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Synthetic Cannabinoids-Further Evidence

Supporting the Relationship Between
Cannabinoids and Psychosis

ARTICLE in BIOLOGICAL PSYCHIATRY FEBRUARY 2016

Impact Factor: 10.26 DOI: 10.1016/j.biopsych.2016.02.001

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Review Biological
Psychiatry

Synthetic CannabinoidsFurther Evidence

Supporting the Relationship Between
Cannabinoids and Psychosis
Liana Fattore

ABSTRACT
Consumption of synthetic mind-altering compounds, also known as new psychoactive substances, is increasing
globally at an alarming rate. Synthetic cannabinoids (SCs) are among the most commonly used new psychoactive
substances. They are usually purchased as marijuana-like drugs, marketed as herbal blends and perceived as risk-
free by inexperienced users. Yet, contrary to 9-tetrahydrocannabinol, SCs may lead to severe health consequences,
including anxiety, tachycardia, hallucinations, violent behavior, and psychosis. This review focuses on the latest
(20102015) evidence of psychotic symptoms induced by ingestion of products containing SCs. Reports suggesting
that SCs may either exacerbate previously stable psychotic symptoms (in vulnerable individuals) or trigger new-onset
psychosis (in individuals with no previous history of psychosis) are reviewed. Pharmacology and toxicology of these
compounds are discussed, with particular reference to their psychoactive effects.
Keywords: Herbal blends, Intoxication, Novel psychoactive substances, Psychosis, Spice, Synthetic cannabinoids
http://dx.doi.org/10.1016/j.biopsych.2016.02.001

SYNTHETIC CANNABINOIDS: NOVEL when unable to obtain marijuana or to alleviate irritability

PSYCHOACTIVE SUBSTANCES WITH MARIJUANA-
LIKE EFFECTS
In the last decade, an increasingly high number of new
psychoactive substances used as alternatives to traditional
drugs of abuse emerged on the illicit drug market. Among
them, synthetic cannabinoids (SCs) represent the largest,
most diversied, and fastest growing group (1). Commonly
known as Spice, K2, or Kronic, these products are diffusion of these products (14). A particularly eventful year
usually sprayed on herbal mixtures, wrapped in foil packets
with the indication not for human consumption (2), and sold
via the Internet as natural legal highs, nail polish removers,
deodorizers, incense, or potpourri (3). Although marketed as
marijuana-like compounds, SCs cause more frequent and
severe negative effects than the natural plant they are
supposed to mimic (4). The contents and effects of SCs are
unpredictable because of the variety of chemicals they contain
and a manufacturing process devoid of quality controls and
regulations.
Owing to the lack of standardization, even ingredients of
the same brand can vary over time and across countries, and
the provided ingredient list (if present) is often incomplete, if
not purposely misleading. Adolescents account for 40% of
users (5). Men are more likely to consume SCs than women
(69), and many rst-time users are experienced marijuana
smokers (10). Most users smoke SCs using a water pipe
(bong) or joint and report weekly (or more frequent) use
along with the experience of side effects, such as dissociation
or paranoia (6). Some individuals smoke SC-based products
associated with abstinence (11).
REGULATION, CONSUMPTION MOTIVES, AND
DETECTION OF SCs
Following identication of the rst SCs as the main active
(nondeclared) ingredients of an herbal blend called Spice
(12,13), many countries have taken measures to control
was 2011 in terms of legislation of synthetic products. Initially,
legislative actions imposed bans on specic substances,
adding such substances to the list of controlled substances.
To bypass regulation, street manufacturers synthesized and
marketed new compounds with minor changes to the chem-
ical composition but with a pharmacologic activity very similar
to the banned drugs. Thus, new, previously unknown SCs are
constantly appearing on the market, making proliferation and
use of these substances difcult to control.
In the United States, the Drug Enforcement Administration
rst banned SCs in 2011, and the Synthetic Drug Abuse
Prevention Act permanently placed other SCs into Schedule I
of the Controlled Substances Act in January 2013, as required
under the Food and Drug Administration Safety and Innovation
Act of 2012 (signed into law by President Barack Obama) (15).
Since then, .250 new, uncontrolled compounds have been
synthesized to take their place. In 2014, 177 different SCs
were reported to the United Nations Ofce on Drugs and
Crime early warning advisory from 58 different countries and
territories (1).

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After the rst legislative actions taken between 2011 and
2012, the European Monitoring Centre for Drugs and Drug
Addiction reported the identication of .20 SCs in 2013 and
another 15 in the rst 9 months of 2014 (10). The European
Drug Emergency Network conrmed an unprecedented
growth in the number of intoxications related to the use of
novel psychoactive substances, including SCs (16). In some
countries, current legislation provides a broader denition of
prohibited drugs, not only covering unidentied and unregu-
lated drugs but also targeting entire classes of substances
rather than specic molecules. This more general approach
has been adopted in the United Kingdom, where all com-
pounds derived from a certain chemical structure are classied
as class B drugs.
First-time consumers typically report using SCs for various
reasons, such as curiosity, wide availability, easy access, and
lower costs compared with marijuana (2). Herbal mixtures
containing SCs are described as natural high marijuana-like
smoking blends and are traded in youth-oriented wrapping
under a captivating brand name. Until recently, they were legal
and easily accessible in service stations, tobacconists, and
online shops, supporting the general perception of SCs being
safe drugs or legal marijuana substitutes. SCs are not
easily detected in routine blood and urine analyses, making
them particularly attractive to individuals undergoing drug
testing in the workplace, a substance use treatment program,
or criminal justice settings.
In the past few years, great efforts have been made to
develop testing strategies able to identify and quantify SCs,
including liquid chromatography tandem mass spectrometry
and matrix-assisted laser desorption/ionization time of ight
mass spectrometry (1719). More recently, a new enzyme-
linked immunosorbent assay urine assay was validated for
screening SCs in urine targeting the JWH-018 compound and
related analytes (20), whereas gas chromatographytriple
quadrupole tandem mass spectrometry has been imple-
mented with electron and chemical ionization for the qualita-
tive identication of many SCs (21). Nonetheless, identication
of SCs is still challenging for toxicology, forensic testing, and
public health laboratories. To further complicate the screening
process, natural agents such as vitamin E are often added to
herbal blends to interfere with detection.
BEYOND 9-TETRAHYDROCANNABINOL
PHARMACOLOGY: WHY DO SCs INDUCE STRONGER
EFFECTS THAN MARIJUANA?
Similar to phytocannabinoids, SCs are highly lipophilic and
easily cross the blood-brain barrier (22). Preclinical studies
demonstrated a conspicuous overlap in the effects of SCs and
9-tetrahydrocannabinol (THC), including hypomotility, anti-
nociception, catalepsy, hypothermia, and discriminative stim-
ulus properties (23,24). However, SCs induce stronger
physiologic and psychoactive effects than THC, such as
seizures, collapses, cardiac toxicity, and acute kidney failure
(25,26).
This potentiated effect might be due to the fact that THC is
a weak, partial agonist of the cannabinoid subtype 1 receptor
(CB1R), whereas SCs act as potent, full agonists at the
same receptor. Moreover, THC displays a modest afnity
540 Biological Psychiatry April 1, 2016; 79:539548 www.sobp.org/journal
Synthetic Cannabinoids and Psychosis
(KI = 3580 nmol) at the CB1R, whereas SCs typically display
a higher afnity (KI = 2729 nmol), with the highest afnity
(KI = .1 nmol) achieved by the AM-694 compound (27).
Similarly, intrinsic activity (i.e., efcacy) at the CB1R is higher
for SCs than for THC (28). When two or more SCs are tested in
drug discrimination protocols, the rank order of drug potency
parallels afnity to CB1Rsthat is, compounds with the high-
est and lowest afnity for CB1Rs also exhibit the highest and
lowest potency in inducing THC-like discriminative stimulus
effects, respectively (23,29,30). These effects were antago-
nized by the selective CB1R antagonist/inverse agonist
rimonabant, demonstrating that the discrimination is CB1R
dependent (31). However, whether the effects of SCs in
humans correlate with their binding proles has not been
investigated so far. Similarly, to date, there are no controlled
data on the effect of full CB1R agonism in humans.
Numerous SCs identied in conscated products display a
higher afnity for peripheral cannabinoid subtype 2 receptors
(CB2Rs) than central CB1Rs (32,33). A comprehensive list of
receptor binding afnity and intrinsic activity of the most
common SCs at both CB1Rs and CB2Rs was published
recently (34). Central and peripheral actions of SCs still need
to be claried; however, they were found to interact with other,
noncannabinoid receptors and neurotransmission systems
(Figure 1). SCs have been shown to 1) stereoselectively
inhibit currents through recombinant homo-oligomeric
5-hydroxytryptamine 3 serotonin receptors (35), 2) increase
5-hydroxytryptamine 1A receptor density and messenger RNA
expression in the rat hippocampus (36), 3) act as antagonists
at the N-methyl-D-aspartate receptor (37), 4) inhibit mono-
amine oxidase activity (38), 5) modulate the function of
strychnine-sensitive 1 glycine receptors (39), and 6) affect
the functioning of the cytokine network (40). Moreover, the
CB2R agonist JWH-133 increases glutamate uptake (41),
whereas MAM-2201 (a new SC recently detected in herbal
products) inhibits glutamate release at Purkinje cell synapses
via activation of presynaptic CB1Rs and induces a
Display higher Antagonize
affinity at NMDA receptors
CB1 receptor
Display higher Stimulate
efficacy at mesolimbic
DA release
CB1 receptor
Display high
affinity at
Synthetic Inhibit
MAO activity
CB2 receptor Cannabinoids
Increase 5-HT
Produce receptor activity
active metabolites
and density
Share metabolic Activate the
strychnine-sensitive
pathways with
medical drugs 1 glycine receptor
Figure 1. Factors explaining intoxication and psychotropic effects of
synthetic cannabinoids with respect to 9-tetrahydrocannabinol (white
circles) and their interactions with other (nonendocannabinoid) neurotrans-
mission systems (blue circles). CB1, cannabinoid subtype 1; CB2, canna-
binoid subtype 2; DA, dopamine; 5-HT, 5-hydroxytryptamine (serotonin);
MAO, monoamine oxidase; NMDA, N-methyl-D-aspartate.

Synthetic Cannabinoids and Psychosis
concentration-dependent suppression of gamma-aminobutyric
acid release (42).
Abuse of SC-containing products is associated with a
higher incidence of severe adverse effects than abuse of
marijuana and, in contrast to THC, may lead to severe
intoxication. Given considerable interbatch and intrabatch
variability of type and quantity of substances contained in
SCs, clinical effects are highly unpredictable. A few fatal
intoxications following consumption of these products have
been reported (4348), some of which were suicides commit-
ted soon after ingestion and occurrence of acute psychosis,
panic attack (49,50), or severe hallucination (51). It should be
taken into account that other (noncannabinoid) ingredients of
these herbal blends may be present as impurities, contami-
nants, additives, or excipients and may exacerbate preexisting
poor health conditions. Factors that may contribute to the high
incidence of adverse effects associated with use of SCs
include 1) pyrolysis by-products of the smoked herbal blend
or the vegetable material on which SCs are sprayed, 2) shared
metabolic pathways with frequently used medications (leading
to adverse drug-drug reactions), and 3) biotransformation in
active metabolites (5255). The extent to which negative
adverse effects of cannabinoid-based products are due to
SCs per se rather than to other ingredients or concomitant
collateral events remains to be determined.
ACUTE EFFECTS OF SCs
Acute intoxication with SCs leads to a wide constellation of
symptoms, most of which have also been reported after
consumption of high doses of marijuana. However, some
symptoms are characteristic of SCs, such as seizures, agi-
tation, hypertension, emesis, and hypokalemia, and are usually
not observed even after high doses of marijuana (56). Clinical
presentation following use of SCs includes agitation, anxiety,
emesis, hallucinations, irritability, memory and cognitive
impairment, nausea and vomiting, shortness of breath or
depressed breathing, chest pain, unresponsiveness, and
psychosis (57,58). Although some SCs appear to be relatively
well tolerated, others have been linked to acute kidney injury
(5961), panic attacks (6264), seizures (6569), tachyarrhyth-
mia (70), and, more recently, severe rhabdomyolysis (71).
In some cases, the onset of action is within minutes of
smoking, and intoxication lasts 25 hours, typically with
recovery within 24 hours. Compared with THC, the duration
of effects seems to be shorter for JWH-018 (12 hours) and
longer for CP-47,497 and its C8 homologue (56 hours) (9).
Most users report that effects continue for approximately 6
hours and slowly taper, although others report that minor
impairments are still perceptible the following day (72). Palpi-
tations, anxiety, hallucinations, and insomnia may be experi-
enced for several days after smoking a SC-containing product
(73).
Repeated consumption of SCs may induce tolerance, as
suggested by the nding that, contrary to rst-time users,
regular users may not experience toxic effects despite high
blood levels of SCs (74). In addition, abrupt discontinuation
of SCs after regular use of high doses may induce with-
drawal symptoms (7578), many of which are similar to
symptoms reported during marijuana withdrawal (e.g., sleep
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disturbances, anxiety, craving, and nausea) (79). Although
convulsions associated with recreational marijuana smoking
are rare, generalized convulsions have been reported after
using various products containing SCs (70,80,81). Long-term
or residual effects of SCs are unknown, but aggression, self-
harm, and self-mutilation, including self-inicted burns, have
been reported (82,83).
There are no specic treatments or antidotes for SC
intoxication, and medical management of patients largely
consists of supportive care. Targeted approaches may be
implemented, such as administration of benzodiazepines for
severe seizures, benzodiazepines and propofol for aggression,
and haloperidol and quetiapine for psychosis (84). Intravenous
lipid emulsion was also found to be benecial (85). In theory,
use of a CB1R antagonist might be helpful in treating
symptoms of intoxications, but no medication with antagonist
activity at the CB1R is commercially available to date.
SCs AND PSYCHOSIS
The debate about a causal link between smoking marijuana
and the occurrence of psychosis is still ongoing despite
decades of research on humans and animals (8689). Use of
products containing SCs has been reported to induce psy-
chosis (90), but no controlled studies have been conducted so
far to characterize the psychotomimetic prole of these
synthetic preparations in humans. Psychotic-like symptoms
can arise during acute SC intoxication, with paranoia, disor-
ganized behavior, visual and auditory hallucinations, and
suicidal thoughts typically lasting signicantly longer than
motor symptoms or anxiety (91). Compelling evidence shows
that SCs are able to trigger psychotic symptoms not only in
vulnerable individuals, who re-experience psychosis after
consumption, but also in subjects with no previous history of
psychosis, who may experience prolonged psychotic epi-
sodes after smoking products containing SCs. There is no
extensive literature available on this topic, and our limited
knowledge is based mainly on reports from Poison Control
Centers and surveys (7,9) and on case reports of individuals
with or without concomitant psychiatric disorders.
Case reports may aid the discovery of a potential associ-
ation between use of SCs and psychotic episodes. However,
they are of lesser utility for understanding whether or not
cases of new-onset psychosis reect exacerbation of preex-
isting prodromal syndrome. Case reports associating the use
of SCs with occurrence of psychosis are summarized in
the present review, with a distinction made between re-
emergence (Table 1) and new-onset (Table 2) episodes of
psychosis. The exact compound ingested was known only in
rare cases (e.g., AM-2201), whereas many cases reported only
the brand name of the product consumed (e.g., Spice,
Aroma, K2). Moreover, some case reports did not indicate
previous mental states of intoxicated patients or concomitant
use of other drugs (92), and others lacked conrmation
through laboratory analysis. Absence of standardized assess-
ment and confounding effects of prescribed/abused drugs or
preexisting mental disorders are limitations to consider before
drawing any conclusion about a causal link between use of
SCs and psychosis.
541
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Table 1. Re-emergence of Psychosis: Case Reports of Psychosis Induced by Synthetic Cannabinoids in Vulnerable
Individuals (20102015)
Product Polydrug
Case/Location (Reference) Psychiatric History Consumeda Symptoms Abuse Treatment
1 patient 25 years old, male/ Cannabis-induced Spice Increased anxiety, imperative None NA
Germany (93) recurrent psychotic (smoked, voices, paranoid
episodes 3 times) hallucinations
5 forensic patients, all male/ Psychotic illness Aroma Agitation, disorganization, NA NA
New Zealand (94) (smoked) paranoia
9/13 forensic patients 1865 Psychotic illness, Aroma Anxiety, psychosis, paranoia Marijuana NA
years old, all male/New antipsychotics for (smoked)
Zealand (95) 6 months before study
1 patient 2030 years old, PTSD Spice Aggression, paranoia, Marijuana 2-week hospitalization 1
male/Arizona (96) (smoked delusions, suicidality risperidone to continue on
daily) discharge
1 patient 2030 years old, Amphetamine-induced Spice 99 Aggression, paranoia of None 2-week hospitalization 1
male/Arizona (96) psychotic episodes (smoked persecution, delusions haloperidol to continue on
regularly) discharge
4 patients 2135 years old, Paranoid (n = 2)/ AM-2201 Elevated affect (maniac), None No additional pharmacotherapy
all male/Slovenia (97) undifferentiated (n = 2) agitation, anxiety, delusions, (n = 1); increase in dose of
schizophrenia behavioral changes benzodiazepines (n = 3)
NA, data not available; PTSD, posttraumatic stress disorder.
a
Brand names under Product Consumed do not refer to specic ingredients, as their compositions and dosages vary greatly between
products and within the same brand packages.

Re-emergence of Psychosis
Coinciding with the increasing number of SCs available on the
Internet in recent years, health professionals reported an
increased use of these drugs among patients with psychiatric
disorders. The psychotropic effects of SCs in patients with
schizophrenia are quite unpredictable, and very diverse clinical
presentations have been reported. The rst hint of a potential
link between SCs and exacerbation of marijuana-induced
psychosis was given in 2010, when a 25-year-old man with
a previous history of marijuana use and recurrent psychosis

Table 2. New-Onset Psychosis: Case Reports of Psychosis Induced by Synthetic Cannabinoids in Subjects With No Previous
History of Psychosis (20102015)
Psychiatric
Case/Location (Reference) History Product Consumeda Symptoms Polydrug Abuse Treatment
7 healthy patients 1630 None Crazy Clown (smoked Anxiety, delirium, psychosis, Past cocaine use Haloperidol, lorazepam
years old, 3 male, 4 ADB-PINACA) aggressive behaviors (1 patient) (male patients only),
female/Georgia (97) intubation
10 healthy patients 2125 None Different herbal blends Hallucinations, paranoid Marijuana/alcohol Antipsychotics (7/10
years old, all male/ (smoked) delusions, disorganized patients) 1 58 days
California (101) speech, anxiety, agitation hospitalization
1 healthy patient 2030 years None Spice (smoked daily) Capgras syndrome, suicidality Marijuana Haloperidol 1 2-week
old, male/Arizona (96) hospitalization
1 healthy student 20 years old, None Spice (smoked daily) Anxiety, tachycardia, hesitant None None
male/Arizona (103) speech, paranoia
2 patients 2022 years old, None Banana Cream Nuke (rst Anxiety, palpitation, psychosis None None
female/California (102) use)
1 healthy patient 36 years old, Drug K2 (smoked daily for Florid persecutory delusion, Multiple Midazolam
male/Hong Kong (108) addiction 1 month before auditory hallucinations, psychoactive
admission) agitation substances
1 healthy soldier, 20 years None Unknown synthetic Agitation, delirium, auditory Alcohol, marijuana, Lorazepam and
old, male/North Carolina cannabinoid delusions, disorganized mephedrone haloperidol 1
(106) speech hospitalization
1 healthy soldier, 22 years Depression, Chronic use of synthetic Anxiety, agitation, suicidal Marijuana, tobacco, Haloperidol
old, female/North Carolina anxiety, cannabinoids ideation cathinones,
(107) PTSD amphetamine
1 patient 23 years old, male/ None Mad Hatter Incense and Severe psychosis None Found dead from self-
Arkansas (51) ZAN-X Extra Relaxation induced, lethal trauma
(smoked)
1 healthy patient 17 years None K2 (smoked daily for Confusion, catatonia, bizarre None Lorazepam followed by
old, male/Minnesota (104) 2 months) behavior, hallucinations ECT
ECT, electroconvulsive therapy; PTSD, posttraumatic stress disorder.
a
Brand names under Product Consumed do not refer to specic ingredients, as their compositions and dosages vary greatly between
products and within the same brand packages.

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Synthetic Cannabinoids and Psychosis
(but stable under controlled amisulpride monotherapy)
required hospitalization because of increased anxiety and
new symptoms (i.e., imperative voices, paranoid hallucina-
tions) after smoking a blend called Spice (93).
Also in 2010, Every-Palmer identied the two SCs
(CP47,497 and JWH-018) responsible for the precipitation of
psychosis in subjects with known psychotic illness (94), a
nding subsequently conrmed by additional studies (95). Re-
emergence of psychosis in these previously stable patients
typically deteriorated their mental states and included agita-
tion, disorganization, and paranoia. In Arizona, two young men
with heterogeneous psychiatric histories (posttraumatic
stress disorder [PTSD] and amphetamine-induced psychosis)
but with similar symptoms (aggression, delusions, paranoia)
required hospitalization after smoking products containing
SCs and received pharmacotherapy with haloperidol or risper-
idone with intent to continue on discharge (96).
When observing patients with a diagnosis of paranoid or
undifferentiated schizophrenia who smoked SCs, Celoga
et al. (97) noticed no exacerbation of previous psychotic
symptoms, but rather a general worsening of emotional
symptoms and occurrence of new psychotic symptoms. The
authors ascribed the absence of deterioration of their mental
states to the ongoing psychopharmacotherapy and reported
that all symptoms were resolved by increasing the dose of
benzodiazepines (97).
New-Onset Psychosis
A severe delirium was described in seven young patients who
were hospitalized simultaneously in Georgia after smoking
incense containing a newly identied SC, ADB-PINACA, at the
same party (98). These patients had no medical history, and
all had been well previously. On admission, they presented
with anxiety symptoms, delirium, psychosis, and aggressive
behaviors, along with hypertension and tachycardia. Following
these and other similar case reports, the Drug Enforcement
Administration temporarily scheduled AB-PINACA and two
other SCs (AB-CHMINACA and THJ-2201) into Schedule I of
the Controlled Substances Act along with their optical,
positional, geometric isomers and salts (14). Reviewing single
cases reveals that intoxication was more severe in men than in
women. The three male patients were confused, markedly
agitated, and combative and required chemical sedation and
intubation for management of violent behavior, whereas the
four female patients were agitated (two were also anxious) but
alert and oriented and did not require therapeutic interventions
(98). However, opposite ndings were reported by Cohen et al.
(92) who described a 16-year-old girl to be unresponsive to
verbal or painful stimuli and to present with catatonia, vertical
nystagmus, and sinus tachycardia after smoking a marijuana-
K2 mixture with her boyfriend, but the boyfriend did not
present with evident symptoms of intoxication or require
hospitalization (92). Sex-dependent differences have been
reported in the manifestation of marijuana-induced psychosis
(99), withdrawal symptoms (100), and prevalence of use, with
men being more likely to use SCs than women (58). However,
no controlled studies have evaluated potential sex-dependent
differences regarding SC use and acute effects so far,
providing no evidence to date to support the notion that
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SCs may exert differential effects in men and women. The
differences described in the two above-mentioned studies are
not only incongruent in themselves but also may simply reect
different doses of drug ingested or different concentrations of
cannabinoids within the same product.
In 2010, the psychiatric ward at the Naval Medical Center in
San Diego, California, reported admission of 10 otherwise
healthy young men with new-onset psychosis (101). Symp-
toms ranged from auditory and visual hallucinations to para-
noid delusions; from psychomotor retardation and agitation to
disorganized behavior and speech; and from odd or at affect
to anxiety, alogia, and thought-blocking, including waxing and
waning stuporous appearance and in some cases insomnia
and suicidal ideation. All patients admitted to having smoked
SCs more than once but denied experiencing psychotic
symptoms before using these products. Most patients needed
antipsychotic treatment, and symptoms resolved within 58
days of hospitalization. However, particularly concerning was
the persistence of psychotic symptoms in three patients well
beyond acute intoxication (i.e., over the next 5 months).
Although patients disclosed the brand of the blend they
smoked, no analysis on the specic SC responsible for the
psychotic symptoms was conducted.
In the same year, two healthy girls smoking SCs for the rst
time called 911 shortly after use and described feeling
unusual, disoriented, anxious, and psychotic (102). More-
over, among other patients with a previous history of mental
(PTSD) and psychiatric (psychosis) disorders, Van Der Veer
and Friday (96) reported a case of persistent psychosis
following use of a product containing SCs in a young man
with no psychiatric history. He reported that he had switched
from marijuana to SCs 34 weeks before requesting admission
and had experienced delusions and suicidal ideation after daily
smoking. Psychotic symptoms required haloperidol treatment
and a 2-week hospitalization period, during which symptoms
ameliorated but did not resolve entirely, so medications were
continued on discharge. This case report strengthens the
notion that switching from smoking marijuana to SCs may
precipitate psychotic episodes in subjects who never experi-
enced psychotic-like symptoms before, conrming the high
risk associated with the use of SCs.
In some cases, it is not possible to differentiate between the
induction of psychosis and the exacerbation of a nascent
primary psychosis. A young student reported starting smoking
a product containing THC-like compounds to alleviate the
increasing anxiety he was experiencing for no apparent reason
(103). As he started smoking, anxiety worsened, and he
developed paranoia with auditory and visual hallucinations
for the rst time in his life. However, whether psychotic
symptoms would have occurred in this individual without
smoking SCs is not known.
More recently, an adolescent with no previous psychiatric
illness presented with psychosis, mild hypertension, and
excitatory catatonia after prolonged use of K2 and required
neuroleptic treatment (104). Once able to communicate, he
described experiencing auditory and visual hallucinations and
disorganized thoughts. Because he relapsed into a catatonic
state, electroconvulsive therapy was initiated, and resolution
of symptoms was evident after six electroconvulsive therapy
sessions. In Arkansas, a 23-year-old man with an unknown
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history of mental illness, psychiatric care, or past or current
use of illicit drugs was found dead at home following self-
induced trauma. It was likely that he developed psychosis after
using a vegetable material labeled Mad Hatter Incense (51).
Many soldiers in the U.S. Armed Forces use SCs despite
risking disciplinary or administrative actions (105). A 20-year-
old male soldier with a previous history of drug abuse (alcohol,
marijuana, mephedrone) but not mental illness experienced
cognitive and attentional impairments, tachycardia, and psy-
chomotor agitation after use of unknown SCs (106). During
hospitalization, he developed psychotic disorders with delu-
sions and negative symptoms persisting .3 months after use.
A 22-year-old female soldier had abused SCs for a long time
and presented with anxiety, agitation, and suicidal ideation,
but the concomitant abuse of other drugs (marijuana, tobacco,
amphetamines, cathinones) and psychiatric comorbidity
(depression, anxiety, PTSD) made it impossible to ascribe
her psychotic symptoms to the use of SCs (107). Similarly, in
China, a 36-year-old man developed acute mental disturbance
after using the product K2 and required intramuscular mid-
azolam for rapid tranquilization (108), but the concomitant use
of multiple psychoactive substances questions a causal link
between use of SCs and occurrence of psychosis-like
symptoms.
CONCLUSIONS
Despite increasing regulatory control measures, recreational
use of SC-based products is widespread and represents a
serious, ever-evolving health and legal concern. The compo-
sition of these synthetic products may markedly vary from
package to package, even within the same brand name.
Because SCs are typically sprayed onto vegetable material,
their concentrations might be unequally distributed, resulting
in some parts being highly concentrated (hot spots) and
exposing the consumer to a serious health risk.
SCs exert stronger physiologic and psychological effects
than THC, for which medical treatments often remain sympto-
matic (i.e., uids, benzodiazepines). Heavy use has been
associated with an earlier onset of psychosis in marijuana
smokers (109), especially in high-potency/skunk marijuana
users (110), and with transient (111113) and persisting
psychosis (96,101,102) as well as with re-emergence and
worsening of preexisting psychotic disorders (56,93,95,108).
The same SC may induce different effects in patients with
schizophrenia (97), and psychotic-like symptoms may also
occur in patients with depression (56,101), attention-decit/
hyperactivity disorder (101), PTSD (96,113), and polydrug use
(6,8,114).
Similar to THC, SCs bind and activate CB1Rs, but with
greater efcacy than THC (115117), and easily cross the
blood-brain barrier (118). However, toxicologic proles of SCs
are quite dissimilar from THC and include undesirable effects,
such as confusion (119), agitation and anxiety (108,120),
altered perception and mental status (92,114,121), paranoia
and irritability (5,122), depression, and suicidal thoughts
(96,101,117). Although differences in pharmacodynamics
might explain why people experience more intense effects
when smoking SCs than marijuana, some differences in
pharmacokinetics may account for the higher severity of toxic
544 Biological Psychiatry April 1, 2016; 79:539548 www.sobp.org/journal
Synthetic Cannabinoids and Psychosis
side effects (123125). The fact that SCs possess a higher
afnity and intrinsic activity (i.e., efcacy) at CB1Rs than THC
might partially explain their high potential to trigger psychotic-
like symptoms. In support, preclinical studies in rodents
showed that chronic stimulation of the cannabinoid CB1R with
a full synthetic agonist (WIN55,212-2) during puberty induces
a reduction in the prepulse inhibition of the acoustic startle
reex (126), which is a reliable index of sensorimotor gating
decits frequently observed in patients with schizophrenia.
Other factors may likely be involved, such as the absence of
natural compounds in SC-based preparations that are typically
present in the cannabis plant (cannabidiol and cannabivarin)
and possess putative anxiolytic and antipsychotic properties
(127,128) as well as weak antagonistic activity at the CB1R
(129). Moreover, SCs have recently been shown to increase
dopamine release preferentially in the rat nucleus accumbens
shell and to decrease gamma-aminobutyric acid Amediated
postsynaptic currents of dopaminergic neurons in the ventral
tegmental area through the activation of CB1Rs (130).
With new analogues constantly being synthesized and
marketed to replace those that will be legally regulated, SCs
will likely remain on the illicit drug market for a long time. Given
the ever-evolving structure of these compounds, clinicians
and emergency staff should be aware that SCs may cause
severe health consequences and unexpected adverse effects
not always associated with marijuana use. Clinicians should
be vigilant and consider the possibility of SC use in patients
normally abusing drugs and presenting with psychiatric
symptoms and negative urine toxicology. Political and educa-
tional efforts are necessary to inform the public about health
consequences of these relatively new drugs for which limited
information is available.
ACKNOWLEDGMENTS AND DISCLOSURES
LF is supported by the Fondazione Banco di Sardegna and University of
Verona (Joint Project); the work supported by these grants is not related to
the ndings presented in this review.
The author reports no biomedical nancial interests or potential conicts
of interest.
ARTICLE INFORMATION
From the Neuroscience Institute, National Research Council (Italy),
and Centre of Excellence Neurobiology of Dependence, Department
of Biomedical Sciences, University of Cagliari, Cittadella Universitaria,
Monserrato, Cagliari, Sardinia, Italy.
Address correspondence to Liana Fattore, Ph.D., Department of Bio-
medical Sciences, University of Cagliari, Cittadella Universitaria, Monser-
rato, Cagliari, Sardinia 09042, Italy; E-mail address: lfattore@in.cnr.it.
Received Apr 3, 2015; revised and accepted Feb 1, 2016.
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