U.S. Department of Justice

Drug Enforcement Administration

Schedules of Controlled Substances: Placement of 1-Butyl-3-(1-

naphthoyl)indole (JWH-073), 1-pentyl-3-(1-naphtoyl)indole (JWH-018), 1-[2-

(4-morpholinyl)ethyl]-3-(1-naphthoyl)indole (JWH-200), 5-(1,1-

dimethylheptyl)-2-(3-hydroxycyclohexyl)-phenol (CP-47,497), and 5-(1,1-

dimethyloctyl)-2-(3-hydroxycyclohexyl)-phenol (cannabicyclohexanol and CP47,497 C8 homologue) into Schedule I

Background, Data, and Analysis:

Eight Factors Determinative of Control

and Findings Pursuant to 21 U.S.C. 812(b)

Prepared by:

Office of Diversion Control, Drug and Chemical Evaluation Section

Washington, D.C. 20537

February 2012
2

I. Background

On March 1, 2011, the Administrator of the Drug Enforcement Administration (DEA) 

published a Final Order in the Federal Register temporarily placing five synthetic cannabinoids 

in Schedule I of the Controlled Substances Act (CSA) upon finding that these substances pose an 

imminent threat to public safety. 76 FR 11075. The five synthetic cannabinoids controlled are 1-

pentyl-3-(1-naphthoyl)indole (JWH-018), 1-butyl-3-(1-naphthoyl)indole (JWH-073), 1-[2-(4-

morpholinyl)ethyl]-3-(1-naphthoyl)indole (JWH-200), 5-(1,1-dimethylheptyl)-2-(3-

hydroxycyclohexyl)-phenol (CP-47,497), and 5-(1,1-dimethyloctyl)-2- (3-hydroxycyclohexyl)-

phenol (cannabicyclohexanol, CP-47,497 C8 homologue). 

Numerous products, marketed under the guise of “herbal incense,” with trade names such as 

“Spice” and “K2,” have conclusively been found to contain these five substances. These 

products are manufactured by lacing plant material with the synthetic cannabinoids and marketed 

as “legal” alternatives to marijuana

1

. They are abused for their psychoactive properties and 

packaged with variable and unpredictable mixtures of one or more synthetic cannabinoids, with 

variable and unpredictable potency, and without any information as to the health and safety risks. 

The products containing these substances have no legitimate uses, while the substances 

contained within have no currently accepted medical use in treatment in the United States and 

have not been investigated for human use.

Aminoalkylindoles (AAIs) JWH-018, JWH-073, and JWH-200, and the cyclohexylphenols 

CP-47,497 and cannabicyclohexanol have been encountered alone and/or laced on plant material. 

Abuse of these substances is believed to be the result of their purported cannabimimetic 

properties and popular status as a “legal” alternative to marijuana (Schifano et al., 2009; 

Lindigkeit et al., 2009; Hudson and Ramsey, 2011). Since 2009, law enforcement encounters 

regarding these five substances have greatly increased in the United States. A limited number of 

clinical reports demonstrate addiction and withdrawal symptoms, general convulsions, 

cardiovascular toxicity, and psychosis associated with the abuse of herbal incense products 

containing these five synthetic cannabinoids. The laced synthetic cannabinoid, and not the plant 

material itself, is considered to be the pharmacologically active component in these products 

(Zuba et al., 2011; Wells and Ott, 2011). 

Numerous state public health and poison centers have warned of the dangers associated with 

the use of synthetic cannabinoids and their associated products being found on the designer drug 

market. In response to the abuse of these substances, as of January 13, 2012, forty-eight states in 

the U.S. have controlled at least one of these five synthetic cannabinoids. Numerous local 

jurisdictions have also placed controls on these designer drugs. Bans of the use of these 

synthetic cannabinoids by military personnel have also been issued in response to the abuse of 

these synthetic cannabinoids and the related products (Bebarta et al., 2010; communications to 

DEA). Through December 31, 2011, the American Association of Poison Control Centers 

 

1 Note that ‘‘marihuana’’ is the spelling originally used in the Controlled Substances Act (CSA). 

This document uses the spelling that is more common in current usage, ‘‘marijuana.’’
3

(AAPCC) reported 9,922 2toxic exposure calls involving synthetic cannabinoids and its products, 

many of which were received en-route to or from emergency departments. Products containing 

at least one or more of the before-mentioned five synthetic cannabinoids have been connected to 

these exposure incidents. 

Prior to the DEA Final Order published on March 1, 2011, the aforementioned substances 

and their associated products were, and still are, readily obtainable on Internet websites and in 

local retail shops (e.g., head shops, convenient stores, and tobacco shops). Even with no known 

legitimate use for these substances, law enforcement, including Customs and Border Protection, 

has had numerous encounters of bulk quantities (>10 g) of these substances. There have been 

reports of driving under the influence of these drugs (DUIDs) and jeopardizing the public safety. 

Additionally, law enforcement has uncovered product manufacturing labs of varying sizes. Law 

enforcement has encountered individuals abusing synthetic cannabinoids-containing products, 

driving under the influence of synthetic cannabinoids-containing products, manufacturing said 

products, and responding to exposure incidents that warrant admission of the users of these 

products to emergency departments. Accidental overdosing with complications is a public health 

concern. Additional health and safety concerns for the unsuspecting user are the lack of 

information regarding product ingredients and composition. Indeed, these herbal products laced 

with synthetic cannabinoids have been shown to vary largely in the amount and the particular 

synthetic cannabinoid(s) under the same retail product name (Auwärter et al., 2009; Dresen et 

al., 2010; Zuba et al., 2011). 

Pursuant to 21 U.S.C. 811(b) and after gathering the necessary data, on June 21, 2011, DEA

requested from the Department of Health and Human Services (HHS) a scientific and medical 

evaluation and a scheduling recommendation for JWH-018, JWH-073, JWH-200, CP-47,497 and 

cannabicyclohexanol. Pursuant to 21 U.S.C. 811 (b) and (c), on January 5, 2012, February 6,

2012, February 13, 2012, HHS provided DEA with the following scientific and medical 

evaluations: “Basis for the Recommendation to place 1-Pentyl-3-(1-naphtoyl)indole (JWH-018) 

and its Salts in Schedule I of the Controlled Substances Act (CSA)”; “Basis for the 

Recommendation to place Naphthalen-1-yl-(1-butylindole-3-yl)methanone (JWH-073) and its 

Salts in Schedule I of the Controlled Substances Act (CSA)”; “Basis for the Recommendation to 

place [1-[2-(4-Morpholinyl)ethyl]-1H-indol-3-yl]-1-naphthalenyl-methanone (JWH-200) and its 

Salts in Schedule I of the Controlled Substances Act (CSA)”; “Basis for the Recommendation to 

Place 5-(1,1- Dimethylheptyl)-2-[(1R,3S)-3-Hydroxycyclohexyl Phenol] and its Enantiomer 5-(1,1-

Dimethylheptyl)-2-[(1S,3R)-3-Hydroxycyclohexyl Phenol](CP 47,497), and their Salts in Schedule I 

of the Controlled Substances Act (CSA)”; and “Basis for the Recommendation to Place 

Cannabicyclohexanol, (C8)-CP 47,497, Also Known as 5-(1,1- Dimethyloctyl)-2-[(1R,3S)-3-

Hydroxycyclohexyl Phenol] and its Enantiomer 5-(1,1- Dimethyloctyl)-2-[(1S,3R)-3-

Hydroxycyclohexyl Phenol], and its Salts in Schedule I of the Controlled Substances Act (CSA).” 

These evaluations then recommended, respectively, that JWH-018, JWH-073, JWH-200, CP47,497 and cannabicyclohexanol be added to Schedule I of the CSA. 

 

2 The figure “9,992” appearing at 77 FR 12512 should read “9,922.”
4

The CSA requires DEA, as delegated by the Attorney General,3to determine whether HHS’s 

scientific and medical evaluation and all other relevant data constitute substantial evidence of 

potential for abuse such that the substance should be scheduled. 21 U.S.C. 811(b).

 

3

28 CFR 0.100(b)
5

II. Eight Factors Determinative of Control

Pursuant to 21 U.S.C. 811(c), DEA must consider eight factors in making any finding of 

substantial evidence of potential for abuse, including the necessary data and law enforcement 

information relevant thereto.

Factor 1: Its Actual or Relative Potential for Abuse

Potential for Abuse

The abuse potential of the Schedule I cannabinoid delta-9-tetrahydrocannabinol (THC), the 

main active ingredient of marijuana, is well documented. The abuse of the five synthetic 

cannabinoids under evaluation is associated with their ability to evoke cannabinoid-like 

subjective effects similar to those evoked by THC.

a. Legislative History and Determination of Abuse Potential 

The legislative history of the CSA provides four factors to consider in determining whether a 

particular drug or substance has potential for abuse:4

i. There is evidence that individuals are taking the drug or other substance in amounts 

sufficient to create a hazard to their health or to the safety of other individuals or to the 

community; or

ii. There is significant diversion of the drug or substance from legitimate drug channels; or

iii. Individuals are taking the substance on their own initiative rather than on the basis of 

medical advice from a practitioner licensed by law to administer such drugs; or

iv. The drug is a new drug so related in its action to a drug or other substance already listed 

as having a potential for abuse to make it likely that the drug or other substance will have 

the same potential for abuse as such drugs, thus making it reasonable to assume that there 

may be significant diversion from legitimate channels, significant use contrary to or 

without medical advice, or that it has a substantial capability of creating hazards to the 

health of the user or to the safety of the community.

i. Individuals are taking JWH-018, JWH-073, JWH-200, CP-47,497, and 

cannabicyclohexanol in amounts sufficient to create a hazard to their health or to the safety 

of other individuals or to the community 

A number of case reports and case series have shown that individuals take these substances 

and products containing these substances in amounts sufficient to induce toxic effects similar to 

those induced by marijuana such as anxiety, tachycardia and hallucinations. Severe toxic effects 

including seizures, tachyarrhythmias and other cardiovascular toxicity, extreme anxiety leading 

to panic attacks and potentially suicide, and the precipitation or exacerbation of psychotic 

episodes have also been reported following abuse of these substances or products containing 

these substances (Lapoint et al., 2011; Vandrey et al., 2012; Simmons et al., 2011a and b; 

Schneir and Baumhaeher, 2011). Further, law enforcement encounters suggest occurrences of 

fatal automotive accidents have been caused by drivers under the influence of products 

 

4 Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. No. 91-1444, 91st Cong., Sess. 1 

(1970); 1970 U.S.C.C.A.N. 4566, 4601.
6

containing synthetic cannabinoids, while one instance of a homicide perpetrated by an individual 

under the influence of JWH-018 has also been reported. 

Because these substances act on the same molecular targets as the active ingredient of 

marijuana, THC, they are likely to share some of its harmful health effects. Briefly, Marijuana's 

potential harmful health effects include cardiovascular effects. Prenatal exposure to marijuana, 

and potentially to synthetic cannabinoids, can significantly impact the cognitive and behavioral 

development of children. Finally, it is now established that marijuana can cause psychological 

and physical dependence. Habitual marijuana users experience craving for the substance and 

abrupt abstinence from chronic marijuana smoking can produce withdrawal symptoms. 

Similarly, HHS states that case reports have demonstrated that herbal products containing 

synthetic cannabinoids produce physical dependence and a withdrawal syndrome (76 FR 40552,

Zimmermann et al., 2009).

ii. Significant diversion of JWH-018, JWH-073, JWH-200, CP-47,497, and 

cannabicyclohexanol from legitimate channels and/or ease with which drug can be obtained

Since March 1, 2011, JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol

have been temporarily controlled in Schedule I and have thus not been legally available unless

for research purposes. Individuals, including minors, have been purchasing these substances 

from internet vendors, gas stations, convenience stores, and head shops, while other reports

indicate U.S. military personnel have likewise been purchasing and abusing these substances. 

These substances and laced products are commonly marketed as “legal highs” and with a 

disclaimer “not for human consumption.” 

Additionally, large seizures of JWH-018, JWH-073, JWH-200, CP-47,497, and 

cannabicyclohexanol have occurred by law enforcement. The National Forensic Laboratory 

Information System (NFLIS) details over 5,450 reports from state and local forensic laboratories 

identifying JWH-018, JWH-073, JWH-200, CP-47,497 or cannabicyclohexanol in drug related 

exhibits for a period from January 2009 to December 2011 from 39 states. 

iii. Individuals are taking JWH-018, JWH-073, JWH-200, CP-47,497, and 

cannabicyclohexanol on their own initiative rather than on the basis of medical advice from 

a practitioner licensed by law to administer such substance. 

There is currently no accepted medical use for JWH-018, JWH-073, JWH-200, CP-47,497, 

and cannabicyclohexanol, and no medical practitioner is currently licensed by law to administer 

them outside of an extremely limited research setting. Indeed, the FDA has not evaluated or 

approved a new drug application (NDA) for these synthetic cannabinoids for any therapeutic 

indication, and no investigational new drug (IND) application is currently active. According to 

the results of the 2011 Monitoring the Future survey of high schools students, 1 in 9 high school 

seniors (11.4%) have used “synthetic marijuana” (products often containing synthetic 

cannabinoids) in the past year (Johnston et al., 2012). It is one of the most frequently mentioned

among high school seniors, second only to marijuana.

iv. JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol are so related in 

their action to a substance already listed as having a potential for abuse to make it likely 

that they will have the same potential for abuse as such substance, thus making it 
7

reasonable to assume that there may be significant diversions from legitimate channels, 

significant use contrary to or without medical advice, or that they have a substantial 

capability of creating hazards to the health of the user or to the safety of the community.

HHS states that JWH-018, JWH-073, JWH-200, CP-47,497 and cannabicyclohexanol are

potent cannabinoid receptor agonists with no antagonist activity and with abuse potential similar

to the Schedule I substances marijuana and THC (the main psychoactive constituent of 

marijuana) (Wachtel et al., 2002). Two types of cannabinoid receptors, cannabinoid-1 (CB1) and 

cannabinoid-2 (CB2), have been characterized (Piomelli, 2005). These synthetic cannabinoids, 

similar to THC, have affinity for both CB1 and CB2 receptors. The cloning of cannabinoid 

receptors has verified the site of action of THC and other cannabinoids (Matsuda et al., 1990; 

Gerard et al., 1991). The CB1 receptors are thought to mediate the psychotropic effects of THC 

(Hanus et al., 1999). 

HHS states that JWH-018, JWH-073, JWH-200, CP-47,497 and cannabicyclohexanol appear 

to be marketed solely for abuse, for their cannabis-like activity and because, prior to March 1, 

2011, they were not controlled under the CSA. Thus, commerce involving these synthetic 

cannabinoids is for the purpose of their abuse and to escape the regulatory and criminal penalties 

of the CSA. If uncontrolled, it is reasonable to assume there will be significant use of these 

synthetic cannabinoids contrary to, or without, medical advice, along with substantial hazards to 

the health of the user and to the safety of the community. 

b. Actual or Relative Abuse Potential

Cannabicyclohexanol, CP-47,497, JWH-018, JWH-073, and JWH-200, similar to THC, are 

CB1 receptor agonists. The CB1 receptors are thought to be responsible for the euphoric and 

psychoactive effects of THC and related cannabinoids (Wells and Ott, 2011). 

i. Animal Studies

Drug Discrimination Studies

The drug discrimination paradigm is used as an animal model of human subjective effects. 

This procedure provides a direct measure of stimulus specificity of a test drug in comparison 

with a known standard drug, or a neutral stimulus (e.g. injection of saline water). The lightheadedness and warmth associated with having a few beers or the jitteriness and increased heart 

rate associated with drinking several cups of coffee are examples of substance-specific stimulus 

effects. The drug discrimination paradigm is based on the ability of nonhuman and human 

subjects to learn to identify the presence or absence of these stimuli and to differentiate among 

the constellation of stimuli produced by different pharmacological classes. In drug 

discrimination studies, the drug stimuli function as cues to guide behavioral choice, which is 

subsequently reinforced with food or money. Repeated pairing of the reinforcer with only drugappropriate responses can engender reliable discrimination between drug and no-drug or 

amongst several drugs. Because some interoceptive stimuli are believed to be associated with 

the reinforcing effects of drugs, the drug discrimination paradigm is used to evaluate the abuse 

potential of new substances. In this procedure, animals are trained to recognize or discriminate 

the stimulus effects of a given dose of a particular training drug from those of (1) a different dose 
8

of the same training drug, (2) a different training drug, or (3) saline/vehicle (i.e., a nondrug 

condition) (Compton et al., 1993; Solinas et al., 2006). 

At the time of temporary scheduling of JWH-018, JWH-073, JWH-200, CP-47,497, and 

cannabicyclohexanol, DEA requested that the National Institute on Drug Abuse (NIDA) conduct 

pharmacological studies on these synthetic cannabinoids. The pharmacological studies 

conducted included animal drug discrimination studies on these substances (NIDA, 2011a,b, 

2012a,b). The data from these studies as well as the data published in the scientific literature 

suggest that the discriminative stimulus effects of JWH-018, JWH-073, JWH-200, CP-47,497, 

and cannabicyclohexanol are similar to those of the Schedule I substance THC, the principal 

active constituent of marijuana. These data are discussed below.

JWH-018, JWH-200, JWH-073, and cannabicyclohexanol were tested for their ability to 

substitute for the discriminative stimulus effects of THC (3 mg/kg) in six male Sprague-Dawley 

rats using a two-lever choice methodology (NIDA, 2011a,b, 2012a,b). Food was available as a 

reinforcer under a fixed ratio 10 schedule when responding occurred on the injection appropriate 

lever. The substances or their vehicle [ethanol/Cremophor EL/0.9% saline (1:1:18) were 

administered as intraperitoneal injections. Dose ranges of 0.1 to 5 mg/kg for JWH-200, 0.03 to 1 

mg/kg for JWH-018, 0.1 to 10 mg/kg for JWH-073 and 0.1 to 2.5 mg/kg for 

cannabicyclohexanol were examined. 

JWH-200 substituted fully (ED50 = 1.16 mg/kg, 30 minutes before testing) for the 

discriminative stimulus effects produced by 3 mg/kg of THC. Response rate was decreased to 

84% of vehicle control following 5 mg/kg JWH-200 (NIDA, 2011b). 

JWH-018 substituted fully (ED50 = 0.39 mg/kg, 60 minutes before testing) for the 

discriminative stimulus effects produced by 3 mg/kg of THC. Response rate was decreased to 

79% of vehicle control following 1 mg/kg JWH-018 (NIDA, 2011a).

JWH-073 substituted fully (ED50 = 0.88 mg/kg, 30 minutes before testing) for the 

discriminative stimulus effects produced by 3 mg/kg of THC. Response rate was decreased to 

34% of vehicle control following 10 mg/kg JWH-073 (NIDA, 2012a).

Cannabicyclohexanol substituted fully (ED50 = 0.80 mg/kg, 30 minutes before testing) for 

the discriminative stimulus effects produced by 3 mg/kg of THC. Response rate was decreased to 

51% of vehicle control following 2.5 mg/kg cannabicyclohexanol (NIDA, 2012b).

The above-mentioned data from the drug discrimination studies performed by the NIDA 

contract researchers are consistent with the several published reports on discriminative stimulus 

effects of these cannabinoids. These reports are described below. 

Järbe and colleagues (2011) showed that JWH-018 (ED50 = 0.14 mg/kg, 30 minutes before 

testing and ED50 = 0.39 mg/kg, 90 minutes before testing) fully substitutes for THC in rats 

trained to discriminate the effects of vehicle from those produced by 3 mg/kg of THC. JWH-018 

was about four-fold more potent than THC. The cannabinoid receptor 1-selective 
9

antagonist/inverse agonist rimonabant produced surmountable blockade of the discriminative 

stimulus effects of both JWH-018 and THC. 

Ginsberg and colleagues (2012) also showed that JWH-018 and JWH-073, similar to THC, 

produced THC-like drug appropriate responding in rhesus monkeys trained to discriminate THC 

(1 mg /kg i.v.) from saline. The ED50 values for JWH-018, JWH-073 and THC were 0.013, 

0.058 and 0.044 mg/kg, respectively and the corresponding durations of actions were 2, 1 and 4 

hours. Rimonabant, a CB1 receptor antagonist, upon pretreatment produced a surmountable 

antagonism of the discriminative stimulus effects JWH-018, JWH-073 and THC. Ginsberg and 

colleagues (2012) using monkeys discriminating the cannabinoid antagonist rimonabant (1 

mg/kg, i.v.) during chronic THC (1 mg/kg/12 hours, s.c.) treatment, an assay sensitive to 

cannabinoid withdrawal, found that JWH-018 (0.32 – 3.2 mg/kg), JWH-073 (0.32-3.2 mg/kg) 

similar to THC (1-10 mg/kg), dose-dependently attenuated the rimonabant discriminative 

stimulus. Based on these data, these researchers concluded that JWH-018, JWH-073, and THC 

share a common receptor mechanism to produce THC-like subjective effects and to attenuate 

withdrawal effects of THC.

Weissman and colleagues (1982) showed that CP-47,497 fully substitutes for THC in animals 

trained to discriminate 3.2 mg/kg THC from its vehicle administered intraperitoneally. CP47,497 (ED50 = 0.1 mg/kg, i.p. 60 minutes before testing) was about 6.8-fold more potent than 

THC (ED50 = 0.68 mg/kg, i.p.). These authors further showed that rats, upon subjecting to 

acquisition task for 56 days (trials) requiring discrimination between THC and CP-47,497, were 

unable to discriminate pharmacologically equivalent doses of these two substances. Thus these 

authors concluded that these two substances possess identical discriminative stimulus properties.

Similar to the present aminoalkylindoles (JWH-018, JWH-073 and JWH-200), and 

cyclohexanols (CP-47,497, and cannabicyclohexanol), various other substances of these two 

chemical classes aminoalkylindoles and cyclohexylphenols have also been shown to produce

THC-like discriminative stimulus effects (Weissman et al., 1982; Compton et al., 1992a; 

Compton et al., 1992b; Compton et al., 1993; Wiley et al., 1998; Vann et al., 2009; Järbe et al., 

2010, 2011). 

Cannabicyclohexanol, CP-47,497, JWH-018, JWH-073, and JWH-200 share 

pharmacological similarities with the Schedule I substance THC (Weissman et al., 1982; 

Compton et al., 1992a; Wiley et al., 1998). Behavioral evaluations in animal models, especially 

drug discrimination studies suggest that aminoalkylindoles and cyclohexylphenols produce 

THC-like discriminative stimulus effects (Weissman et al., 1982; Compton et al., 1992a; 

Compton et al., 1992b; Compton et al., 1993; Wiley et al., 1998; Järbe et al., 2010). There are 

also numerous anecdotal self-reports substantiating that these substances and the associated 

products are abused by humans for their hallucinogenic effects, as well as, published reports 

indicating an increase in the abuse of these substances (Lindigkeit et al., 2009; Every-Palmer et 

al., 2011; AAPCC Press Releases). In evaluating symptoms upon smoking herbal incense 

products, Hermanns-Clausen and colleagues (2009) reported similarities between cases 

resembling severe cannabis-intoxication. Furthermore, the observed health effects are not 

anticipated based on the declared herbs (Auwärter et al., 2009; Lindigkeit et al., 2009; Zuba et 

al., 2011; Ernst et al., 2011). Tachyphylaxis has been described for the JWH-018 after 
10

approximately three days of use, possibly attributable to receptor down-regulation (Wells and 

Ott, 2011).

The Mouse Tetrad Test

The mouse tetrad is a well-established paradigm for evaluating substances for 

cannabimimetic properties (Martin et al., 1991). This tetrad includes pharmacological models 

that evaluate catalepsy, locomotor activity, hypothermia and antinociception in mice. JWH-018, 

JWH-200, CP-47,497 and cannabicyclohexanol were shown to be active in all four parameters of 

the mouse tetrad whereas JWH-073 was only tested, and shown to be active, in three of the four 

parameters of the tetrad test (Wiley et al., 1998; Compton et al., 1992b).

ii. Clinical studies and reports

Cannabicyclohexanol, CP-47,497, JWH-018, JWH-073, and JWH-200 have not been 

evaluated in human abuse liability studies. Furthermore, no studies have been undertaken to 

evaluate the toxicology and safety of these substances in humans.

An internet-based survey conducted with adults reporting at least one lifetime use of a 

“Spice” product, evaluated subjective effects of these synthetic cannabinoids were evaluated 

(Vandrey et al., 2012). Most respondents (85%) indicated that Spice products produced 

subjective effects similar to cannabis, while fewer than 10% reported similarities between Spice

products and other licit and illicit drugs. Despite producing effects similar to marijuana, 54% of 

respondents also reported Spice products produced subjective effects that were unique and 

discernible from other licit and illicit drugs. Authors stated that the frequency of hallucinations 

(28%) following Spice product use is also greater than what would be expected for cannabis 

consumption. Most respondents (87%) reported having a positive experience following use of a 

Spice product, though negative or unwanted effects following use were reported by 40% of the 

sample. 

A case report from San Diego, CA, describes the presentation of two patients presented to the 

emergency department (ED) predominantly exhibiting anxiety after recreationally using a Spice

product that was subsequently confirmed to contain the synthetic cannabinoids, JWH-018 and 

JWH-073 (Schneir et al., 2011). One of the patients described feeling anxious, tremulous, and 

experiencing palpitations soon after using the product. Physical examination of one patient 

revealed normal vital signs, occasional inappropriate laughter, normal-sized pupils, bilaterally 

reddened conjunctiva, and a few beats of lateral gaze nystagmus bilaterally. The other patient 

displayed normal-sized pupils, bilaterally reddened conjunctiva, and tachycardia.

A recent case report by Schneir and Baumhaeher (2011) describes a 19-year-old male patient 

who had two witnessed generalized convulsions soon after smoking a Spice product that was 

later confirmed to contain JWH- 018 and three other different synthetic cannabinoids (JWH-081, 

JWH-250, and AM-2201). Convulsions have been described in another published report for 

which there was no laboratory confirmation for the presence of synthetic cannabinoids (Simmons 

et al., 2011a). In another report, in which there was laboratory confirmation for metabolites of 

the synthetic cannabinoid JWH-018, a patient was interpreted by the authors as having had a 

possible convulsion (Simmons et al., 2011b). 
11

c. Actual Abuse

As of January 13, 2012, forty-eight states in the U.S. have controlled at least one of these five 

synthetic cannabinoids. Numerous local jurisdictions have also placed controls on these designer 

drugs. Bans of the use of these synthetic cannabinoids by military personnel have also been 

issued in response to the abuse of these synthetic cannabinoids and their related products 

(Bebarta et al., 2010; communications to DEA). These substances have been developed over the 

last 30 years to investigate their cannabimimetic properties. Subsequently, these substances have 

been identified as ingredients in numerous retail products (Auwärter et al., 2009; Zuba et al., 

2009; Hudson et al., 2010; Uchiyama et al., 2010a,b, 2011; Dresen et al., 2010; EMCCDA, 

2009). JWH-018 was the first synthetic cannabinoid to be identified as a product ingredient in

Germany in 2008. 

Forensic Laboratory Data

The National Forensic Laboratory Information System (NFLIS) is a program sponsored by 

DEA's Office of Diversion Control. NFLIS compiles information on exhibits analyzed in state 

and local law enforcement laboratories. The System to Retrieve Information from Drug 

Evidence (STRIDE) is a DEA database which compiles information on exhibits analyzed in DEA 

laboratories. NFLIS and STRIDE together capture data for all substances reported by forensic 

laboratory analyses. More than 1,700 unique substances are reported to these two databases.

Large seizures of JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol have 

occurred by law enforcement. NFLIS details over 5,450 reports from state and local forensic 

laboratories identifying JWH-018, JWH-073, JWH-200, CP-47,497 and/or cannabicyclohexanol 

in drug related exhibits for a period from January 2009 to December 2011 from 39 States (Table 

1). 
12

Table 1. Selected Synthetic Cannabinoids Number of Exhibits (State and Local Labs) in NFLIS 

(January 2009 - December 2011)

2009 2010 2011 Drug 

Totals

1-Pentyl-3-(1-naphtoyl)indole (JWH-018) 19 2,013 2,598 4,630

1-Butyl-3-(1-naphthoyl)indole (JWH-073) 2 298 407 707

1-[2-(4-morpholinyl)ethyl]-3-(1-

naphthoyl)indole (JWH-200) 0 61 41 102

5-(1,1-dimethylheptyl)-2-(3-

hydroxycyclohexyl)-phenol (CP-47,497) 0 0 3 3

Cannabicyclohexanol 0 5 5 10

21 2,377 3,054 5,452

NFLIS database queried 02-21-2012. State and 

Local Forensic Laboratory drug reports TOTALS

First, second and third drug reports analyzed, 

by submission date.

Drugs reported to NFLIS in December 2011 are 

likely incomplete as of February 21, 2012, due 

to laboratory reporting lag time.

STRIDE also details reports from federal forensic laboratories identifying JWH-018, JWH073, and JWH-200 in drug related exhibits for a period from January 2009 to December 2011 

(Table 2).

Table 2. Selected Synthetic Cannabinoids Number of Exhibits (Federal Labs) in STRIDE 

(January 2009 - December 2011).

2009 2010 2011

Drug 

Totals

1-Pentyl-3-(1-naphtoyl)indole (JWH-018) 4 48 149 201

1-Butyl-3-(1-naphthoyl)indole (JWH-073) 1 6 59 66

1-[2-(4-morpholinyl)ethyl]-3-(1-

naphthoyl)indole (JWH-200) 0 0 6 6

5-(1,1-dimethylheptyl)-2-(3-

hydroxycyclohexyl)-phenol (CP-47,497) 0 0 0 0

Cannabicyclohexanol 0 0 0 0

5 54 214 273

STRIDE database queried 02-21-2012. Federal 

Forensic Laboratory drug reports TOTALS

All drug reports analyzed, by submission date
13

According to the results of the 2011 Monitoring the Future survey of high schools students, 1 

in 9 high school seniors (11.4%) have used synthetic marijuana in the past year (Johnston et al., 

2012). It is one of the most frequently mentioned among high school seniors in this survey, 

second only to marijuana.

State public health and poison centers have issued warnings in response to adverse health 

effects associated with herbal incense products containing synthetic cannabinoids. These effects 

included tachycardia, elevated blood pressure, unconsciousness, tremors, seizures, vomiting, 

hallucinations, agitation, anxiety, pallor, numbness and tingling. Scientific literature reports by 

emergency department physicians and toxicologists have been published which characterize the 

abuse of JWH-018 (Vearrier and Osterhoudt, 2010; Canning et al., 2010; Schneir et al., 2011; 

Banerji et al., 2010; Hermanns-Clausen et al., 2009). Additionally, numerous public health and 

poison centers have issued warnings regarding the abuse of synthetic cannabinoids and the 

associated products. Bans of the use of these synthetic cannabinoids by military personnel have 

been issued in response to the abuse of synthetic cannabinoids and the related products (Bebarta 

et al., 2010; communications to DEA).

Dresen and colleagues (2011) analyzed 101 serum samples from 80 subjects provided by 

different hospitals, detoxification and therapy centers, forensic psychiatry centers, and Institutes 

of Forensic Medicine. The prevalence of positive samples for the presence of cannabinoids of 

the aminoalkyindole type was highest amongst those originating from forensic psychiatric 

centers, 63.3% positive samples (Dresen et al., 2011). Additionally, U.S. Drug Courts have 

communicated concerns related to the abuse of synthetic cannabinoids and provided DEA with 

data demonstrating a response rate of greater than 30% by juveniles subject to routine drug 

screens. Both reports suggest drug replacement in treatment settings.

HHS states in their recommendations to place JWH-018, JWH-073, JWH-200, CP-47,497 

and cannabicyclohexanol in Schedule I of the CSA that these substances are cannabinoid 

agonists. HHS also states that based on their pharmacological similarity to THC, it is reasonable 

to assume JWH-018, JWH-073, JWH-200, CP-47,497 and cannabicyclohexanol will have a 

potential for abuse that is similar to that of marijuana and THC (both in Schedule I). Although 

these substances were originally developed as legitimate research tools, HHS is unaware of any 

legitimate commercial uses of JWH-018, JWH-073, JWH-200, CP-47,497 and 

cannabicyclohexanol. HHS believes that JWH-018, JWH-073, JWH-200, CP-47,497 and 

cannabicyclohexanol are marketed solely for abuse because the substances elicits cannabis-like 

activity and are not controlled under the CSA. Thus, commerce involving JWH-018, JWH-073, 

JWH-200, CP-47,497 and cannabicyclohexanol is for the purpose of their abuse and to escape 

the regulatory and criminal penalties of the CSA. If uncontrolled, it is reasonable to assume that 

there will be significant use of JWH-018, JWH-073, JWH-200, CP-47,497 and 

cannabicyclohexanol contrary to or without medical advice, and substantial hazards to the health 

of the user or to the safety of the community.
14

Factor 2: Scientific Evidence of its Pharmacological Effect, if Known

The aminoalkylindoles JWH-018, JWH-073, and JWH-200 were developed as research tools 

to investigate the CB1 and CB2 receptors (Pacheco et al., 1991; Huffman et al., 1994; Wiley et 

al., 1998). In addition to binding studies, JWH-018 and JWH-200 have been evaluated in 

functional assays and behavioral studies (Pacheco et al., 1991; Bell et al., 1991; Eissenstat et al., 

1995; Wiley et al., 1998; Atwood et al., 2010). The cyclohexylphenols CP-47,497 and 

cannabicyclohexanol have been evaluated in binding and behavioral studies (Weissman et al., 

1982; Melvin et al., 1984; Compton et al., 1993; Atwood et al., 2011), while CP-47,497 has also 

been evaluated in drug discrimination studies (Weissman et al., 1982).

HHS states in their recommendations to place JWH-018, JWH-073, JWH-200, CP-47,497 

and cannabicyclohexanol in Schedule I of the CSA that in vitro and preclinical studies suggest 

that the pharmacological effects of JWH-018, JWH-073, JWH-200 CP-47,497 and 

cannabicyclohexanol are similar to those of THC. 

Receptor Binding Profile

Homogenates of rat brain cortices for CB1 receptor binding were used to examine JWH-018 

and JWH-073’s binding to cannabinoid receptors (Aung et al., 2000). JWH-018 (Ki = 9.0 +/-

5.00 nM) and JWH-073 (Ki = 8.9 +/- 1.8 nM) bind with high affinity to the central CB1 receptor, 

with higher affinity than THC (CB1 Ki = 40.7 +/- 1.7 nM) (Aung et al., 2000). 

According to HHS, NIDA studies showed that JWH-200 had a Ki of 134.0 nM at the CB1 

receptor, and a Ki of 20.5 nM at the CB2 receptors. Similarly several other published reports 

indicate that JWH-200 bind to CB1 receptors with a relatively high affinity (Eissenstat et al., 

1995; Huffman et al., 2003; Yamada et al., 1996).

In rat cortical membranes, using displacement of tritiated CP-55,940, cannabicyclohexanol 

and CP-47,497 were found to bind to the CB1 receptor with affinities of 4.73 +/- 1.34 and 9.54 

+/- 0.35 nM, respectively, compared to THC’s lower affinity of 40.7 +/- 1.7 nM (Compton et al., 

1993). In similar preparations, JWH-200 was found to bind to the CB1 receptor with an affinity 

of 42 +/- 5 nM (Huffman et al., 2003).

Receptor Activation

In cultured HEK293 cells, JWH-018 increased ERK 1⁄2 MAPK phosphorylation and induced 

CB1 receptor internalization. These results indicate that JWH-018 behaves as a agonist at the 

CB1 receptor (Atwood et al., 2010). JWH-018 was also shown to inhibit forsklin-stimulated 

cAMP production (Chin et al., 1999). 

According to HHS, NIDA studies using a CB1 agonist functional assay, showed that JWH073 has agonist activity with an EC50 of 164 nM and an average maximal response of 56.3% of 

that of the reference CB1 agonist, WIN 55,212-2. Similarly, JWH-073 had an EC50 of 104.8 nM 

in another functional assay of cannabinoid receptor activation using [35S]GTP S in rat cerebellar 

membranes (Griffin et al., 1998). 
15

According to HHS, NIDA studies using a CB1 agonist functional assay showed agonist 

activity of JWH-200 at the CB1 receptor with an EC50 of 305.5 nM and an average maximal 

response of 75.4% relative to the reference CB1 agonist, WIN 55,212-2 (NIDA, personal 

communication).

According to HHS, NIDA studies using CB1 agonist functional assay showed that 

cannabicyclohexanol has agonist activity at the CB1 receptor with an EC50 of 52.7 nM and an 

average maximum response of 90.47% of that of the reference CB1 agonist WIN 55,212-2

(NIDA, personal communication).

HHS states that inhibition of contractions of rodent vas deferens tissue occurs after treatment 

with THC, and is an in vitro assay used to assess CB1 receptor agonist activity (Christopoulos et 

al., 2002; Pertwee et al., 1992). JWH-200 was found to inhibit electrically evoked contractions 

in the mouse vas deferens assay (Eissenstat et al., 1995; Bell et al., 1991). It has been 

established that the potencies of aminoalkylindole agonists required to inhibit smooth muscle 

contraction in vitro correlated with their antinociceptive potency, as measured by both 

acetylcholine (Ach) and acetic acid-induced writhing assays (Ward et al., 1990). 

Cannabicyclohexanol and JWH-073 were shown to induce CB1 internalization (Atwood et 

al., 2011). JWH-200 and CP-47,497 caused G-protein-dependent inhibition of adenylyl cyclase 

in rat striatum and cerebellum membranes (Pacheco et al., 1991; Howlett et al., 1988), consistent 

with CB1 receptor signal transduction (Turu and Hunyady, 2010) and CB1 receptor brain 

localization (Mackie, 2005).

Animal Studies – Behavioral Effects

The mouse tetrad is a well-established paradigm for evaluating substances for 

cannabimimetic properties (Martin et al., 1991). This tetrad includes pharmacological models 

that evaluate catalepsy, locomotor activity, hypothermia and antinociception in mice. JWH-018, 

JWH-200, CP-47,497 and cannabicyclohexanol were shown to be active in all four parameters of 

the mouse tetrad whereas JWH-073 was only tested, and shown to be active, in three of the four 

parameters of the tetrad test (Wiley et al., 1998; Compton et al., 1992b).

Cannabinoid drug discrimination studies are an accepted animal model for predicting 

subjective effects in humans (Balster and Prescott, 1992), and drug discrimination data is 

presented for all five substances under Factor 1. Briefly, all five substances were found to 

substitute fully for THC, suggesting their subjective effects would be similar to those of THC. 

Cytotoxic Effects

CP-47,497 and cannabicyclohexanol were found to be cytotoxic towards NG 108-15 cells 

(Tomiyama and Funada, 2011). Their findings suggest that caspase-cascades may play an 

important role in the apoptosis induced by these two cannabinoids. 
16

Factor 3: The State of Current Scientific Knowledge Regarding the Drug or Other 

Substances

The cyclohexylphenols CP-47,497 and cannabicyclohexanol (CP-47,497-C8 homologue) 

were designed to investigate SAR based on the potent substance, 9-nor-9 -

hydroxyhexahydrocannabinol (HHC) (Weissman et al., 1982; Melvin et al., 1984). Interest in 

AAI structural class was generated by the mouse vas deferens and prostaglandin synthetase 

activity of pravadoline and subsequent finding that AAIs bind to the cannabinoid receptor 

(Huffman, 2009). The pharmacophoric model for AAI binding at the CB1 was first introduced 

by Eissenstat and colleagues (1991). The aminoalklylindoles with affinity for CB1 are 

structurally based on a central indole ring substituted at the 1-and 3-positions, with a possible 2-

position methyl group. JWH-200 was investigated based on structural similarities to the 

extensively studied substance WIN-55,212-2. Further structural modifications at the 1-position 

gave JWH-018 and JWH-073. These substances have been termed ‘synthetic’ or ‘non-classical’ 

due to activity at the CB1 and CB2 while being structurally distinct from naturally occurring 

cannabinoids.

The appearance of these substances in the designer drug market can be traced to the initial 

forensic laboratory confirmation in mid-December 2008. A commercial laboratory in Frankfurt, 

Germany announced the identification of JWH-018 in samples of herbal incense and others were 

identified shortly after this initial determination (Piggee, 2009).

Chemistry and Physical Properties

N

O

1-butyl-3-(1-naphthoyl)indole

1

3

1

3

N

O

1-pentyl-3-(1-naphthoyl)indole

1

3

N

N

O

O

1-[2-(4-morpholinyl)ethyl)]-

3-(1-naphthoyl)indole

OH

OH

5-(1,1-dimethylheptyl)-2-

(3-hydroxycyclohexyl)-phenol

OH

OH

5-(1,1-dimethyloctyl)-2-

(3-hydroxycyclohexyl)-phenol
17

Table 3. The chemical and physical properties of 1-butyl-3-(1-naphthoyl)indole

1-butyl-3-(1-naphthoyl)indole

CAS # 208987-48-8

Chemical Formula C23H21NO

Molecular Weight 327.42

Synonyms JWH-073

Systemic Name (IUPAC, CAS) naphthalen-1-yl-(1-butyl-1H-indol-3-

yl)methanone

Table 4. The chemical and physical properties of 1-pentyl-3-(1-naphthoyl)indole

1-pentyl-3-(1-naphthoyl)indole

CAS # 209414-07-3

Chemical Formula C24H23NO

Molecular Weight 341.45

Synonyms JWH-018; AM678

Systemic Name (IUPAC, CAS) naphthalen-1-yl-(1-pentyl-1H-indol-3-

yl)methanone

Table 5. The chemical and physical properties of 1-[2-(4-morpholinyl)ethyl]-3-(1-

naphthoyl)indole

1-[2-(4-morpholinyl)ethyl-3-(1-

naphthoyl)indole

CAS # 103610-04-4

Chemical Formula C25H24N2O2

Molecular Weight 384.47

Synonyms JWH-200

Systemic Name (IUPAC, CAS) (1-(2-morpholinoethyl)-1H-indol-3-

yl)(naphthalene-1-yl)methanone

Melting Point 104-1060C (Bell et al., 1991)
18

Table 6. The chemical and physical properties of 5-(1,1-dimethylheptyl)-2-[ 3-

hydroxycyclohexyl]-phenol

5-(1,1-dimethylheptyl)-2-[(1R,3S)-3-

hydroxycyclohexyl]-phenol

CAS # 114753-51-4, (-)-CP-47,497; 70434-82-1, 

(+)-CP-47,497 

Chemical Formula C21H34O2

Molecular Weight 318.49

Synonyms CP-47,497

Systemic Name (IUPAC, CAS) 2-(hydroxycyclohexyl)-5-(2-methyloctan2-yl)phenol

Appearance solid

Table 7. The chemical and physical properties of 5-(1,1-dimethyloctyl)-2-[3-hydroxycyclohexyl]-

phenol

5-(1,1-dimethyloctyl)-2-[(1R,3S)-3-

hydroxycyclohexyl]-phenol

CAS # 70434-92-3, (+)-CP-47,497 C8 homologue

Chemical Formula C22H36O2

Molecular Weight 332.52

Synonyms Cannabicyclohexanol; CP-47,497 C8 

homologue

Systemic Name (IUPAC, CAS) 2-3-hydroxycyclohexyl)-5-(2-

methylnonan-2-yl)phenol

Appearance solid

Laboratory analyses of numerous herbal incense products have been conducted and results 

have been published in the scientific literature detailing the identification of these synthetic 

cannabinoids in products and the variations in the amount of the substance laced on the plant 

material in products sold through retail channels (Auwärter et al., 2009; EMCDDA, 2009; 

Dresen et al., 2010; Uchiyama et al., 2010a,b, 2011; Hudson et al., 2010; Zuba et al., 2011).

Metabolism and Pharmacokinetics

Metabolism studies have been conducted for JWH-018 (Teske et al., 2010; Sobolevsky et al., 

2010; Wintermeyer et al., 2010; Möller et al., 2011) and JWH-073 (Chimalakonda et al., 2011; 

Grigoryev et al., 2011; Moran et al., 2011; Hutter et al., 2012), as well as for CP-47,497 

(Dowling and Regan, 2011; Dresen et al., 2011).

Brents and colleagues reported in vitro and in vivo activities for JWH-018 metabolites 

(Brents et al., 2011). These results prompted other researchers to suggest that these active 

metabolites in conjunction with higher CB1 receptor activity relative to THC may contribute to a 

greater prevalence of adverse health effects (Fattore and Fratta, 2011).
19

Medical Application

DEA is not aware of any currently accepted medical use for cannabicyclohexanol, CP47,497, JWH-018, JWH-073, or JWH-200. A letter dated October 6, 2010 was sent from the 

DEA Deputy Administrator to the Assistant Secretary for Health of HHS as notification of intent 

to temporarily place these five substances in Schedule I. DEA solicited comments from HHS, 

including whether there is an exemption or approval in effect for the substances in question 

under the Federal Food, Drug and Cosmetic Act. In a letter to the DEA Acting Administrator 

dated November 22, 2010, the Assistant Secretary of Health responded that there were no current 

INDs or NDAs for these synthetic cannabinoids.

Factor 4: Its History and Current Pattern of Abuse

Synthetic cannabinoids have been developed over the last 30 years to investigate their 

cannabimimetic properties and as research tools to investigate the cannabinoid systems (Huffman 

et al., 1994; Wiley et al., 1998). Subsequently, these substances have been identified as 

ingredients in numerous retail products (Auwärter et al., 2009; Lindigkeit et al., 2009; Hudson et 

al., 2010; Nakajima et al., 2011; Uchiyama et al., 2010a; Uchiyama et al., 2010b; Uchiyama et 

al., 2010a,b, 2011; Microgram Bulletin, 2009; Dresen et al., 2010; EMCCDA, 2009). 

Synthetic cannabinoids trafficking was first reported in the United States in a December 2008 

encounter, where a shipment of Spice was seized and analyzed by U.S. Customs and Border 

Patrol in Dayton, Ohio. Around the same time, in December 2008, JWH-018 and 

cannabicyclohexanol were identified by German forensic laboratories (EMCDDA, 2009). These 

substances may have existed and been abused some time prior to their identification (Psychonaut 

Web Mapping Research Group, 2009).

The popularity of these purported hallucinogenic substances and their associated products 

appears to have spread rapidly since January 2010 in several regions of the United States based 

on seizure exhibits and media reports. This trend appears to mirror those experienced in Europe 

since 2008 (EMCDDA, 2009). These substances are primarily found as ingredients in other 

products. These have also been abused alone as self-reported on internet discussion boards 

(Atwood et al., 2010). Their abuse has been characterized with both acute and long term public 

health and safety issues. 

As of January 13, 2012, forty-eight states in the U.S. as well as numerous local jurisdictions 

and countries have controlled at least one of the five synthetic cannabinoids of JWH-018, JWH073, JWH-200, CP-47,497, and cannabicyclohexanol. Bans of the use of these synthetic 

cannabinoids by military personnel have also been issued in response to the abuse of synthetic 

cannabinoids and the related products (Bebarta et al., 2010; communications to DEA). 

Large seizures of JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol have 

occurred by law enforcement. NFLIS details over 5,450 reports from state and local forensic 

laboratories identifying JWH-018, JWH-073, JWH-200, CP-47,497 and/or cannabicyclohexanol 

in drug related exhibits for a period from January 2009 to December 2011 from 39 states.
20

Data gathered from published studies, supplemented by reports on Internet websites and 

personal communications indicate that these substances are often abused via smoking (Vandrey 

et al., 2012) for their psychoactive properties. Initial reports suggest the duration of effects in 

humans for JWH-018 to be 1-2 hours and CP-47,497 to be 5-6 hours (EMCDDA, 2009). The 

synthetic cannabinoids-laced products, such as Spice, “K2,” and many others, are marketed as 

“legal” alternatives to marijuana. This characterization and their reputation as potent herbal 

intoxicants increased their popularity (Lindigkeit et al., 2009). These substances alone or laced 

on plant material have the potential to be more harmful than cannabis due to their method of 

manufacture and the potency of the substances. These substances display higher potency in vitro 

and in vivo when compared to THC (Wiley et al., 1998; Compton et al., 1992; see Factor 2). 

Smoking mixtures of these substances abused for the purpose of achieving intoxication have 

resulted in numerous emergency room visits and calls to poison centers.

Youths appear to be the primary abusers, as supported by law enforcement encounters and 

reports from emergency rooms. However, all age groups have been discussed in media reports 

as abusing these substances and related products. Individuals, including minors, are purchasing 

these substances from Internet websites, gas stations, convenience stores, and head shops. There 

have also been reports of U.S. military personnel purchasing and abusing these synthetic 

cannabinoids (Johnson et al., 2011), which has prompted bans of the use of these synthetic 

cannabinoids by military personnel (Bebarta et al., 2010; communications to DEA). These 

substances, and products laced with these substances, are commonly marketed as “legal highs”

and with the disclaimer “not for human consumption.” As detailed in reports, law enforcement 

and public health officials are encountering the abuse of these substances.

Numerous herbal incense products have been found to contain one or more of these synthetic 

cannabinoids laced on plant material. There is no known explanation for the addition of these 

synthetic cannabinoids to plant material being marketed as herbal incense, other than for their 

psychoactive properties (Lindigkeit et al., 2009). The psychoactive properties are directly linked 

to the synthetic cannabinoids laced on the plant material sold as retail products (Auwärter et al., 

2009; Atwood et al., 2010, 2011; EMCDDA, 2009). To lace the plant material, the synthetic 

cannabinoid(s) is dissolved in a solvent and sprayed on the plant material or the plant material is 

soaked in a solution of the dissolved substance (Vardakou et al., 2010; Wells and Ott, 2011; 

observation from manufacturing laboratory encounters). No smell has been attributed to these 

products nor do these substances such as JWH-018 (marketed as Bonsai 18) have any role as a 

plant food. Two research articles propose that the packaging is professional and conspicuous and 

intended to target young people who are possibly eager to use cannabis, but who are afraid of the 

judicial consequences and/or association with illicit drugs (Lindigkeit et al., 2009; Schifano et 

al., 2009).

Dresen and colleagues (2011) found these substances are being abused by individuals in 

treatment with a positive rate of 63.3% in forensic psychiatric centers based on their sampling 

(Dresen et al., 2011). U.S. Drug Courts have communicated concerns related to the abuse of 

synthetic cannabinoids and a response rate of greater than 30% by juveniles subject to routine 

drug screens from a sampling.
21

Summary

JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol have been found alone 

and found laced on products that are marketed as herbal incense. The abuse of these substances 

and their associated products for their psychoactive effects has been widely reported and their

popularity appears to have spread rapidly since January 2010. Prior to being temporarily placed 

in Schedule I on March 1, 2011, these products were promoted as legal alternatives to marijuana, 

were widely available over the Internet, and were found to be sold in gas stations, convenience 

stores, tobacco and head shops to all populations. As of January 13, 2012, forty-eight states in 

the U.S. as well as numerous local jurisdictions and countries have controlled at least one of the 

five synthetic cannabinoids. 

Factor 5: The Scope, Duration, and Significance of Abuse

HHS states that the current scope and duration of use of these five synthetic cannabinoids is 

likely underestimated because of the lack of widely available toxicological methods to identify 

its use using routine analyses (Peters and Martinez-Ramirez 2010). 

Since these substances were never intended for human consumption, minimal information 

exists as to the health implications resulting from exposure to these substances (Griffiths et al., 

2010; Vardakou et al., 2010). As forensic procedures and toxicology screens are being 

developed, the amount of information concerning these substances and the associated products is 

increasing. As a result, a better understanding regarding the abuse and harmful effects of these 

substances is being developed. The scientific literature and reports received by DEA suggest 

tolerance and dependence to synthetic cannabinoids may develop (Zimmerman et al., 2009). 

Prior to the Final Order temporarily scheduling these substances, these products were sold over 

the Internet and found to be abused by diverse populations. 

According to forensic laboratory data, the first documented encounter in the United States 

regarding synthetic cannabinoids laced on plant material occurred in conjunction with a U.S. 

Customs and Border Patrol analysis of Spice products entering the United States. However, 

these products are believed to have existed since 2004 (Psychonaut Web Mapping Research 

Group, 2009). 

Large seizures of JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol have 

occurred by law enforcement. NFLIS details over 5,450 reports from state and local forensic 

laboratories identifying JWH-018, JWH-073, JWH-200, CP-47,497 and/or cannabicyclohexanol 

in drug related exhibits for a period from January 2009 to December 2011 from 39 States.

The abuse of synthetic cannabinoids has been associated with both acute and long-term 

public health and safety concerns. In the past year, increased exposure incidents have been 

documented by poison centers in the United States. The American Association of Poison Control 

Centers (AAPCC) has reported receiving 9,922 calls corresponding to products purportedly laced 

with these synthetic cannabinoids through December 31, 2011. Data from the U.S. 57 Poison 

Centers (PCs) indicate that they received 2,924 exposure calls in 2010 and 6,998 exposure calls 
22

in 2011, relating to these synthetic cannabinoids.5 A majority of exposure incidents resulted in 

seeking medical attention at health care facilities. 

Exposure calls refer to actual or potential human exposure to a synthetic cannabinoid (e.g., 

inhalation, ingestion, topical exposure). The calls represented exposed individuals from all 50 

states and the District of Columbia. There were a few calls regarding exposed individuals in 

Puerto Rico, U.S. Territories, foreign countries, and a category identified as “overseas/US 

military/diplomatic.” Most of the synthetic cannabinoids reported by the poison centers were 

identified as “K2”/herbal blend (50.2%) and THC homologue (18.3%). In 25% of the cases, the 

product involved was unknown. Several exposures were determined to be JWH-018 (141), 

JWH-073 (12), HU-210 (6), JWH-015 (2), JWH-250 (2), and JWH-210 (1). A large majority of 

the exposures were due to intentional abuse, misuse, or suspected suicide (92.0%). The most 

common forms of the known synthetic cannabinoids were aerosol/mist/spray/gas, 

tablets/capsules/caplets, and powder/granules. Most of the exposures (86.0%) were described as 

acute.

6

 Exposures described as acute-on-chronic7or chronic8accounted for approximately 4% 

and 3% of the cases, respectively. Males accounted for 74% of all exposures for 2010 and 2011. 

In every age group, predominantly males were exposed to the synthetic cannabinoids. Most of 

the exposed individuals were aged 18-25 years (42.4%) and under 18 (29.2%). A few of the 

callers (1.0%) identified the exposed individuals as being in their 20s. The most common route

of administration for the synthetic cannabinoids is inhalation/nasal.

 

5 The content of this report does not necessarily reflect the opinions or conclusions of the American Association of 

Poison Control Centers.

The American Association of Poison Control centers (AAPCC; http://www.aapcc.org) maintains the national 

database of information logged by the country’s 57 Poison Centers (PCs). Case records in this database are from 

self-reported calls: they reflect only information provided when the public or healthcare professionals report an 

actual or potential exposure to a substance (e.g. an ingestion, inhalation, or topical exposure, etc.), or request 

information/educational materials. Exposures do not necessarily represent a poisoning or overdose. The AAPCC is 

not able to completely verify the accuracy of every report made to member centers. Additional exposures may go 

unreported to PCs and data referenced from the AAPCC should not be construed to represent the complete incidence 

of national exposures to any substance(s). 

6 The AAPCC describes an acute chronicity as a single, repeated or continuous exposure occurring over a period of 

eight hours or less.

7 Acute-on-chronic is a single exposure that was preceded by a continuous, repeated, or intermittent exposure 

occurring over a period exceeding eight hours.

8 Chronic is a continuous, repeated, or intermittent exposure to the same substance lasting longer than eight hours.
23

Source: The American Association of Poison Control Centers (AAPCC) National Poison Data 

System.

DHHS states that case reports have demonstrated that herbal products containing synthetic 

cannabinoids produce physical dependence and a withdrawal syndrome (Zimmermann et al.

2009; Vardakou et al., 2010). In one case report, the authors concluded that the patient satisfied 

criteria for a diagnosis of DSM-IV and ICD-10 dependency syndrome (Zimmermann et al.

2009). These signs of dependence and withdrawal are similar to that experienced with cannabis 

abuse (Zimmermann et al., 2009, Müller et al., 2010a; Vardakou et al., 2010). Tolerance to these 

drugs may develop fairly rapidly with larger doses being required to achieve the desired effect 

(Zimmerman et al., 2009; EMCDDA, 2009). Psychosis is also attributed to the abuse of these 

substances (Every-Palmer, 2010, 2011; Müller et al., 2010a; Law enforcement reports to DEA). 

The popularity and use of these substances was identified as a major problem in Europe in 

2008 (EMCDDA, 2009). It is believed that Internet advertising has contributed to the popularity 

of these substances and deep concerns exist regarding the limited knowledge of the 

manufacturers of these substances (Schifano et al., 2009). 

24 33

99 116

201176

248

326345

413

482461

397

428

532550

598622

707

647670681

613

553

0

100

200

300

400

500

600

700

800

Jan

'10

Feb

'10

Mar

'10

Apr

'10

May

'10

Jun

'10

Jul

'10

Aug

'10

Sep

'10

Oct

'10

Nov

'10

Dec

'10

Jan

'11

Feb

'11

Mar

'11

Apr

'11

May

'11

Jun

'11

Jul

'11

Aug

'11

Sep

'11

Oct

'11

Nov

'11

Dec

'11

Number of Exposure Calls

Month/Year

Number of Synthetic Cannabinoids

(e.g., Spice, K2, THC Homologues)

Exposure Calls to U.S. Poison Centers 

January 2010 - December 2011
24

The increased abuse of these synthetic cannabinoids in the United States is supported by an 

increasing number of encounters by law enforcement. Over the past year, in the United States, 

there has been a significant increase in availability, trafficking, and abuse of these substances as 

evident from the increasing number of encounters reported by forensic laboratories (NFLIS and 

STRIDE data). The initial indication of the evidence of abuse of both JWH-018 and 

cannabicyclohexanol appeared in 2009 upon identification in products. Since then, other 

synthetic cannabinoids including JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol 

were encountered and others are emerging in response to enacted state legislation (JWH-081, 

JWH-250, JWH-398, JWH-210, JWH-122, JWH-251, JWH-019, JWH-203, RCS-8, RCS-4, 

AM2201, and AM 694). This represents a transition to new synthetic cannabinoids in order to 

circumvent legal controls, where product manufacturing and synthesis laboratories have been

discovered, and laboratories have been found manufacturing products by lacing plant material 

with synthetic cannabinoids. 

The amount of information regarding these substances and related products appears to be 

rapidly increasing in the scientific literature. Hudson and colleagues (2010) analyzed 16 

different Spice products and multiple products marketed under the same name for a total of 40 

analyses. The products contained previously identified synthetic cannabinoids along with new 

structurally related substances. Each product analyzed and marketed in this Spice class of 

products contained multiple synthetic cannabinoids. In the majority of exhibits, JWH-018 and 

cannabicyclohexanol were found together on the same material, and in a few instances one or the 

other was the sole synthetic cannabinoid identified. To a lesser extent, other synthetic 

cannabinoids such as JWH-073, JWH-081, JWH-398, and CP-47,497 were also found in these 

products. The investigators stated that variants of products were anticipated to differ in 

ingredients and these ingredients varied in relative amounts from batch to batch. Furthermore, 

the authors proposed that ingredient variability might account for the differential effects 

anecdotally reported by the users of these products.

Other product analyses have yielded very important information regarding these synthetic 

substances. Dresen and colleagues (2010) analyzed 140 samples from 68 different products 

during the period of June 2008 to September 2009. The investigators found the composition of 

the products changed over time and neither the seller nor consumer could predict the 

composition of these products. Products were found to contain cannabicyclohexanol and JWH018, and new synthetic cannabinoids JWH-073, JWH-250, and JWH-398 were also identified. 

In another study by Lindigkeit and colleagues (2009), 11 herbal incense products were analyzed 

from the German market. Products were found to vary in amount of synthetic cannabinoid laced 

on the plant material, ranging from 2.3 mg/g to 22.9 mg/g. Prior to their ban in Germany, all 

products analyzed contained cannabicyclohexanol or JWH-018. After their ban, new synthetic 

cannabinoids were found in second generation products. The analysis of numerous products 

from the Japanese market by Uchiyama et al. (2010a) found JWH-018 and cannabicyclohexanol 

being observed as ingredients, with JWH-073 and CP-47,497 detected in the analyzed products 

to a lesser extent. A total of 46 different herbal products were analyzed and 44 were found to 

contain synthetic cannabinoids.
25

Summary

The abuse of synthetic cannabinoids, characterized by reported adverse health effects, is 

documented in the scientific literature and by law enforcement encounters. Numerous calls have 

been received by poison centers regarding the abuse of products potentially laced with synthetic 

cannabinoids as well as presentation at emergency departments. Some of the adverse health 

effects reported in response to the abuse of these substances include vomiting, anxiety, agitation, 

irritability, seizures, hallucinations, tachycardia, elevated blood pressure, and loss of 

consciousness.

Factor 6: What, if Any, Risk There is to the Public Health

Law enforcement, military, and public health officials have reported exposure incidents that 

demonstrate the dangers associated with these substances to both the individual abusers and 

other affected individuals. As reiterated by Dowling and Regan (2011), these substances were 

never intended for human use. Two suicides, one also involving a homicide, have been linked to 

the abuse of synthetic cannabinoids (law enforcement communication to DEA). Warnings 

regarding the dangers of synthetic cannabinoid abuse and associated products have been issued 

by numerous state public health departments and poison centers and private organizations. 

Detailed product analyses describe variations in the amount and type of synthetic cannabinoid 

laced on the plant material; this is true even within samplings of the same product (Hudson et al., 

2010). Wells and Ott (2011) stated concern regarding the possibility of the occurrence of a 

serotonin syndrome related to synthetic cannabinoids of the indole structural class, and this 

concern was in part due to the similarity to serotonin. Additionally, it has been suggested that 

extreme variability in composition and potency place abusers of these products at risk of serious, 

if not lethal, outcomes (Fattore and Fratta, 2011).

HHS states that JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol share 

the pharmacological effects of THC, and that substances with cannabinoid agonist activity 

present similar risks to the public health as JWH-018, JWH-073, JWH-200, CP-47,497, and 

cannabicyclohexanol. Because they share pharmacological similarities with the Schedule I 

substance THC, the synthetic cannabinoids JWH-018, JWH-073, JWH-200, CP-47,497, and 

cannabicyclohexanol pose risks to the abuser (Compton et al., 1992; Weissman et al., 1992; 

Wiley et al., 1998). According to HHS, in silico analyses predicted the adverse health effects of 

these synthetic cannabinoids on cardiovascular, reproductive and genetic systems. The chronic 

abuse of products laced with synthetic cannabinoids has been linked to addiction and withdrawal 

(Vardakou et al., 2010). Two separate controlled investigations involving a total of four subjects 

were undertaken to evaluate the effects of two products. Both products were found to be laced 

with JW-018 and one of the products also contained cannabicyclohexanol. Two researchers 

described potent effects upon smoking the product “Spice Diamond.” Ten minutes postexposure the subjects experienced noticeable effects in the form of reddened conjunctivae, 

significant increases in pulse rates, xerostomia (dry mouth), and an alteration of mood and 

perception (Auwärter et al., 2009). Another report described sickness, sedation, and xerostomia 

which were accompanied by hot flashes and burning eyes, all of which immediately followed the 

smoking of the product “Smoke.” (Teske et al., 2010). This issue is further complicated by the 

finding that similar products have been found to vary in the synthetic cannabinoid and amount 
26

laced on the plant material. Dependence, withdrawal, and psychotic episodes have also been 

associated with products purported to contain these synthetic cannabinoids (Zimmermann et al., 

2009; Müller et al., 2010a). Numerous emergency department admissions have been connected 

to these substances and emergency room physicians have described morbidity associated with 

these substances and products (reported by law enforcement; Vearrier and Osterhoudt, 2010; 

Schneir et al., 2011; communications to DEA from public health officials). Additionally, violent 

episodes are linked to smoking these substances (multiple law enforcement communications). 

Health warnings have been issued by numerous state public health departments and poison 

centers describing adverse health effects associated with smoking (inhaling) these products 

including, agitation, vomiting, tachycardia, elevated blood pressure, seizures, hallucinations and 

non-responsiveness. These findings are further supported by the occurrence of paranoia and 

hallucinations described by some patients (Banerji et al., 2010; Bebarta et al., 2010). 

Numerous individuals have presented at emergency departments in response to exposure to 

products containing synthetic cannabinoids. In one case reported by Schneir and colleagues 

(2011), two females (20 and 22 years of age) presented at the ED in response to smoking an 

herbal incense product. Both individuals reported daily smoking of various Spice products. The 

case reports listed adverse health effects which were consistent with those associated with these 

substances and associated products, such as, anxiety, tremors, psychosis, and elevated pulse. 

Laboratory analysis of the herbal incense product found JWH-018 and JWH-073 to be present. 

The urine drug screen for one of patients was negative for other drugs of abuse. 

Vearrier and Osterhandt (2010) reported the emergency room admission of a 17-year old 

female in response to smoking JWH-018. Approximately fifteen minutes after a single “bong 

hit” from a water pipe, she presented at the emergency department with tachycardia (mildly 

elevated), agitation, muscle fasciculations, and hypokalemia. A urine immunoassay for drugs of 

abuse tested positive for tetrahydrocannabinol. Two of her friends were also taken to the hospital 

in response to trying a “new marijuana” for the first time.

Canning and colleagues (2010) described the presentation of an 18-year old after smoking an 

herbal incense product with acute intoxication complicated by severe gastrointestinal distress. 

The previously healthy individual presented thirty minutes after smoking the product “K2 

Summit” with tremors, blurred peripheral vision, nausea, and persistent vomiting with retching. 

The patient was described by his friends as "having difficulty walking" and “mumbling.” Liquid 

chromatography–mass spectrometry/mass spectrometry (LCMS/MS) analysis of a serum sample 

obtained from the patient 4.5 h post exposure identified JWH-018 at concentration of 0.5 ng/mL. 

A drug screen was negative for other drugs of abuse.

Müller and colleagues (2010b) describe the rapid onset of a panic attack in a 21-year old 

male with attention deficient hyperactivity disorder after a third-ever consumption of Spice. The 

patient developed blurred vision and unsteady gait and reported profuse sweating, severe 

weakness, and massive heart palpitations. Additionally, the patient experienced acute onset of an 

agonal state with the fear of being perceived as ignorant by friends. The panic attack was 

followed by a vegetative hyperirritability that lasted for more than two hours. 
27

Kamat and colleagues (2012) described the presentation of an 18-year-old man who smoked 

a product alleged to contain synthetic cannabinoids and one hour later developed a severe global 

headache. Imaging revealed an intracranial hemorrhage determined to be caused by a small 

artery aneurysm. No toxicological or forensic analysis was performed to confirm the presence of 

synthetic cannabinoids in the product smoked or in the patient’s blood.

Self-reports on internet discussion boards describe abuse of these substances alone as well as 

abuse of these substances as product ingredients. The effects of these substances are described 

as being highly potent and cannabis-like. JWH-018 has been described as both a potent and 

efficacious CB1 receptor agonist. This likely explains the ability of this substance and its herbal 

products to produce cannabis-like effects (Atwood et al., 2010). The duration of effects in 

humans compared to cannabis seems to be shorter for JWH-018 (1-2 hours) and longer for 

cannabicyclohexanol (5-6 hours) (Auwärter et al., 2009). The most common route of 

administration of these substances and associated products is by smoking, either by using a 

standard pipe or a water pipe, or by rolling the plant material in cigarette papers.

Since abusers obtain these drugs through unknown sources, purity of these drugs is uncertain, 

thus posing significant adverse health risk to these users (EMCDDA, 2009; Dresen et al., 2010). 

As mentioned above, there are reported instances of emergency department admissions in 

association with the abuse of these synthetic cannabinoids. 

Convulsive effects

A recent case report by Schneir and Baumhaeher (2011) describes a 19-year-old male patient 

who had two witnessed generalized convulsions soon after smoking a Spice product that was 

later confirmed to contain JWH- 018 and three other different synthetic cannabinoids (JWH-081, 

JWH-250, and AM-2201). Convulsions have also been described in another published report for 

which there was no laboratory confirmation for the presence of synthetic cannabinoids in the 

products involved (Simmons et al., 2011a). In yet another report, in which there was laboratory 

confirmation for metabolites of the synthetic cannabinoid JWH-018, a patient was interpreted by 

the authors as having had a possible convulsion (Simmons et al., 2011b). 

Convulsions associated with recreational use of Cannabis sativa (marijuana) use appear to be 

rare (Ng et al., 1990; Gordon and Devinsky, 2001), and have been reported after accidental 

ingestion in children (Bonkowsly et al., 2005; Spadari et al., 2009). Shneir and colleagues 

discuss the hypothesis that the absence of the anticonvulsant cannabidiol (Consroe et al., 1981) 

in the synthetic cannabinoids-containing products might contribute to the frequency and 

mechanism of convulsions associated with these products. 

Automotive accidents

Abusers have been suspected of driving under the influence of these substances. In one 

incident where an automobile was driven through a residence, the individual claimed to have no 

memory of the event. A laboratory analysis of the product and pipe from the incident encounter 

found JWH-018 and the urine analysis identified JWH-018 metabolites. A hospital drug analysis 

in response to this event found no other drugs of abuse based on the hospital drug screen.
28

Psychosis

Large scale epidemiological studies indicate that marijuana may increase risk of psychosis in 

vulnerable populations, i.e., individuals predisposed to develop psychosis (Andreasson et al., 

1987) and exacerbate psychotic symptoms in individuals with schizophrenia (Schiffman et al., 

2005; Hall et al., 2004; Mathers and Ghodse, 1992; Thornicroft, 1990; 76 FR 40552-89). 

Recent reports suggest that synthetic cannabinoid-receptor agonists-containing products may 

also precipitate psychosis in vulnerable individuals (Every-Palmer et al., 2010, 2011). Some of 

those reports do not have definite forensic identification of the cannabinoid substances present in 

the products, such as Spice, “K2,” or “Aroma.” 

Semi-structured interviews were used to examine the use and effects of JWH-018 purported 

to be the main active ingredient of the product “Aroma” by 15 patients with serious mental 

illness in a New Zealand forensic and rehabilitative service (Every-Palmer et al., 2011). All 15

subjects were familiar with a locally available JWH-018 containing product called “Aroma” and 

86% reported having used it. They credited the product’s potent psychoactivity, legality, ready 

availability and non-detection in drug testing as reasons for its popularity, with most reporting it 

had replaced cannabis as their drug of choice. Anxiety and psychotic symptoms were common 

after use, with 69% of users experiencing or exhibiting symptoms consistent with psychotic 

relapse after smoking JWH-018. This manifested as the sudden re-emergence of florid 

psychosis: predominantly agitation, disorganization and delusional beliefs (paranoid and 

grandiose types) in previously stable patients with histories of mental illness (Every-Palmer, 

2010).

A case report presents the synthetic cannabinoid-containing product Spice as a trigger for an 

acute reactivation of cannabis induced recurrent psychotic episodes (Muller et al., 2010). The 

authors discuss the case of a twenty-five year old male who had a history of cannabis-induced 

recurrent psychotic episodes but had been stable with only minor symptoms over the previous 

two years. Immediately after Spice abuse, cannabis-induced recurrent psychotic symptoms were 

reactivated, but in addition the patient experienced further psychotic symptoms not previously 

displayed. 

Fatalities

A fatality confirmed to be related to the abuse of JWH-018 was reported in 2011. A 19-year 

old sophomore in South Carolina died four days after collapsing on a campus basketball court.

Toxicological analysis revealed ingestion of JWH-018. The coroner ruled the cause of death 

drug toxicity and organ failure. 

Other fatalities have been reported to be linked to the abuse of synthetic cannabinoidcontaining products, but toxicology confirmation has generally lacked, and thus the exact 

substances involved were not determined.

Summary

The abuse of these substances presents the potential for accidental overdose with a risk of 

complications. 
29

Factor 7: Its Psychic or Physiological Dependence Liability

HHS states that the pharmacological profile of JWH-018, JWH-073, JWH-200, CP-47,497 

and cannabicyclohexanol strongly suggests that they possess a physiological and psychological 

dependence liability that is similar to that of marijuana and related cannabinoids, such as THC. 

Thus, they would have a high psychic and physiologic dependence capacity.

Physical dependence is a state of adaptation manifested by a drug class-specific withdrawal 

syndrome produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, 

and/or administration of an antagonist (American Academy of Pain Medicine, American Pain 

Society and American Society of Addiction Medicine consensus document, 2001). No 

laboratory controlled clinical studies of the psychic or physical dependence potential of these 

five cannabinoids are currently available. 

In an internet-based survey study conducted with adults reporting at least one lifetime use of 

a Spice product, a series of questions were included to evaluate participants’ possible dependence 

on these synthetic cannabinoids (Vandrey et al., 2012). It was found that a subset of respondents 

met DSM-IV (American Psychiatric Association, 2000) criteria for abuse (37%) and dependence 

(12%). Using Spice in a hazardous situation was the most commonly endorsed abuse criteria 

(27%), and being unable to cut down or stop Spice use (38%), experiencing symptoms of 

tolerance (36%), using for longer periods than originally intended (22%) and having interference 

with other activities (18%) were the most commonly reported dependence criteria. Despite 

endorsing problems related to Spice use, no respondent had ever sought or received treatment. 

Withdrawal symptoms following cessation of Spice use were rare, and most prevalent among 

more frequent users. The most commonly reported withdrawal effects were headaches (15%), 

anxiety/nervousness (15%), coughing (15%), insomnia/sleep disturbance (14%), anger/irritability 

(13%), impatience (11%), difficulty concentrating (9%), restlessness (9%), nausea (7%), and 

depression (6%). These effects are, overall, similar to those reported during withdrawal from 

marijuana (Budney et al., 1999).

Case reports have shown that herbal products containing synthetic cannabinoids could 

produce physical dependence and a withdrawal syndrome. The HHS analysis discusses one case 

report in which the authors concluded that the patient satisfied criteria for a diagnosis of DSM-IV 

and ICD-10 dependency syndrome (Zimmermann et al. 2009). In the report, a 20-year old 

German patient had smoked “Spice Gold” daily for an 8-month period. Samples of “Spice Gold”

have been verified to contain JWH-018. During this time, he increased his dose from 1g to 

approximately 3g/day, indicating the possible development of tolerance. The patient reported a 

desire to continue use of the product despite cognitive impairment. His use of “Spice Gold” led 

him to neglect professional obligations, and he was voluntarily admitted to the hospital. During 

his admittance, the patient experienced elevated blood pressure, restlessness, drug craving, 

nightmares, sweating, nausea, tremor and headache. The patient was still described as “irritable” 

on day 10. The time course for the resolution of symptoms was not detailed (Zimmermann et al., 

2009).

Because these substances act through the same molecular target as THC, the main active 

ingredient of marijuana, it can be reasonably expected that their physical dependence liability 
30

will be similar. Long-term, regular use of marijuana can lead to physical dependence and 

withdrawal following discontinuation as well as psychic addiction or dependence. The 

marijuana withdrawal syndrome consists of symptoms such as restlessness, irritability, mild 

agitation, insomnia, EEG disturbances, nausea, cramping and decrease in mood and appetite that 

may resolve after four days, and may require in-hospital treatment (Haney et al., 1999). It is 

distinct and mild compared to the withdrawal syndromes associated with alcohol and heroin use 

(Budney et al., 1999; Haney et al., 1999).

Budney et al. (1999) examined the withdrawal symptomatology in 54 chronic marijuana 

abusers seeking treatment for their dependence. The majority of the subjects (85 percent) 

reported that they had experienced symptoms of at least moderate severity. Fifty-seven percent 

(57 percent) reported having six or more symptoms of at least moderate severity while 47 

percent experienced four or more symptoms rated as severe. The most reported mood symptoms 

associated with the withdrawal were irritability, nervousness, depression, and anger. Some of the 

other behavioral characteristics of the marijuana withdrawal syndrome were craving, 

restlessness, sleep disruptions, strange dreams, changes in appetite, and violent outbursts. 

Factor 8: Whether the substance is an immediate precursor of a substance already 

controlled

JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol are not considered 

immediate precursors of any controlled substance of the CSA as defined by Title 21, U.S.C § 

802(23).
31

III. Findings for Schedule Placement Pursuant to 21 U.S.C. 812(b)

21 U.S.C. 812(b) requires the evaluation of a substance’s abuse potential, accepted medical 

use, and safety for use under medical supervision for scheduling under the CSA as a controlled 

substance. After consideration of the above eight factors determinative of control of a substance 

(21 U.S.C. 811(c)), and a review of the scientific and medical evaluation and scheduling 

recommendation provided by HHS, DEA finds that JWH-018, JWH-073, JWH-200, CP-47,497, 

and cannabicyclohexanol meet the following criteria for placement in Schedule I of the CSA 

pursuant to 21 U.S.C. 812 (b)(1):

1. JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol have a high 

potential for abuse.

Each of the five substances considered in this review is a synthetic substance that 

produces cannabinoid-like effects. HHS states that the pharmacological similarity of JWH-018, 

JWH-073, JWH-200, CP-47,497 and cannabicyclohexanol to THC makes it reasonable to 

assume that their potential for abuse is high and would be similar to that of marijuana and THC, 

both of which are cannabinoids and are controlled in Schedule I of the CSA. According to the 

results of the 2011 Monitoring the Future survey of high schools students, 1 in 9 high school 

seniors (11.4%) have used “synthetic marijuana” in the past year (Johnston et al., 2012). It is one 

of the most frequently mentioned among high school seniors in the survey, second only to

marijuana.

2. JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol have no currently 

accepted medical use in treatment in the United States.

HHS states that there are no approved NDAs for JWH-018, JWH-073, JWH-200, CP-47,497 

and cannabicyclohexanol in the United States. There is no known therapeutic application for 

JWH-018, JWH-073, JWH-200, CP-47,497 and cannabicyclohexanol. Therefore, JWH-018, 

JWH-073, JWH-200, CP-47,497 and cannabicyclohexanol have no currently accepted medical 

use in the United States. 

3. There is a lack of accepted safety for use of JWH-018, JWH-073, JWH-200, CP-47,497, 

and cannabicyclohexanol under medical supervision.

HHS states that, the safety for use under medical supervision of JWH-018, JWH-073, JWH200, CP-47,497 and cannabicyclohexanol is not determined. In addition, case reports have 

shown a number of adverse consequences thought to be related to abuse of JWH-018, JWH-073, 

and synthetic cannabinoids related to JWH-200, CP-47,497, and cannabicyclohexanol. Thus, 

there is a lack of accepted safety for use of these substances under medical supervision.
32

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