Daniel Castellanos, MD

A new wave of drug-related issues with “synthetic drugs” or “designer drugs” is emerging in both emergency departments (EDs) and the community at large. Two of the main groups of these drugs are synthetic cannabinoid products (SCPs) and synthetic cathinones (SCs). SCPs are commonly referred to as Spice, “fake pot,” or “fake marijuana.” SCs are commonly known and sold as “bath salts.” New brands of these drugs are continuously coming on the market and are sold under a variety of street and commercial names (

Synthetic cannabinoids are sprayed on a variety of herbal or dried plant matter for the purposes of being smoked to achieve a “high.” These products are sold over the Internet and in gas stations, liquor stores, convenience stores, smoke shops, and “head shops.” The packages are typically labeled “not for human consumption” but the “omission” of the SCPs on the product labeling suggests that there may be an intentional marketing strategy to misrepresent these as natural products.

[[{"type":"media","view_mode":"media_crop","fid":"20925","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_7819250574263","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"1372","media_crop_rotate":"0","media_crop_scale_h":"214","media_crop_scale_w":"200","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image"}}]]When smoked, these substances can produce psychoactive effects similar to those of cannabis. These effects are due to the addition of SCPs-not to the ingredients listed on the product labels. SCPs have become increasingly popular among youths because of their reported “marijuana-like” effects; their ready availability; and the lack of routine, reliable urine toxicology testing. Users smoke the product by wrapping it in joints, smoking it in pipes, or inhaling fumes via vaporizers.

Synthetic cannabinoids are not analogues of tetrahydrocannabinol (THC) and are not produced by cannabis plants, but they act on the same receptors as does THC. They are a large and chemically varied group of molecules with some similarities to THC. As of 2013, few formal human studies have been published. The risks associated with the use of SCPs appear greater than those seen with cannabis. Most of the newer SCPs are more potent than cannabis. As a result, smaller doses of SCPs may produce the same effect as larger amounts of cannabis. Since a variety of SCPs exist, with manufacturers constantly substituting different compounds in their products, toxicity and accidental overdosing are more likely to occur.

The prevalence of SCP use is largely unknown. Easy access and the misperception that SCPs are “natural” and therefore harmless have likely contributed to their popularity among young people. SCP users typically have used marijuana and other drugs. After marijuana, SCPs are the most frequently used illicit drugs by high school seniors. One of 9 high school students reported having used an SCP in 2012.

 Eight percent to 14% of college students have reported use of SCPs, with use more common in males and an average initiation age of 18.

 Poison control centers have registered 1413 calls inquiring about “synthetic marijuana” between January 1 and June 30, 2013.

 In 2010, an estimated 11,406 ED visits in the US involved an SCP; three-fourths of these visits involved patients aged 12 to 29.

Similar to cannabis, SCPs are popular among youths who use it to become intoxicated (“get high”). Adolescents and young adults with a history of marijuana and other drug use and who are being monitored with urine toxicology tests are at risk for using SCPs because they can obtain a cannabis-like high without the risk of being detected. There has recently been increased use of SCPs by military personnel on leave, and consequently, all branches of the US military have banned these products.

SCPs appear to produce a variety of psychoactive effects, many of which are similar to those experienced by marijuana users. However, SCP users can experience a variety of negative psychoactive effects not typical with marijuana use. Agitation and anxiety are the most common negative effects (

Cognitive changes are described as “difficulty in thinking clearly,” confusion, sedation and somnolence, disorganization, and memory “changes/problems.” Behavioral disturbances associated with SCP use are varied-agitation and restlessness are most commonly reported. Some SCP users, like marijuana users, experience euphoria when intoxicated. More commonly, users experience negative mood changes, such as anxiety and irritability. These negative mood changes appear to typify “highs” associated with SCP rather than marijuana use.

Multiple reports connecting SCP use and suicide can be found in the media and throughout the Internet. In contrast, the scientific literature contains only 4 subjects across 3 studies that describe suicide and suicidal behaviors with SCP use. Therefore, clinicians are urged to use caution in associating SCP use with suicide.

Psychotic and pseudopsychotic symptoms are frequently experienced by SCP users. These include disorganized thinking and speech, thought blocking, paranoid thoughts, flat or inappropriate affect, perceptual distortions, delusions, and auditory and visual hallucinations. Because of limitations in the study designs, it is not possible to determine whether these symptoms are consistent with a psychotic process or are manifestations of acute intoxication. Use of SCPs have been associated with acute psychosis as well as exacerbation of previously stable psychotic disorders. Some individuals may experience psychosis that persists for weeks after the acute intoxication.

SCP use can produce a variety of physical effects. Many symptoms appear to be a result of the cannabinoid receptor agonistic effects of these agents, which can affect any organ system in the body. Cardiovascular and GI effects are common, and potentially serious renal (acute kidney injury) and neurological (seizures) effects have also been observed.

 A full review of these physical symptoms is beyond the scope of this article, but 

Findings from case reports indicate that SCPs can produce effects beyond acute intoxication; tolerance and withdrawal symptoms may be observed following prolonged use. These preliminary reports suggest that dependency may be associated with long-term SCP use.

Tony is a 20-year-old college student living at home with his parents. He has been found smoking marijuana at home on several occasions by his parents. Tony has agreed to abstain from smoking marijuana and provide a urine specimen for testing. Four times over the past week, Tony has returned home lethargic and irritable, with blood-shot eyes. His parents suspect that he has been smoking again. Tony becomes easily agitated when questioned. Toxicology testing has been negative. During an interview in your office, Tony adamantly denies marijuana use. From the history and presentation you suspect SCP use. You ask Tony directly when was the last time he smoked Spice. He appears surprised and responds, “I’m not sure.” After further discussion, he admits to smoking Spice.

Bath salts typically take the form of a white or brown crystalline powder, are sold in packages labeled “not for human consumption,” and are frequently marketed as “plant food” or “jewelry cleaner.” These are not the same substances we put in our bathtubs. These products produce toxic effects as well as disturbing psychopathological symptoms. They are a synthetic modification of the naturally occurring alkaloid cathinone, which can be extracted from the leaves of 

, commonly known as the khat plant. SCs are stimulants that include 3,4 methylenedioxypyrovalerone, mephedrone, methylone, and ethylone.

Information on the prevalence of bath salt use is even more limited than that on synthetic cannabinoids. The annual prevalence rates for bath salts in a large high school sample was low: 1.3% for 12th graders.

 The drug seems to be most popular with persons who are between 20 and 29 years old.

 Poison centers have seen bath salts exposures in persons from 6 to 59 years old. During the first half of 2013, 528 calls to poison centers about exposures to bath salts were received.

In contrast, the lifetime prevalence rates for 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy, Molly) was reported to be 7.2% in grade 12, while annual prevalence stood at 3.8%.

 In 2011, annual Ecstasy use was found to be at 4% to 5% for 19- to 24-year-olds and around 2% for those aged 25.

SCs produce amphetamine- and cocaine-like effects. They enhance the synaptic activation of norepinephrine, dopamine, and serotonin either by inhibiting their reuptake or by stimulating their release from storage vesicles. SCs are similar to amphetamines, methamphetamines, and MDMA in their mechanism of action and physiological effects.

SCs are typically taken orally or are injected or snorted; worse outcomes are associated with snorting and injection. Users report a variety of psychoactive effects, including a sense of well-being, a sense of profound insight and introspection, closed- and open-eyed visuals, increased appreciation of music, and increased empathy. Hallucinations and psychosis have been attributed to the effects of serotonin. The affinity of these drugs for the serotonergic receptors is estimated to be 3 times weaker than that of MDMA, which suggests that the development of psychosis with SC use is a result of using larger quantities.

Case reports have described patients with new-onset auditory and visual hallucinations, psychosis, agitation, and aggression, as well as symptoms congruent with mania.

 Physical effects of SC use include increased blood pressure, blurred vision, dehydration, nausea, vomiting, dilated pupils, and tachycardia(

). The observed peripheral cardiovascular effects are largely due to norepinephrine, which is also thought to contribute to the alerting, locomotor stimulation, and anorexic effects seen with these drugs.

MDMA is a synthetic drug that is structurally similar to the SCs. It acts as a CNS stimulant and has a weak hallucinogenic property more accurately described as increased sensory awareness. It produces feelings of increased energy, euphoria, emotional warmth, and empathy toward others, and distortions in sensory and time perception. MDMA is popular among youths at nightclubs or “raves” (long dance parties). MDMA is usually taken as a capsule or tablet. Its effects last approximately 3 to 6 hours, but users frequently take a second dose to prolong the effects. MDMA is commonly taken in combination with other drugs.

Research on the addictive properties of SCs and Ecstasy has produced varying results. Users report symptoms of dependence, such as cravings, continued use despite knowledge of physical or psychological harm, tolerance, and withdrawal symptoms. SCs have been shown to cause greater dopamine release than MDMA and may therefore have a greater abuse liability.

Unlike marijuana, SCPs do not have a typical, or “signature,” odor or look. The discovery of paraphernalia (eg, rolling papers, pipes, straws) raises the index of suspicion. A diagnosis of SCP, SC, or MDMA use is primarily supported by clinical history. Another method that should be considered as part of the overall diagnosis monitoring and treatment plan is the use of urine drug testing. Unfortunately, clinical laboratories do not routinely test for these recreational drugs because of financial constraints, analytical capabilities, and time limitations.

There are a variety of biological specimens used for laboratory drug testing, including urine, blood, sweat, saliva, hair, and nails. Each provides a different level of sensitivity, specificity, and accuracy. Urine is most often the preferred test substance because of its ease of collection. Also, concentrations of drugs and metabolites tend to be high in urine, allowing longer detection times than concentrations in the serum.

The expansion of laboratories that offer testing for Spice and bath salts has been useful to clinicians, but the utility of such tests is currently limited in scope. Manufacturers of these synthetic products are constantly changing the psychoactive ingredients to circumvent existing laws. Thus, a positive toxicology finding is useful in affirming the diagnosis but a negative result does not rule out the possibility of SCP or SC use. The expanding development of new SCPs and SCs is likely to continue to outpace the development of commercial laboratory testing. As a result, laboratory testing should be used in conjunction with a thorough clinical history and mental status interview to establish the diagnosis.

Recently, SCPs also have been detected in mixtures containing other new psychoactive substances, such as stimulants, hallucinogens, and sedative/hypnotics. In a small number of cases, SCPs have been detected in what appear to be Ecstasy tablets. Clinicians should be aware that what is labeled as Ecstasy might not be pure MDMA but rather methamphetamine or amphetamine. In addition, these drugs are often mixed with fillers to increase quantity. The most common fillers in Ecstasy are amphetamines and dextromethorphan.

SCP use should be considered if a person:

• Presents with signs and symptoms consistent with cannabis use

• Presents with unexplained anxiety and/or agitation with negative routine urine toxicology screens

• Is in a situation in which his or her urine is being routinely monitored for illicit substance use

• Presents with otherwise unexplained sudden-onset psychosis

DSM-5 requires the clinician to use the diagnostic code that applies to the class of the substance and to record the name of the specific substance. Patients who are found to be using SCPs should receive a diagnosis of a synthetic cannabis use disorder (with the corresponding severity).

• Reports a history of stimulant use (high levels of caffeinated substances; cocaine; amphetamines; or other, synthetic drugs)

• Presents with symptoms consistent with stimulant use

• Presents with unexplained anxiety, agitation, aggression, impulsivity, and/or irritability

• Is being routinely monitored for illicit substance use but presents with negative urine drug tests

• Has unexplained sudden onset of a mood disorder or psychosis

Patients who use bath salts who meet DSM-5 criteria for a stimulant use disorder should receive a diagnosis of an SC use disorder. Ecstasy use should elicit a diagnosis of amphetamine use disorder.

Interventions for acute intoxication with all designer drugs target the presenting symptoms. No medications are currently available to treat designer drug intoxication per se. Symptoms of SCP and SC intoxication may be self-limited and resolve spontaneously. In EDs, hydration and monitoring may suffice for patients who have mild to moderate signs and symptoms of intoxication. Patients who present with symptoms of anxiety, panic, agitation, and arousal after SCP or SC exposure may benefit from a benzodiazepine. An antipsychotic medication may be indicated when a patient presents with symptoms of psychosis, particularly when the psychosis is associated with behavioral disturbances (eg, agitation, aggression); the patient has a history of a psychotic disorder; or the psychotic symptoms do not appear to be remitting spontaneously or with supportive measures.

Our review of the literature did not identify any studies that have addressed formal treatment of SCP or SC use. It is likely that someone who is using Spice or bath salts is also abusing or has abused other substances. Because substance abuse and addiction are multidimensional and disrupt so many aspects of a person’s life, treatment is complex. Effective substance use treatments are typically comprehensive and incorporate various components, each targeting a particular aspect of the illness.

SCPs and SCs are two groups in the world of designer drugs that present potentially dangerous health effects. Identifying patients who use these drugs can be difficult. Clinicians are urged to familiarize themselves with these drugs and the typical presentations of patients who use them-the implications of a misdiagnosis can be far-reaching.

Differentiating between designer drug–induced symptoms and symptoms of a major mental illness is critical to management of patients. Because treatment of bipolar disorder or schizophrenia requires lifelong use of psychotropic medications, the ability to rule out drug-induced symptoms is crucial.

When treating patients who have chronic psychiatric disorders, it is important to identify precipitating and exacerbating factors, most frequent among them is unrecognized substance abuse. Designer drugs can produce symptoms that mimic both psychosis and mania. These drugs can also exacerbate manic, psychotic, and other mood symptoms in patients who have these disorders.

Newer, more specific, cost-effective laboratory testing, such as gas chromatography–mass spectrometry, rather than routine urine drug testing (immunoassay) may provide more tools for the clinician.

Dr Castellanos is Professor and Founding Chair in the department of psychiatry and behavioral health at the Herbert Wertheim College of Medicine at Florida International University, Miami. Dr Junquera is Assistant Professor in the department of psychiatry and behavioral health at the Herbert Wertheim College of Medicine, and Founding Residency Program Director at Citrus Health Network, Inc. The authors report no conflicts of interest concerning the subject matter of this article.

 Johnston LD, O’Malley PM, Bachman JG, Schulenberg JE. 

Monitoring the Future: National Survey Results on Drug Use 1975-2012. Volume 1: Secondary School Students.

 Ann Arbor, MI: Institute for Social Research, University of Michigan; 2013.

Johnston LD, O’Malley PM, Bachman JG, Schulenberg JE. 

Monitoring the Future: National Survey Results on Drug Use 1975-2011. Volume 2: College Students and Adults Ages 19-50

. Ann Arbor, MI: Institute for Social Research, University of Michigan; 2013.

Stogner JM, Miller BL. A spicy kind of high: a profile of synthetic cannabinoid users. 

. May 2013. http://informahealthcare.com/doi/a/10.3109/14659891.2013.770571. Accessed September 5, 2013.

 American Association of Poison Control Centers. 

. June 30, 2013. http://production-aapcc.dotcloud.com/alerts/synthetic-marijuana. Accessed September 5, 2013.

Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. 

The DAWN Report: Drug-Related Emergency Department Visits Involving Synthetic Cannabinoids.

 December 4, 2012. http://www.samhsa.gov/data/2k12/DAWN105/SR105-synthetic-marijuana.pdf. Accessed September 5, 2013.

Castellanos D, Thornton G. Synthetic cannabinoid use: recognition and management. 

 Centers for Disease Control and Prevention. Acute kidney injury associated with synthetic cannabinoid use: multiple states, 2012. 

. February 15, 2013. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6206a1.htm. Accessed September 5, 2013.

Zimmermann US, Winkelmann PR, Pilhatsch M, et al. Withdrawal phenomena and dependence syndrome after the consumption of “spice gold.” 

Vandrey R, Dunn KE, Fry JA, Girling ER. A survey study to characterize use of Spice products (synthetic cannabinoids). 

 June 30, 2013. http://www.aapcc.org/alerts/bath-salts. Accessed September 5, 2013.

 Advisory Council on the Misuse of Drugs. Consideration of the cathinones. 2010. https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/119173/acmd-cathinodes-report-2010.pdf. Accessed September 5, 2013.

 Kasick DP, McKnight CA, Klisovic E. “Bath salt” ingestion leading to severe intoxication delirium: two cases and a brief review of the emergence of mephedrone use. 

 Hadlock GC, Webb KM, McFadden LM, et al. 4-Methylmethcathinone (mephedrone): neuropharmacological effects of a designer stimulant of abuse. 

Articles

Psychiatrists are urged to familiarize themselves with these new drugs and the typical presentations of patients who use them since implications of misdiagnosis can be far-reaching.

Daniel Castellanos, MD

Articles

“Designer Drug” Use and Abuse: Implications for Psychiatrists