring manner. And for patients who present with psychotic symptoms, medical staff should also be ready to consider involuntary short-term commitment to an inpatient psychiatric unit.

Once they recover, patients need to be educated about the dangers of substances such as SLIDs that, because of their novelty, may be perceived as less dangerous alternatives to traditional illicit drugs.