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Abstract

Synthetic cannabinoids have recently gained popularity as a recreational drug because they are believed to result in a marijuana-like high. This investigation compared synthetic cannabinoids and marijuana exposures reported to a large statewide poison center system. Synthetic cannabinoid and marijuana exposures reported to Texas poison centers during 2010 were identified. The distribution of exposures to the two agents with respect to various demographic and clinical factors were compared by calculating the rate ratio (RR) of the synthetic cannabinoid and marijuana percentages for each subgroup and 95% confidence interval (CI). The proportion of synthetic cannabinoid and marijuana exposures, respectively, were 87.3% and 46.5% via inhalation (RR 1.88, 95% CI 1.38–2.61), 74.9% and 65.7% in male (RR 1.14, 95% CI 0.87–1.51), 40.2% and 56.6% age ≤19 years (RR 0.71, 95% CI 0.52–0.98), 79.2% and 58.6% occurring at a residence (RR 1.35, 95% CI 1.02–1.82), 8.4% and 16.2% managed on-site (RR 0.52. 95% CI 0.28–1.00), and 59.3% and 41.4% with serious medical outcomes (RR 1.43, 95% CI 1.03–2.05). Compared to marijuana, synthetic cannabinoid exposures were more likely to be used through inhalation, to involve adults, to be used at a residence, and to result in serious outcomes.

Keywords

marijuana poison center synthetic cannabinoid

Introduction

Marijuana has long been used for its neuropsychiatric effects including enhanced relaxation and perceptual alterations such as heightened sensory awareness and a slowing of time.¹ The primary active ingredient of marijuana is δ-9-tetrahydrocannabinol (THC), which binds to the endogenous cannabinoid receptors, CB₁ and CB₂.² Synthetic cannabinoids also affect the cannabinoid receptors. These agents were created to be potential pharmaceutical agents, attempting to take advantage of the potentially useful clinical attributes of marijuana and THC.^2,3 Hundreds of these agents have been created, including JWH-018, JWH-073, CP-47,497, and HU-210. These chemicals have also been called marijuana homologs; however, most literature refers to these agents as synthetic cannabinoids.

Synthetic cannabinoids have recently gained popularity as a recreational drug because they are believed to result in a marijuana-like high.^4,5 These compounds are sprayed onto herbal substances which then are packaged and sold under many names including K2, K2 Summit, Spice, Spice Gold, Spice Silver, Spice Diamond, Genie, Zohai, Space, Skunk, Yucatan Fire, Halo, Black Mamba, Damiana, and Drolle. These products are marketed as ‘herbal incense’ and ‘not for human consumption.’ They are available through the Internet, in gas stations, and in specialized stores such as head shops.^2,6 Their popularity has likely been enhanced by them not being detected in typical urine drug screens for THC.^4,5

Although banned in many European countries, synthetic cannabinoids are legal in much of the United States.^2,3,7 However, this trend is changing. In March 2010, Kansas became the first state to ban synthetic cannabinoids.² At least 16 states and the US military have taken action to control these substances.^2,3 On November 24, 2010, the US Drug Enforcement Administration (DEA) made possessing and selling products containing JWH-018; JWH-073; JWH-200; CP-47,497; and cannabicyclohexanol illegal for at least 1 year.³

Review of the literature failed to identify any data comparing the demographics of users, the circumstances of exposure, or the clinical effects upon patients exposed to synthetic cannabinoids versus marijuana. Poison centers receive calls requesting assistance in the management of potentially adverse exposures to a variety of substances, including marijuana and synthetic cannabinoids.^6,8–12 This investigation compared synthetic cannabinoids and marijuana exposures reported to a large statewide poison center system.

Methods

This was a retrospective review study of data from the Texas poison center network (TPCN), a system comprised of 6 poison centers that serve the 25 million population in Texas. All six centers collect demographic and clinical data using a common electronic database whose fields and permissible coding options are determined by the American Association of Poison Control Centers (AAPCC).

Cases included all synthetic cannabinoid and marijuana exposures reported to the TPCN during calendar year 2010. The single year was chosen because virtually no synthetic cannabinoid exposures were reported to the TPCN prior to 2010. Exposures involving additional substances were excluded because these other substances might have modified the clinical effects. Additionally, Texas Health and Safety Code 161.042 requires the mandatory reporting of overdoses of Penalty Group 1 substances to the Texas Department of State Health Services (DSHS). Penalty Group 1 is a criminal possession classification of substances, primarily opiates and their derivatives. The reporting is performed through the TPCN. Although marijuana is not a Penalty Group 1 drug, a study found that reporting of exposures involving marijuana in addition to Penalty Group 1 drugs to Texas poison centers may be affected by this statute.¹² Reporting of exposures to marijuana alone would not be affected by this statute.

Demographic data collected for the synthetic cannabinoid and marijuana cases included the route of the exposure, patient gender, and age. The circumstances of exposure data included the reason for the exposure, exposure site, and management site. The clinical effects included the medical outcomes and reported adverse clinical effects. The medical outcome or severity of an exposure is assigned by the poison center staff and is based on the observed or anticipated adverse clinical effects. Medical outcome is classified according to the following criteria: no effect (no symptoms due to exposure), minor effect (some minimally troublesome symptoms), moderate effect (more pronounced, prolonged symptoms), major effect (symptoms that are life-threatening or cause significant disability or disfigurement), and death. Some exposures are not followed to a final medical outcome because of resource constraints or the inability to obtain subsequent information on the patient. In these instances, the poison center staff records the expected outcome of the exposure. These expected outcomes are grouped into the following categories: not followed but judged as nontoxic exposure (symptoms not expected), not followed but minimal symptoms possible (no more than minor symptoms possible), and not followed but judged as a potentially toxic exposure.

Differences between synthetic cannabinoids and marijuana were evaluated for statistical significance by calculating the ratio of the synthetic cannabinoid and marijuana percentages for each subgroup and 95% confidence interval (CI) by Poisson probability. The ratios were considered statistically significant if the 95% CI excluded 1.00. The DSHS institutional review board considers this analysis exempt from ethical review.

Results

During 2010, 418 synthetic cannabinoid and 99 marijuana exposures not involving other substances were reported to the TPCN. Demographic data and exposure circumstances are compared in Table 1. Synthetic cannabinoid exposures were significantly more likely than marijuana to have occurred through inhalation and significantly less likely to have involved ingestion. Most exposures to both substances involved male patients; however, marijuana users were significantly younger than the synthetic cannabinoid users.

Table 1.

Comparison of synthetic cannabinoid and marijuana exposures reported to Texas poison centers during 2010, demographic and circumstance variables^a

Variable	Synthetic cannabinoid		Marijuana		RR^b	95% CI^c
Variable	No.	%	No.	%	RR^b	95% CI^c
Total	418		99
Demographic
Route
Inhalation	365	87.3	46	46.5	1.88	1.38–2.61
Ingestion	40	9.6	38	38.4	0.25	0.16–0.40
Inhalation and ingestion	8	1.9	1	1.0	1.89	0.25–84.08
Other/unknown	5	1.2	14	14.1	0.08	0.02–0.25
Patient gender
Male	313	74.9	65	65.7	1.14	0.87–1.51
Female	102	24.4	34	34.3	0.71	0.48–1.08
Unknown	3	0.7	0	0.0	–	–
Patient age (years)
≤19	168	40.2	56	56.6	0.71	0.52–0.98
≥20	242	57.9	42	42.4	1.36	0.98–1.94
Unknown	8	1.9	1	1.0	1.89	0.02–7.64
Circumstances
Exposure reason
Unintentional	41	9.8	18	18.2	0.54	0.30–1.00
Intentional	373	89.2	73	73.7	1.21	0.94–1.58
Other/unknown	4	1.0	8	8.1	0.12	0.03–0.44
Exposure site
Own/other residence	331	79.2	58	58.6	1.35	1.02–1.82
School	4	1.0	10	10.1	0.09	0.02–0.33
Other	19	4.5	6	6.1	0.75	0.29–2.29
Unknown	64	15.3	25	25.3	0.61	0.38–1.01
Management site
On-site (non-HCF)	35	8.4	16	16.2	0.52	0.28–1.00
Already at/en route to HCF	311	74.4	65	65.7	1.13	0.87–1.50
Referred to HCF	64	15.3	15	15.2	1.01	0.57–1.91
Other	8	1.9	3	3.0	0.63	0.15–3.70

HCF: health care facility.

^a Includes only those exposures not involving other substances.

^b RR: rate ratio (ratio of the synthetic cannabinoid percent to marijuana percent).

^c CI: confidence interval. Interval not including 1.00 is considered statistically significant.

The reason for the exposure was similar for the two substances, with most occurring for intentional reasons such as abuse or misuse. However, a higher proportion of unintentional exposures occurred with marijuana than with synthetic cannabinoids. Significantly more exposures to synthetic cannabinoids than marijuana occurred in a residence. Conversely, synthetic cannabinoid exposures were significantly less likely to have occurred at a school than marijuana. Most patients exposed to both substances were already at or en route to a health care facility when the poison centers were contacted; however, a higher proportion of marijuana users than synthetic cannabinoid users remained on-site.

The clinical effects of these two exposures are presented in Table 2. Significantly more synthetic cannabinoid exposures were classified as moderate effect, while more marijuana exposures were classified as no effect. The proportion of marijuana exposures classified into one of the ‘not followed’ categories was twice that for synthetic cannabinoid exposures. If the moderate effect and major effect categories are grouped together and the moderate effect, major effect, and not followed but judged to be potentially toxic categories are grouped together, the proportions of these larger groupings were significantly higher for synthetic cannabinoids than for marijuana.

Table 2.

Comparison of synthetic cannabinoid and marijuana exposures reported to Texas poison centers during 2010, medical outcome and adverse clinical effects^a

Variable	Synthetic cannabinoid		Marijuana		RR^b	95% CI^c
Variable	No.	%	No.	%	RR^b	95% CI^c
Total	418		99
Medical outcome
No effect	25	6.0	15	15.2	0.39	0.20–0.81
Minor effect	104	24.9	21	21.2	1.17	0.73–1.97
Moderate effect	176	42.1	16	16.2	2.61	1.56–4.66
Major effect	14	3.3	0	0.0	–	–
Not followed—judged nontoxic, minimal	40	9.6	21	21.2	0.45	0.26–0.80
Not followed—potentially toxic	58	13.9	25	25.3	0.55	0.34–0.92
Unrelated effect	1	0.2	1	1.0	0.24	0.00–18.59
Moderate or major	190	45.5	16	16.2	2.81	1.69–5.02
Moderate, major, or potentially toxic	248	59.3	41	41.4	1.43	1.03–2.05
Common adverse clinical effects
Tachycardia	153	36.6	13	13.1	2.79	1.58–5.36
Agitation/irritability	80	19.1	8	8.1	2.37	1.15–5.68
Drowsiness/lethargy	73	17.5	14	14.1	1.23	0.69–2.37
Vomiting	62	14.8	8	8.1	1.84	0.88–4.44
Hallucinations/delusion	47	11.2	2	2.0	5.57	1.46–47.30
Hypertension	40	9.6	3	3.0	3.16	1.01–15.96
Nausea	39	9.3	3	3.0	3.08	0.98–15.57
Confusion	37	8.9	7	7.1	1.25	0.55–3.33
Dizziness/vertigo	37	8.9	3	3.0	2.92	0.93–14.81
Chest pain	29	6.9	9	9.1	0.76	0.35–1.83

^a Includes only those exposures not involving other substances.

^b RR: rate ratio (ratio of the synthetic cannabinoid percentage to marijuana percentage).

^c CI: confidence interval. Interval not including 1.00 is considered statistically significant.

The 10 most frequently reported adverse clinical effects were similar for synthetic cannabinoids and marijuana; 9 of these occurred more commonly with the synthetic cannabinoids (Table 2). Among these, the synthetic cannabinoids were associated significantly more with tachycardia, agitation, hallucinations, and hypertension.

Discussion

Compared to marijuana, more than four times as many exposures to synthetic cannabinoids were reported to the TPCN during 2010. However, it is unlikely that the public use of synthetic cannabinoids is quadruple that of marijuana. According to the United Nations Office of Drugs and Crime, marijuana is the most widely used illicit drug, with 165 million users worldwide.¹³ Marijuana is also the most widely used illicit substance in the United States, with self-reported use greatest among 18- to 25-year-olds.¹⁴ The 2010 Monitoring the Future Survey actually showed an increasing trend of marijuana use in high school aged adolescents.¹⁵

One explanation for there being more calls to the TPCN for synthetic cannabinoids is that physicians have extensive experience managing marijuana exposures and thus may be less likely to feel the need to contact poison centers for help. Conversely, they have little experience with the synthetic cannabinoids and may be more likely to call a poison center for assistance. Another explanation for this discrepancy is that synthetic cannabinoids may cause more severe adverse clinical effects than marijuana, resulting in more calls to the TPCN seeking assistance.

Compared to marijuana, synthetic cannabinoid exposures occurred significantly more through inhalation and less via ingestion. This may be because the synthetic cannabinoids are primarily marketed as herbal incense, which may predispose users to smoke the products, while marijuana has a long history of being ingested as well as inhaled. As far as the authors are aware, this is the first study noting that synthetic cannabinoids were ingested. The brief on ‘Spice’ published by the European Monitoring Center for Drugs and Drug Addiction includes an unreferenced statement that ingestion has occurred.⁷ Published case reports on the use of synthetic cannabinoids have all noted that inhalation was the route of drug delivery.^4,5,16

As with marijuana, most synthetic cannabinoid users are male. Marijuana users were more likely to be less than 20 years old. The cause of this age difference is unclear. Despite synthetic cannabinoids being available through the Internet, in gas stations, and specialized stores such as head shops, long established marijuana sources may enable adolescents to still be able to more easily obtain marijuana. In addition, adults may be more likely to try a ‘new’ agent compared to adolescents.

While cardiovascular effects of marijuana can vary, they usually include an increase in heart rate and a decrease in vascular resistance.^14,17,18 Blood pressure usually has a small increase.¹⁴ Similar cardiovascular effects with synthetic cannabinoids have been seen in case reports and self-administration testing.^4,5,19,20 In our comparison of these two agents, both tachycardia and hypertension occurred significantly more frequently with the synthetic cannabinoids than marijuana. Most users of both of these agents do so in order to attain the neuropsychiatric effects. Compared to marijuana, our data reflected that the synthetic cannabinoids caused significantly more agitation and hallucinations. Agitation has been commonly reported with the synthetic cannabinoids.^4,5,19 Hallucinations/delusions were found in 11.2% of our synthetic cannabinoid users. None of the case reports with the synthetic cannabinoids noted the patients to have hallucinations; however, some noted alterations of perception.^4,19,20

As with the signs and symptoms noted above, the medical outcome classification also reflected that synthetic cannabinoids caused more serious clinical effects than marijuana. This coding by the poison center specialists may have occurred because of the more serious signs and symptoms noted above. Another explanation for the differences in outcome coding may be the lack of familiarity with the synthetic cannabinoids; potentially resulting in poison center specialists listing more serious codes.

Our data reflect that despite both the THC in marijuana and the synthetic cannabinoids affecting the same cannabinoid receptors, patients exposed to these products present differently. The reasons for the differences are not clear. Compared to THC, the synthetic cannabinoids’ affinity is 4 times more at the CB₁ receptor and 10 times more at the CB₂ receptor.^21,22 This difference in affinity may contribute to the synthetic cannabinoids’ increased frequency of adverse clinical effects. Clinical effects could also be modified by other agents in the marijuana or in the herbals to which the synthetic cannabinoids are added. For example, cannabidiol, a nonpsychoactive cannabinoid present in many marijuana products, modulates the effects of THC.²³ Interpretation of the clinical effects for each of these agents is further limited by variations in the products themselves. Marijuana potency and effects are modified by many factors.²³ In addition, there are numerous synthetic cannabinoids, many of which are structurally unrelated to THC, potentially resulting in different clinical effects.²⁴ Different synthetic cannabinoids have been found in herbal products with the same packaging, further limiting the ability to establish the relationship between specific synthetic cannabinoids and clinical effects.

This study is subject to various limitations. The reporting of synthetic cannabinoids and marijuana to TPCN is voluntary. Thus, the TPCN database might not be representative of all of the exposures occurring in the state. Moreover, user calls to poison centers may also be limited by marijuana’s illegality and the negative press related to both agents. Users may call only when they are particularly concerned, such as when they are experiencing serious adverse effects.

Another limitation is that exposures were based on verbal reports by the patients, their friends or family, or the health care providers treating them. The exposures were not verified by toxicology tests.

In conclusion, compared to marijuana, synthetic cannabinoids were more likely to be used through inhalation, to involve adults, to be used at a residence as opposed to school, and result in serious outcomes with higher rates of tachycardia, hypertension, agitation, and hallucinations.

Footnotes

Funding

This work was supported by a contract with the Commission on State Emergency Communications in Texas.

Declaration of Conflict of Interests

The authors declared no conflicts of interest.

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