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REVIEW ARTICLE
Synthetic cannabinoids: A review of the clinical
implications of a new drug of choice
Shaina A. Freund, MHS, PA-C; Adrian S. Banning, MMS, PA-C
ABSTRACT
Synthetic marijuana use is an emerging public health
problem in the United States, and can cause agitation, severe
psychosis, bizarre hallucinations, and possibly death. This
article describes these products, which are unregulated and
can vary widely in composition, and how clinicians can recognize patients with synthetic cannabinoid toxicity and treat
them appropriately to minimize morbidity and mortality.
Keywords: synthetic cannabinoids, marijuana, drug use,
acute kidney injury, spice, K2
S
ynthetic
h
cannabinoids
b
d are a novell group off psychoh
active chemicals that have become prominent in the
last decade, particularly with adolescents, young
adults, and marijuana users.1-4 These drugs are a growing
national concern due to their potential for severe adverse
reactions, which cause an increasing number of patients to
seek medical care in EDs across the country.3,4 According
to a national survey, synthetic marijuana was reported
as one of the most common drugs used, second only to
cannabis among 10th and 12th graders, and third to cannabis and inhalants among 8th graders.5 In 2015, nearly
7,800 calls were made to national poison control centers
about synthetic marijuana use, a 111% increase from the
number of calls in 2014.4 Many clinicians are unaware
of the existence of synthetic cannabinoids or their serious and even lethal consequences.2-4 Products marketed
as synthetic marijuana are composed of inconsistent
concentrations of synthetic cannabinoid compounds in
combination with other drug additives, causing a wide
variation of effects on users.6 Due to the unpredictable
nature of these adverse reactions, clinicians must maintain
a high index of suspicion for synthetic cannabinoid use
in patients with no obvious cause for neuropsychiatric
symptoms, especially patients with negative drug screenShaina A. Freund practices pediatrics at New York-Presbyterian
Hospital—Weill Cornell Medical Center in New York City. Adrian
S. Banning is an assistant clinical professor in the PA program at
Drexel University. The authors have disclosed no potential conflicts of
interest, financial or otherwise.
DOI:10.1097/01.JAA.0000525914.28344.e2
Copyright © 2017 American Academy of Physician Assistants
ing tests. This article aims to increase clinician awareness
of the prevalence, pharmacology, clinical manifestations,
diagnosis, and treatment of patients presenting with acute
signs and/or symptoms of synthetic cannabinoid toxicity.
WHAT ARE SYNTHETIC CANNABINOIDS?
Synthetic cannabinoids were created in controlled scientific
laboratories for research on the endocannabinoid system
and as potential therapeutic substances; when sold and
used illicitly, they are sprayed on crushed psychoactively
inert organic material to mimic marijuana.2,3,7 These products are sold most commonly under the brand names “K2”
and “Spice,” or simply labeled “synthetic marijuana,” and
are labeled “not for human consumption” in order to elude
current drug laws.8 They are sold in retail headshops (stores
that sell items used for the consumption of tobacco and
cannabis) and online as “legal highs,” “incense,” or “potpourri.”3,9 Users usually smoke the mixture in pipes or
joints but oral ingestion also has been reported.8
The US Drug Enforcement Agency (DEA) has attempted
to keep up with the major synthetic cannabinoids found
in these herbal blends and categorizes them as schedule I
substances, making them illegal to possess or distribute.5,6
JAAPA Journal of the American Academy of Physician Assistants
Copyright © 2017 American Academy of Physician Assistants
www.JAAPA.com
REVIEW ARTICLE
Key points
Many clinicians are unaware of the existence of
synthetic cannabinoids or their serious and even lethal
consequences.
Synthetic cannabinoids pose a higher public health risk
than marijuana and have a more severe constellation of
adverse reactions.
Because they cannot be detected by routine drug
screening tests, synthetic cannabinoids are desirable to
patients who want the effects of cannabis without legal
repercussions.
However, no laws encompass synthetic cannabinoids as a
whole, and the ever-changing marketplace and emerging
varieties of synthetic cannabinoids make it difficult to
maintain legislation controlling their legality.10
ADVERSE REACTIONS
AND CLINICAL MANIFESTATIONS
Patients who use synthetic marijuana report being drawn
to the product due to its perceived safety and inability to
be detected by traditional drug screen, as well as its reported
psychotropic effects similar to delta-9 tetrahydrocannabinol (THC), a chemical found in cannabis.2,9,11,12 Unpredictable adverse reactions to the drug are numerous, vary
extensively, and may be severe when they occur due to the
widely variable chemical compositions of the different
products available.
Although many cannabis users believe that the adverse
reactions to cannabis and synthetic cannabinoids are
similar, synthetic cannabinoids pose a much higher public
health risk with a much more severe constellation of adverse
reactions, as borne out by media reports, poison control
center calls, and ED visits.2-4,13
The most common adverse reactions to synthetic cannabinoids include anxiety, agitation, tachycardia, and
psychosis including bizarre hallucinations (auditory and
visual), delusions, and paranoia.4,9,11,14 Psychotic episodes
are intense and may be prolonged or persistent in some
patients. Some case reports have described acute-onset
psychosis that persisted for more than 5 months.9,11,14 Other
reported psychologic included panic attacks, altered mental status and changes in perception, irritability, restlessness,
flat affect, thought blocking, disorganized thoughts and
speech, alogia, sedation, confusion, disorientation, insomnia, amnesia, catatonia, depression, agitation, aggression,
and suicidal ideation.7,9,11-13,15,16 Physical signs and symptoms
include nausea, vomiting, headache, blurred vision, hypertension, tachycardia, hypokalemia, encephalopathy, tremors, seizures, and unresponsiveness.7,9,11-14,16,17
In 2012, the CDC released a report identifying acute
kidney injury (AKI) in patients who had recently used
synthetic cannabinoids and in whom no other identifiable
cause existed for the renal findings.18 Since then, multiple
www.JAAPA.com
other cases of AKI, specifically acute tubular necrosis
diagnosed via renal biopsy, have been linked to synthetic
cannabinoid use in men.19 Other documented severe complications of synthetic cannabinoid use include pneumonia,
rhabdomyolysis, intracranial hemorrhage, dysrhythmias,
and myocardial infarction.20-22
Physical dependence on synthetic cannabinoids may
occur following persistent daily use, as evidenced by the
emergence of withdrawal symptoms following cessation
of use, such as agitation, irritability, anxiety, nausea, and
mood swings.7,23 These symptoms most commonly occur
within 24 to 48 hours of stopping synthetic cannabinoid
use, but may persist longer in some patients.23
Multiple case reports have linked synthetic cannabinoid
use to accidental deaths among young people whose only
toxicologic findings were varying blood concentrations of
synthetic cannabinoids.24,25 The common synthetic cannabinoid toxicologic findings in all of these deaths serve as
an alarming realization that serious outcomes may occur
following synthetic cannabinoid use, and that a lethal serum
concentration of synthetic cannabinoids may exist. To what
extent these adverse reactions, withdrawal symptoms, and
fatal intoxications are directly related to synthetic cannabinoid use is unclear. Adverse reactions may be related to
the synthetic cannabinoid itself, an interaction with additives
to the herbal mixtures, or due to polysubstance use.2,7,13
Though effects of synthetic cannabinoids most commonly
include anxiety, agitation, and psychosis, a classic presentation cannot be described because patients tend to present
and withdraw erratically due to the ever-changing chemical preparations of these drugs. The unpredictable toxidromes associated with severe outcomes demonstrate the
urgency with which clinicians must recognize the potential
effects of synthetic cannabinoids in their patients.6,14,17
PHARMACOLOGIC PROPERTIES
Pharmacologic knowledge of synthetic cannabinoids is
limited. Delta-9 THC, the primary psychoactive chemical
present in natural cannabis, exerts its effect as a partial
agonist at cannabinoid type 1 (CB1) receptors in the brain
and nervous system.26 Synthetic cannabinoids were created
to simulate the effects of delta-9 THC and act as potent
cannabinoid receptor agonists in the body, which is one
of the reasons the products are often inappropriately labeled
“synthetic marijuana.”3,6,13 However, synthetic cannabinoids are full agonists at not only CB1 receptors, but also
cannabinoid type 2 (CB2) receptors located throughout
the body. Research suggests that synthetic cannabinoids
have both greater potency and efficacy than delta-9 THC
due to more efficacious binding at cannabinoid receptors,
particularly CB1 receptors. Furthermore, synthetic cannabinoid products do not contain cannabidiol, a psychoactive ingredient present in natural cannabis extracts that
may be protective against the acute psychotic episodes
associated with delta-9 THC.14
Volume 30 • Number 11 • November 2017
Copyright © 2017 American Academy of Physician Assistants
Synthetic cannabinoids: A review of the clinical implications of a new drug of choice
Results of multiple studies indicate that cannabidiol may
produce anxiolytic and antipsychotic effects in humans
and animals.27-29 Its pharmacologic effects include antagonism of delta-9 THC at cannabinoid receptors by prolonging the effects of endogenous cannabinoids and agonist
activity at the 5-HT1A serotonergic receptor.28 Though its
exact mechanism at these receptors is not fully understood,
cannabidiol may play a protective role and offset some
negative effects of delta-9 THC; its absence from synthetic
cannabinoids may explain their severe reactions.27,28
The exaggerated adverse reactions to synthetic marijuana
may have many causes:
• Wide variability in drug concentration because synthetic
cannabinoid products are created by spraying a drugcontaining solution onto dried organic material.3,14
• Additives to synthetic cannabinoid products, including
nicotine, caffeine, high concentrations of vitamin E, the
psychoactive alkaloid harmaline, and the synthetic opioid
O-desmethyltramadol, the active metabolite in tramadol.13,30
This variability may cause significant drug-drug reactions
when metabolized, both between the synthetic cannabinoids
themselves, or with the other drugs that may be found in
different preparations of the product.6
Overall, the increased potency and efficacy of synthetic
cannabinoids over delta-9 THC, combined with the lack
of cannabidiol, unpredictable drug concentrations, and
numerous additives all likely contribute to the increased
risk of severe adverse reactions in patients who use synthetic
cannabinoids.9,12
DETECTION IN BLOOD SERUM AND URINE
Routine testing for synthetic cannabinoids is not widely
accessible.31 This clinical undetectability makes synthetic
cannabinoids desirable to those who want the effects of
cannabis without legal repercussions.31 Research is still
being conducted on ways to detect the metabolites of
synthetic cannabinoids in urine and blood specimens.31-33
Many of the metabolites are renally excreted, so urinary
screening methods are being developed but are not yet
widely used.32
The main methods of identifying synthetic cannabinoids
or their metabolites in blood or urine are liquid chromatography-tandem mass spectrometry and gas chromatography/mass spectrometry. 25,34 However, these
methods have limitations for use in clinical practice: no
standardized process for detection, and no standard
reference samples because of the many varieties of synthetic cannabinoids.3,32 Additionally, these tests are
time-consuming, expensive, and limited to laboratories
equipped with the proper technology.25,34 Research is
under way on the use of untargeted screening methods
for synthetic cannabinoids in blood and urine, which
may show promise in the ability to detect a wide array
of different synthetic cannabinoids in a qualitative urine
drug screen.25 This screening method may be the first
step in developing screening tests to be made widely
available in clinical settings where these patients are
likely to present.
TREATMENT
No data-driven guidelines exist detailing a recommended
treatment regimen for patients with acute synthetic cannabinoid intoxication or prolonged adverse reactions, and
no drug-specific reversal agent is available. Studies suggest
that synthetic cannabinoids have a variable half-life, with
estimates ranging from 2 to 48 hours or more; however,
this does not explain the prolonged toxicologic effects that
some patients experience.6,8,12 These inconsistencies in halflife and residual effects may be explained by the large
number of different products available to users.
A combination of observation, supportive care, and
symptomatic treatment appears to be the best management
for these patients, as most symptoms resolve in 24 to 48
hours.6,9,17,31 Benzodiazepines, most frequently lorazepam
2 mg IV or IM for one or multiple doses, have been the
most common and effective treatment reported to alleviate
the common acute symptoms of agitation, restlessness,
irritability, anxiety, panic attacks, and seizures.9,11,15 Antipsychotic medications, including haloperidol, risperidone,
olanzapine, and quetiapine, have been used successfully
to treat psychotic symptoms, agitation, paranoia, and
withdrawal symptoms.7,11 In other patients, diphenhydramine has been effective for aggression, agitation, and
catatonia when given alone and in combination with other
treatments.11 Antiemetics also may be considered for nausea and vomiting associated with synthetic cannabinoid
use and withdrawal.35
Supportive measures should be considered on a case-bycase basis, and may include routine observation, vital signs
and cardiac monitoring, IV fluid administration to prevent
AKI and dehydration, environmental management of agitated
or violent patients, and neurologic assessments as needed.35
Some patients have been hospitalized for days to weeks,
including inpatient admission to psychiatric units for both
acute-onset as well as persistent psychosis after synthetic
cannabinoid use.15,17 Not all patients regained baseline
psychiatric function despite more radical interventions,
including electroconvulsive therapy for persistent symptoms.15,17 Finally, consider polydrug use because coingestion
may be a confounding factor in these patients, and consultation with toxicology or a poison control center may be
warranted. Counseling or referral for formal substance use
treatment may be appropriate for patients developing dependency on synthetic cannabinoids or other drugs.2,9
CONCLUSION
Synthetic cannabinoids are a growing national concern due
to their popularity and unpredictable, severe, and sometimes
long-lasting adverse reactions.2 These drugs are being marketed to adolescents and young adults using flashy packaging,
JAAPA Journal of the American Academy of Physician Assistants
Copyright © 2017 American Academy of Physician Assistants
www.JAAPA.com
REVIEW ARTICLE
ambiguous labels, and the knowledge that they cannot be
detected by conventional drug screening.2,3,5 When screening
for illicit drug use, clinicians should ask patients about synthetic cannabinoid use, particularly those who have had a
change in mental status without an obvious cause.
Limited knowledge of the pharmacologic properties and
clinical effects of synthetic cannabinoid products make
further research in humans ethically challenging, and no
studies exist exploring the drug’s potentially prolonged
residual effects.2,12 Healthcare providers must be aware of
the prevalence and potential clinical manifestations of these
products so they can educate their patients and peers, and
have a high index of suspicion for synthetic cannabinoid
use in patients with symptoms such as those described in
this article. JAAPA
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Volume 30 • Number 11 • November 2017
Copyright © 2017 American Academy of Physician Assistants
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