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Synthetic cannabinoid JWH-018 and psychosis: An explorative study


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Aroma, Spice, K2 and Dream are examples of a class of new and increasingly popular recreational drugs. Ostensibly branded "herbal incense", they have been intentionally adulterated with synthetic cannabinoids such as JWH-018 in order to confer on them cannabimimetic psychoactive properties while circumventing drug legislation. JWH-018 is a potent cannabinoid receptor agonist. Little is known about its pharmacology and toxicology in humans. This is the first research considering the effects of JWH-018 on a psychiatric population and exploring the relationship between JWH-018 and psychotic symptoms. This paper presents the results of semi-structured interviews regarding the use and effects of JWH-018 in 15 patients with serious mental illness in a New Zealand forensic and rehabilitative service. 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. Most patients had assumed the product was "natural" and "safe". Anxiety and psychotic symptoms were common after use, with 69% of users experiencing or exhibiting symptoms consistent with psychotic relapse after smoking JWH-018. Although psychological side effects were common, no one reported becoming physically unwell after using JWH-018. Three subjects described developing some tolerance to the product, but no one reported withdrawal symptoms. It seems likely that JWH-018 can precipitate psychosis in vulnerable individuals. People with risk factors for psychosis should be counseled against using synthetic cannabinoids.
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Drug and Alcohol Dependence 117 (2011) 152–157
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Synthetic cannabinoid JWH-018 and psychosis: An explorative study
Susanna Every-Palmer
Te Korowai-Wh¯
ariki, A Capital and Coast District Health Board Service, Ratonga Rua O Porirua, Regional Forensic Service, Raiha Street,
P O Box 50-233 Porirua, New Zealand
article info
Article history:
Received 7 July 2010
Received in revised form 6 January 2011
Accepted 15 January 2011
Available online 11 February 2011
Psychoses, substance-induced
Designer drugs
Qualitative research
Psychotic disorders
Forensic psychiatry
Background: Aroma, Spice, K2 and Dream are examples of a class of new and increasingly popular
recreational drugs. Ostensibly branded “herbal incense”, they have been intentionally adulterated with
synthetic cannabinoids such as JWH-018 in order to confer on them cannabimimetic psychoactive prop-
erties while circumventing drug legislation. JWH-018 is a potent cannabinoid receptor agonist. Little is
known about its pharmacology and toxicology in humans. This is the first research considering the effects
of JWH-018 on a psychiatric population and exploring the relationship between JWH-018 and psychotic
Method: This paper presents the results of semi-structured interviews regarding the use and effects of
JWH-018 in 15 patients with serious mental illness in a New Zealand forensic and rehabilitative service.
Results: 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 avail-
ability and non-detection in drug testing as reasons for its popularity, with most reporting it had replaced
cannabis as their drug of choice. Most patients had assumed the product was “natural” and “safe”. Anxiety
and psychotic symptoms were common after use, with 69% of users experiencing or exhibiting symp-
toms consistent with psychotic relapse after smoking JWH-018. Although psychological side effects were
common, no one reported becoming physically unwell after using JWH-018. Three subjects described
developing some tolerance to the product, but no one reported withdrawal symptoms.
Conclusion: It seems likely that JWH-018 can precipitate psychosis in vulnerable individuals. People with
risk factors for psychosis should be counseled against using synthetic cannabinoids.
© 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
While cannabis use has a long history, the emergence of syn-
thetic cannabinoids such as JWH-018 is recent. This article explores
the relationship between JWH-018 and psychotic symptoms and
reports 15 forensic inpatients’ experiences with synthetic cannabi-
noid containing products (SCCPs).
1.1. Background: SCCPs emerge as a new drug trend
Spice, Aroma, K2 and Dream are examples of a large
and evolving group of smokable products branded as ‘herbal
incense’, but found by users to have potent cannabis-like prop-
erties. Spice first started appearing on internet sites and in
specialized shops around 2004 (Dresen et al., 2010). Warn-
ing messages on the product stating it was not intended for
human consumption contrasted with sophisticated packaging
Tel.: +64 4 385 5999; fax: +64 4 918 2477.
E-mail addresses: Susanna,
and marketing, promoting the product as a cannabis alternative
which was undetectable by conventional drug testing methodol-
It was not until December 2008 that researchers reported the
reason for Spice’s cannabis-like properties: Spice had been ‘laced’
with undeclared synthetic cannabinoids JWH-018 and CP 47,497
(Auwärter et al., 2009). It is believed that these synthetic cannabi-
noids were dissolved in a solvent which was then sprayed on a
plant-derived base for delivery (Vardakou et al., 2010). The herbal
ingredients cited on Spice’s packaging did not appear to contribute
to its psychoactivity; in fact they were not even present in most of
the samples tested (Piggee, 2009).
Since being identified in “herbal” products JWH-018 and CP
47,497 and have been banned in a number of European countries
and some American States (Vardakou et al., 2010). Three weeks
after CP-compounds and JWH-018 were banned in Germany,
second generation products (e.g., analogues such as JWH-073)
appeared on the market, suggesting the manufacturers had
anticipated prohibition and had already synthesized an array
of alternatives (Lindigkeit et al., 2009). Currently “headshops”
and the internet offer an ever-expanding array of synthetic
cannabinoids originating from 3 chemically distinct groups
0376-8716/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.
S. Every-Palmer / Drug and Alcohol Dependence 117 (2011) 152–157 153
(JWH-, CP- and HU-compounds), alongside oleamide, a fatty acid
with cannabinoid-like activity (EMCDDA, 2009; Hudson et al.,
2010; Lindigkeit et al., 2009; Uchiyama et al., 2009; United States
Drug Enforcement Administration, 2009).
The rapid proliferation of synthetic cannabinoid products over
the last 4 years has been labeled the “Spice phenomenon”
(EMCDDA, 2009). Griffiths et al. (2010) consider the Spice phe-
nomenon to be a “case study” of how existing models of drug
control and response are being challenged by globalization, inter-
net technology and innovation in the drug market.
1.2. Synthetic cannabinoids and psychosis
Little data is available on the psychological and other risks of
synthetic cannabinoids.
Psychotic relapses following the use of a JWH-018 product in 5
patients in our forensic service have already been reported (Every-
Palmer, 2010). There is one published case report of tolerance and
withdrawal phenomena in the literature (Zimmermann et al., 2009)
and another of drug induced psychosis (Müller et al., 2010). Both
these cases were attributed to Spice, which at the time contained
JWH-018 and CP 47,497.
There is also an increasing number of reports describing patients
presenting for emergency medical care after using “Spice” products.
Common features of many of these presentations have included
anxiety symptoms, agitation, tachycardia, paranoia and halluci-
nations (Banerji et al., 2010; Bebarta et al., 2010; Piggee, 2009;
Vearrier and Osterhoudt, 2010). Inter-batch variation in the type
and quantity of cannabinoids present has also resulted in accidental
overdosing requiring hospitalization (Auwärter et al., 2009).
A number of self-reports of users experiencing anxiety and
psychotic symptoms following the use of JWH-018 and other
cannabinoids can be found on the internet (e.g., http://www. JWH018.shtml#Train Wrecks
& Trip Disasters).
1.3. Synthetic cannabinoid use in New Zealand
JWH compounds (e.g., JWH-018, JWH-015 and JWH-073) are
currently unregulated in New Zealand and are widely available in
‘headshops’ and over the internet.
New Zealand may be a particularly opportune market for
cannabimimetic drugs with an annual prevalence of cannabis use
at 14.6%, one of the highest in the world (United Nations Office
on Drugs and Crime, 2010). Cannabis use is particularly prevalent
in criminal populations with 55% of New Zealand prison inmates
qualifying for lifetime diagnoses of cannabis abuse or dependence
(New Zealand Department of Corrections, 1999).
In forensic psychiatric services, substance use is prohibited, and
abstinence is monitored by urine drug screens. However, the arrival
of unregulated synthetic cannabinoids into the market is posing
new challenges to forensic and other mental health services.
2. Methodology
2.1. The sample
Subjects were recruited from a Regional Forensic and Rehabilitation service.
Inclusion criteria were patients between the ages of 18 and 65 who were able to
give informed consent and were residing in a low security forensic inpatient unit,
or waiting placement in such a setting. Clients who were considered high risk of
assault or too unwell to be interviewed alone were excluded for safety reasons.
The author is a forensic psychiatrist and patients currently or previously under
her care were excluded from the study, due to potential conflicts of interest.
Fifteen subjects were recruited over a two week period from a pool of 21 patients
meeting the inclusion criteria. Two of the original 21 were excluded from the study
as they were absent during the data collection period and 4 patients declined to
Five of the 15 subjects recruited had previously been identified by staff as expe-
riencing psychotic relapses in the context of synthetic cannabinoid use, becoming
objectively agitated, disorganized and delusional after smoking the product.
The study had ethical approval from the New Zealand Central Regional Ethics
2.2. Recruitment
The interviewer visited the two inpatient units where the research was con-
ducted on 7 occasions. A brief explanation of the study was provided to patients.
Subjects who were interested in participating were individually provided with writ-
ten and oral information about the study and informed oral consent was obtained.
2.3. Interviews
Semi-structured interviews were conducted by the author in a private interview
room within the inpatient units. The interview explored the subjects’ experience
with synthetic cannabinoids, including knowledge, personal use, subjective expe-
rience and their observations of how these substances appeared to have affected
others. A formal inquiry into each subject’s current mental state was not conducted,
but the interviewer noted her observations of the subject’s presentation immedi-
ately after the interview, including whether the subject seemed thought disordered.
Interviews took place in March and April 2010.
2.4. Data collection and analysis
Short-hand notes recording the subjects’ responses were taken during the inter-
view. Patients were not willing to consent to audio recording due to the sensitive
nature of the material discussed, and fears about confidentiality. Following the inter-
view, short-hand notes were transcribed into long-hand and were annotated with
the interviewer’s observations from the interview. The transcripts were analyzed
manually in order to identify key themes and recurrent ideas. Data were coded
and indexed in terms of similarity and contrast of content. All data recorded was
de-identified to preserve confidentiality.
Quotations in Section 3are used to illustrate emergent trends. Interviewee
quotes are identified by: (a) a number between 1 and 15 to differentiate among
respondents, and (b) the letter N, O or H to denote the subject’s reported frequency
of synthetic cannabinoid use over the preceding year (N: never, O: occasional-less
than weekly, H: high use-daily or weekly).
2.5. Urinalysis
All patients had been subject to regular random urine drug testing for cannabi-
noids, opiates, opioids, amphetamines and benzodiazepines.1The urine drug screen
results from the last 18 months were reviewed.
3. Results
3.1. Patient demographics
All 15 participating subjects were male. At the time of the study
the service had a 5:1 male to female ratio, and no female patients
met the inclusion criteria.
All patients had a history of psychotic illnesses and had been
compulsorily treated with therapeutic doses of antipsychotic med-
ication, with active monitoring of compliance, for at least 6 months
prior to the study. Five patients were also taking mood stabilizers.
They had all achieved stable mental states prior to the decompen-
sations reported in this study. The demographics of the subjects are
summarized in Table 1.
All subjects had been within the service for some years, and
had been referred to a low security rehabilitation facility as their
mental states had improved. They all had unescorted leave off the
unit, although in three cases leave privileges had been temporarily
revoked due to the patients’ recent deterioration in mental state.
All participants had used cannabis in the past. None of the partic-
ipating patients had tested positive for THC in their most recent
urine drug screens. Review of urine drug screens for the cohort
over the previous 18 months showed a positive result for cannabi-
noids was a low probability event. Of 153 urine tests, only 7 (from
1Random drug screening used an immunoassay technique, based on the KIMs
154 S. Every-Palmer / Drug and Alcohol Dependence 117 (2011) 152–157
Table 1
Summary of subject demographics.
Feature Number (%) [n= 15]
Male 15 (100%)
Female 0 (0%)
Age range Early twenties to
mid-forties, mean
34, sd 7.9
Schizophrenia 10 (67%)
Schizoaffective disorder 4 (27%)
Bipolar affective disorder with psychotic features 1 (7%)
Current treatment with antipsychotic medication 15 (100%)
Index offence
Serious violent offence (as defined by NZ
Sentencing Act)
10 (67%)
Non violent offence or violent offence not
regarded as serious
5 (33%)
Lifetime prevalence of cannabis use 15 (100%)
Positive urine drug screen for cannabis in the last
18 months
4 (27%)
4 different patients) were positive for cannabinoids. No patient
tested positive for amphetamines or opioids, and positive tests for
benzodiazepines and opiates correlated with prescribed medicine.
3.2. Trends
On analysis and coding of the interview transcripts four common
themes were identified relating to the use of synthetic cannabinoids
in the service: their popularity, psychoactivity, effects on mental
state and pleasurable feelings of rebellion associated with their use.
Results are summarized in Table 2.
3.2.1. Popularity. All subjects were familiar with a locally available
SCCP, Aroma. Four patients had some historical experience with
similar products called Kronic Skunk, Dream and Spice. All these
products consist of a base of unidentified plant matter which has
been shown to contain JWH-018 (personal correspondence. Mark
Heffernan, Senior Policy Analyst, National Drug Policy, New Zealand
Ministry of Health).
Of the patients surveyed 87% (13/15) reported having used
Aroma over the last year. Of the two clients who denied ever trying
SCCPs, one was spontaneously identified by two other clients as
being a co-smoker and ‘middleman’ provider of the product to oth-
ers, casting some doubt over his credibility. Five patients reported
high use (daily or almost daily), one reported using weekly, and
seven reported infrequent or occasional use (20 times or less in the
last year).
Most patients reported that SCCPs were more popular than
cannabis in the service despite being more expensive (Aroma
retails at NZ$20/g compared to a cannabis street price of approxi-
mately NZ$13.2/g [Wilkins and Sweetsur, 2006]). Patients credited
Aroma’s legality, easy availability, product consistency, non-
detection in drug tests and perceived safety as reasons to favour
it over marijuana.
Aroma has cancelled out all the cannabis here. No one smokes
cannabis anymore. Why would you? It [Aroma]’s a good substitute,
its legal, it’s not in urine and it’s easier to go to [name of local
shop that sells Aroma] than to go down to a tinny house [cannabis
dealer].” (8-H)
3.2.2. Psychoactivity. All 13 patients who acknowledged having
smoked Aroma said that they used it as a cannabis substitute.
[Aroma]’s like marijuana, but health wise it’s better....It’s strong.
It gets you real whacked and makes you high.”(2-H)
Five subjects commented that they preferred Aroma to cannabis
due to its potency. One subject preferred cannabis and the others
were indifferent. A common complaint was that the SCCPs “did not
last as long as cannabis”, with the psychoactive effects being con-
sistently described as having a rapid onset of action and a duration
of 1–2 h following inhalation.
Patients did not know what conferred Aroma its psychoactive
properties. Three patients correctly speculated that it ‘had been
sprayed with chemicals’, the others were either unsure or described
it as a “natural” or “herbal” product. A number of patients com-
mented that it was “safe”, this assumption seemingly based on its
legality and easy availability.
I used to smoke marijuana, but I don’t do that when I’m on medi-
cation. Aroma won’t interfere with medication....It’s a better buzz
than marijuana. It’s quite safe” (10-O)
3.2.3. Effects on mental state. Five patients reported experiences
consistent with a psychotic relapse within 24 h of smoking Aroma
which lasted “2 days” to “several weeks”. Two of these patients
also reported pronounced anxiety symptoms. They attributed these
symptoms to Aroma. However, of the 5 patients in this study who
had previously been identified by clinical staff as suffering a proba-
ble JWH-018-induced psychotic relapse (Every-Palmer, 2010), only
1 subjectively acknowledged the effects Aroma had on their men-
tal state. The other 4 had little insight into their mental illnesses
and denied being adversely affected by SCCPs, for example one
man who objectively became floridly psychotic and aggressive after
admittedly smoking Aroma reported:
Staff say we’re not allowed to smoke it, because it would cause
risks, but they don’t know. It doesn’t cause risks to me. It just makes
me cool, calm and clients who are sick, it causes risks
to them.”(3-O)
Table 2
Summary of subjects’ experiences with synthetic cannabinoid containing products (SCCPs).
Experience Yes No Unsure
Of all subjects who participated in the study (n= 15)
Familiar with synthetic cannabinoid containing products (SCCPs) 15/15 (100%) 0/15 (0%) 0/15 (0%)
Admitted using SCCPs over the last year 13/15 (87%) 2/15 (13%) 0/15 (0%)
Admitted using SCCP ‘Aroma’ over the last year 13/15 (87%) 2/15 (13%) 0/15 (0%)
Admitted using other SCCPs (e.g., Kronic Skunk, Dream, Spice,) 4/15 (27%) 10/15 (67%) 1/15 (7%)
Of the subjects who reported SCCP use (n= 13)
Described psychoactive effects from SCCP 13/13 (100%) 0/13 (0%) 0/13 (0%)
Considered SCCP a “herbal” or “natural” product 7/13 (54%) 3/13 (23%) 3/13 (23%)
Reported or exhibited psychotic symptoms following SCCP use 9/13 (69%) 3/13 (23%) 1/13 (7%)
Reported observing psychotic symptoms in others following SCCP use 7/13 (54%) 5/13 (38%) 1/13 (7%)
Reported experiencing anxiety symptoms following SCCP use 2/13 (15%) 10/13 (77%) 1/13 (7%)
Reported tolerance (requiring increasing amounts to achieve the same effects) 3/13 (23%) 10/13 (77%) 0/13 (0%)
Reported withdrawal symptoms 0/13 (0%) 13/13 (100%) 0/13 (0%)
S. Every-Palmer / Drug and Alcohol Dependence 117 (2011) 152–157 155
Table 3
Patients describe their experience with SCCPs.
“I can’t touch it, it makes me real paranoid...I smoked a big doobie. Nothing happened for a while. I walked down the street, then started feeling real sick, shaking, dizzy. My
heart was pounding and I was freaking out. Then I felt that something bad was leaping out at me. I tried to escape, stumbled onto the road and was almost hit by a car. I was
real fucked up.” (10-O)
“It made me feel wasted. It made me not feel like myself. I was having psychotic thinking... Wanting to do evil things. It made me think it would be cool to have rocket launches
and weapons and stuff...In all I smoked under 11[times]. Every time it made me feel not good and those thoughts started coming back... I don’t smoke it anymore... It’s no
good for your brains.” (11-O)
“It made me feel like my world was closing in. It made me feel anxious and worried and my heart was pounding...It felt weird, I was really warm, really hot, I had never felt that
hot before, even in summer...I just felt paranoid... I smoked cannabis years ago. This was kind of similar, but cannabis never made me feel hot and anxious. I think Aroma’s
dangerous.” (15-O)
“X and Y used to smoke it with me. They would freak out. He got real paranoid. She used to go off her nut, scream and yell and totally freak out. That would bring the heat on us.”
“One client, I smoked with him a few times, he’d be completely normal at the start, then he’s just sitting there with his lips moving, talking to someone who’s not even there. Some
people take it- they get sick, you know, straight away.” (8-H)
Overall 9/13 (69%) of the Aroma users experienced or exhibited
psychotic symptoms after using this synthetic cannabinoid. Seven
patients also reported that they had noticed other patients become
unwell after using Aroma. Descriptions of these experiences are
reported in Table 3.
3.2.4. Rebellion. All the patients knew psychoactive substances
including SCCPs were prohibited in the service. A number of
patients discussed the high level of supervision and loss of auton-
omy associated with their forensic status, and how they felt that
using SCCPs allowed them to reassert their control.
It doesn’t stink, people can’t tell you’ve been smoking it. It never
turns up in their tests, so we get away with it, no problems. You can
smoke it anywhere. We were smoking it right here, in front of all
the nurses. It’s classic, (laughs) they just think its tobacco.” (3-H)
3.2.5. Other themes. Some patients felt SCCP use had negatively
affected the atmosphere of the unit. Two non-users talked about
other patients spending all their money on SCCPs and then coercing
their peers to share cigarettes. Several patients alluded to an ‘in-
group, out-group’ dynamic between users and non-users. A black
market had also evolved, with some clients purchasing SCCPs and
selling them to others at a profit.
4. Discussion
4.1. Limitations of the study
This was a small study (n= 15) of a highly select patient group.
The participants were all men with serious mental illness with risk
profiles mandating intensive supervision in a forensic service. This
group is particularly vulnerable to psychosis, but paradoxically may
also currently have some degree of protection (compared to vul-
nerable people in the community), as all subjects were receiving
assertive treatment and environmental support. The experiences
of this group cannot necessarily be extrapolated to a wider pop-
ulation, particularly those without mental illness, females and
This study describes only the subjective experiences that sub-
jects chose to share with the interviewer and as such is subject
to bias including selection bias, under-reporting and exaggeration.
Although patients and staff report deteriorations in the subjects’
mental states in relation to synthetic cannabinoid use, this study
only suggests, but does not prove a causal link.
4.2. Discussion of findings
In this cohort of forensic inpatients in a low-secure setting all
the subjects were familiar with synthetic cannabinoids and 86%
Table 4
Psychoactive compounds detected in Aroma.
Compound Concentration
Cannibicyclohexanol (mg/g) Not detected
JWH-018 (mg/g) 27.91 ±1.09
Oleamide (mg/g) 210.90
Other psychoactive compounds Not detected
Source:Uchiyama et al. (2010); Personal correspondence Ruri Kikura-Hanajari,
8 October 2010.
reported having used them. They credited the products’ potent psy-
choactivity, legality, ready availability and non-detection in drug
testing as reasons for their popularity, reporting they had replaced
cannabis as the drugs of choice in our service. Synthetic cannabi-
noids do not appear in conventional urine drug testing so users
could evade detection and sanction by their care team. This had
engendered a conspiratorial culture in which users took some plea-
sure in small acts of insurrection, in an environment where the
balance of power usually resides on the side of the health profes-
Furthermore, most patients assumed SCCPs were “herbal”,
“natural” and “safe”. This may be due to by their legality,
easy availability and marketing as “organic”. However, synthetic
cannabinoids are not herbal, natural nor safe. Nine patients expe-
rienced symptoms consistent with a psychotic relapse after using
JWH-018 containing products (5 self reported, 4 reported by health
professionals). Three patients reported tolerance, but nobody
endorsed withdrawal symptoms.
Substance abuse is a robust predictor of an increased probabil-
ity of violence and criminality in the mentally disordered (Soyka,
2000). Whether JWH-018, like cannabis, is a potential mediator of
antisocial behaviour is at this stage unclear, but the unfettered use
of psychoactive compounds in high risk patients is concerning for
both individual and societal reasons.
4.3. Pharmacology of Aroma
All patients were smoking the same product, a SCCP marketed
as Aroma. This product comprises a dried herb material which is
a vehicle for high concentrations of JWH-018 and oleamide. Of 46
products tested by Uchiyama et al. (2010) Aroma contained the
highest concentration of oleamide and the second highest concen-
tration of JWH-018. (See Table 4.)
4.4. JWH-018 and psychosis
Although to date there is little data about the possible psy-
chiatric sequelae of synthetic cannabinoids, the link between
cannabis and psychosis is well established and has been extensively
reviewed (e.g., Henquet et al., 2005; Fergusson et al., 2006; Moore
156 S. Every-Palmer / Drug and Alcohol Dependence 117 (2011) 152–157
et al., 2007; Murray et al., 2007). Cannabis contains at least 90
different cannabinoids, with THC being the primary psychoactive
ingredient (Gaoni and Mechoulam, 1964). In experimental stud-
ies, THC produces transient and dose related psychotic symptoms
(D’Souza et al., 2004) and impaired memory (Solowij and Michie,
2007). Consumer surveys (e.g., Thomas, 1996) provide further evi-
dence that cannabis intoxication can produce transient psychotic
experiences. Large prospective epidemiological studies (e.g., van Os
et al., 2002; Zammit et al., 2002; Arseneault et al., 2002) show a link
between cannabis use and the development of chronic psychotic
illnesses such as schizophrenia.
All the patients in this study had established psychotic illnesses.
Cannabis use in such patients is common (Green et al., 2004;
Boydell et al., 1999) and has been associated with poor clinical and
functional outcomes including: an earlier disease onset (Foti et al.,
2010); more positive symptoms (Bühler et al., 2002; Mauri et al.,
2006); a higher relapse rate (Swofford et al., 1996), and a reduced
treatment response (Foti et al., 2010). In first-episode schizophre-
nia cannabis use is associated with a greater reduction in cerebral
grey matter volume in users compared with non users over time
(Rais et al., 2008).
It cannot be assumed that the psychiatric risks of synthetic
cannabinoids will equate to those associated with cannabis, how-
ever, it is hypothesized that JWH-018 may pose comparable or even
greater risks due to the following observations:
1. JWH-018 produces similar effects to THC in animal experiments
(EMCDDA, 2009).
2. There are an emerging number of reports of users experienc-
ing psychotic symptoms in the context of JWH-018 use on the
internet and in the literature (Müller et al., 2010; Every-Palmer,
3. The pharmacological profile of JWH-018 raises the theoretical
possibility of increased cognitive and psychiatric side effects
compared to cannabis.
(a) In vitro data suggests that JWH-018 possesses approximately
a four-fold higher affinity to the CB1receptor and ten-fold
affinity to CB2receptor compared with THC (Aung et al.,
2000; Huffman et al., 2005). CB1receptors are abundant in
central nervous system, particularly in the basal ganglia, hip-
pocampus and cerebellum (Howlett et al., 2004; Fergusson
et al., 2006). These receptors regulate the release of several
key neurotransmitters, including dopamine and serotonin.
It is thought that cannabis may lead to psychosis through
THCs’s effects on dopaminergic and serotonergic pathways
via CB1receptors (Fergusson et al., 2006). While THC exerts
only partial CB1agonism, JWH-018 is a full and potent agonist
at CB1receptors (Atwood et al., 2010).
(b) Unlike cannabis, SCCPs do not contain cannabidiol.
Cannabidiol and THC are the two major components of
cannabis, and they exhibit opposing pharmacological and
physiological actions. Cannabidiol is a CB1and CB2antag-
onist which appears to have antipsychotic (Leweke et al.,
2009; Zuardi et al., 2006; Morgan and Curran, 2008) and
anxiolytic properties (Guimarães et al., 1990) and may be
neuroprotective in humans (Hermann et al., 2007; Morgan
et al., 2010). While cannabidiol may afford cannabis users
some inherent protection against psychotic symptoms
(Morgan and Curran, 2008) and cognitive impairment
(Morgan et al., 2010) this protection is lacking in SCCPs.
(c) Some SCCPs like Aroma also contain oleamide, a fatty
acid demonstrated to functionally activate CB1cannabinoid
receptors in vitro (Leggett et al., 2004), which may have
potentiating effects.
4. SCCPs may appeal to vulnerable populations who might not
otherwise smoke cannabis including those who have suf-
fered adverse effects from cannabis or have been warned
against using cannabis (e.g., a possible predisposition to
psychotic illness) and those being monitored for drug use
(e.g., in prisons, forensic hospitals). There are increasing
reports of young people using SCCPs (e.g., EMCDDA, 2009;
legal-weed). In the forensic population studied in this research,
the base rate of ongoing cannabis use was low due to institu-
tional deterrents and education regarding the risks of cannabis.
However, those disincentives did not exist to the same extent
with SCCPs, which were being consumed in greater quantities
than cannabis had previously been. Although it is likely that
most people who smoke SCCPs will not experience psychotic
symptoms, the risks are much higher for these vulnerable
4.5. Management
It is known that in forensic populations drug treatment pro-
grams associated with the best outcomes are assertive and use
some form of leverage, such as mandatory drug testing (Lamb et al.,
1999). Currently there are no widely available drug testing meth-
ods to identify JWH-018 use, although laboratory techniques have
recently been developed for identifying JWH-018 in serum (Teske
et al., 2010) and JWH-018 metabolites in urine (Sobolevsky et al.,
2010). Until these techniques become more widely available clini-
cians will need to rely on clinical skills. These include: specifically
asking patients about “herbal highs”; being alert to the physio-
logical and effects of SCCP use such as conjuctival injection and
tachycardia (Auwärter et al., 2009; Sobolevsky et al., 2010) and
having a high index of suspicion in the context of an unexplained
deterioration in mental state in the context of a negative urine drug
screen. Health professionals need to be cogniscant and responsive
to novel drug trends in order to counsel their clients appropriately.
In countries where synthetic cannabinoids remain legal, there
needs to be ongoing review and monitoring of their safety at a
national level. Discussion also needs to be held around the accu-
rate labeling of products containing psychoactive compounds, so
that users are aware of the potential risks.
5. Conclusion
Synthetic cannabinoids pose difficult social, political and health
challenges. There are more than 100 known compounds with
cannabinoid receptor activity, and no doubt more will be syn-
thesized in the future. Almost nothing is known about the
pharmacology and toxicology of compounds such as JWH-018,
however, it seems that they can cause psychosis in vulnerable
individuals. Health professionals need to maintain a high degree
of vigilance for novel substance use, and the possible psychiatric
consequences. People with risk factors for psychosis should be
counseled against using synthetic cannabinoids.
Role of funding source
Nothing declared.
Conflict of interest
No conflict declared.
With grateful thanks to all the subjects who gave up their time
to participate in this research, to Mark Heffernan from the New
S. Every-Palmer / Drug and Alcohol Dependence 117 (2011) 152–157 157
Zealand Ministry of Health who peer reviewed this manuscript
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... Compared to natural cannabis users and non-cannabis users, frequent SC users were found to perform worse on cognitive tasks, including working memory, inhibition, and long-term memory (18). The most well-known adverse effects linked to SCs are probably psychological symptoms, including agitation, anxiety, and psychosis (16,19). Psychotomimetic and dissociative effects, often referred to as "zombie effect, " have been noted in up to 28% of the people who admitted using an SC (20,21). ...
... The risk of an adverse psychotomimetic experience after cannabis use is dose-related, with higher doses increasing the risk (59-61). The current finding that synthetic cannabinoids induce stronger psychotomimetic effects is in line with the many case reports and epidemiological data showing SCs to elicit psychotomimetic effects in vulnerable populations or patients with schizophrenia and healthy individuals (19,55,56,(62)(63)(64). The lack of cannabidiol (CBD), the non-psychoactive constituent of cannabis, might explain the increased risk of experiencing psychotomimetic effects after SC use. ...
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Due to differences in potency, efficacy, and affinity for CB1 receptors, similarities and differences in psychoactive effect profiles of natural cannabis and synthetic cannabinoids (SCs) cannot reliably be derived from equipotent dose comparisons. Instead, the current study proposes to compare the intrinsic psychoactive effects of natural cannabis (THC) and an SC, JWH-018, at psychotropic dose equivalence. Participants from two placebo-controlled studies were matched for their levels of subjective high to compare neurocognitive and psychotomimetic effects of THC and JWH-018. At equal subjective intoxication levels, both drugs impaired psychomotor, divided attention, and impulse control, with no significant difference between the two drugs. Both drugs also caused significant psychotomimetic effects, but dissociative effects were considerably more pronounced for JWH-018 than THC. We conclude that psychotropic dose equivalence provides a uniform approach for comparing the neurocognitive and psychotomimetic profiles of CB1 agonists, which can also be applied to other drug classes.
... Delta-9-Tetrahydrocannabinoid (THC) is the major psychoactive component found in 'traditional' cannabis, where it partially binds to the brain's endogenous cannabinoid receptors that ordinarily have homeostatic roles (Every-Palmer, 2011). SCRAs also bind to these cannabinoid receptors, but typically more fully and potently than THC, often producing a different and far stronger effect that can include significant agitation and psychosis (Tracy et al., 2017). ...
... Similar to previous studies, prior relationships with cannabis was a significant motivation for participants to use SCRAs in conjunction with availability, cost, difficult to detect in mandatory drugs testing, and ease of access; (Every-Palmer, 2011;Kalk et al., 2016;Ralphs et al., 2017;User Voice, 2016). This raises concerns not only for the effectiveness of forensic security systems, but also speaks to the vulnerability of those entering the Criminal Justice System and the impact this has on mental health, social care, and rates of recidivism, highlighting the need for early societal interventions that target macro-level stresses and view these issues through the lens of a wider cultural context. ...
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There has been an enormous growth in New Psychoactive Substances (NPS), sometimes erroneously referred to as 'legal highs', over the past 15 years. There are currently at least 800 such compounds, and we lack adequate data on all their effects and harms. Synthetic cannabinoid receptor agonists (SCRAs), often referred to by the generic name 'spice', are particularly notable in this regard. There has been a lack of research on forensic patients' experiences of SCRAs, their consumption, and any adverse impact they might have. This work qualitatively explored the experience of NPS and SCRA use in 19 male patients recruited from three secure forensic services in the South of England. The majority of participants discussed experiences of using SCRAs whilst in prison as opposed to their current forensic hospital admission. Three key themes emerged which describe participants experiences of SCRA use: (i) perpetuating cycle of drug use, mental ill-health, and crime; (ii) environmental injustices and consequences; and (iii) shame and stigma associated with SCRA use. The findings provide insights into the challenges faced by forensic patients as a result of SCRA use, as well as notable opportunities. A common call was for greater psychoeducation on drug harms and treatment opportunities.
... CB1 and CB2 agonist [149] Psychosis [151], hallucinations, vertigo, paresthesias, shaking, shivering, hypertension, dry mouth, vomiting, mydriasis, hypokalemia, extrasystoles, tachycardia, conjunctival hyperemia [134], and ischemic stroke [135] JWH-073 (1-butyl-3-(1-naphthoyl)indole) CB1 and CB2 agonist [149,152] Altered mood and perception, red or bloodshot eyes, nausea, vomiting, listlessness, fever, sweating, and dryness of the mouth [150] JWH-019 (1-hexyl-3-(1-naphthoyl)indole) CB1 and CB2 agonist [152] Confused speech, unstable appearance [150] JWH-081 (1-pentyl-3-[1-(4-methoxynaphthoyl)]indole) CB1 and CB2 agonist [152] Slurred speech [153] JWH-122 (1-pentyl-3-(4-methyl-1-naphthoyl)indole) ...
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Synthetic Cannabinoids (CBs) are a novel class of psychoactive substances that have rapidly evolved around the world with the addition of diverse structural modifications to existing molecules which produce new structural analogues that can be associated with serious adverse health effects. Synthetic CBs represent the largest class of drugs detected by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) with a total of 207 substances identified from 2008 to October 2020, and 9 compounds being reported for the first time. Synthetic CBs are sprayed on natural harmless herbs with an aim to mimic the euphoric effect of Cannabis. They are sold under different brand names including Black mamba, spice, K2, Bombay Blue, etc. As these synthetic CBs act as full agonists at the CB receptors, they are much more potent than natural Cannabis and have been increasingly associated with acute to chronic intoxications and death. Due to their potential toxicity and abuse, the US government has listed some synthetic CBs under schedule 1 classification. The present review aims to provide a focused overview of the literature concerning the development of synthetic CBs, their abuse, and potential toxicological effects including renal toxicity, respiratory depression, hyperemesis syndrome, cardiovascular effects, and a range of effects on brain function.
... Synthetic cannabinoids, also called "Spice," are synthetic cannabinoid receptor agonists (SCRAs) which have been originally developed for their potential therapeutic role by exploiting the endocannabinoid system [38][39][40]. Since then, "Spice" products have been sold as legal marijuana surrogate, becoming very popular among younger people and now representing the widest class of NPS. ...
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Novel psychoactive substances (NPS) represent a severe health risk for drug users. Even though the phenomenon has been growing since the early 2000s, the mechanisms of action of NPS at the receptors and beyond them are still scarcely understood. The aim of the present study was to provide a systematic review of the updated knowledge regarding the molecular mechanisms underlying the toxicity of synthetic opioids, cannabinoids, cathinones, and stimulants. The study was conducted on the PubMed database. Study eligibility criteria included relevance to the topic, English language, and time of publication (2010–2020). A combined Mesh and free-text protocols search was performed. Study selection was performed on the title/abstract and, in doubtful cases, on the full texts of papers. Of the 580 records identified through PubMed searching and reference checking, 307 were excluded by title/abstract and 78 additional papers were excluded after full-text reading, leaving a total of 155 included papers. Molecular mechanisms of synthetic opioids, synthetic cannabinoids, stimulants, psychedelics, and hallucinogens were reviewed and mostly involved both a receptor-mediated and non-receptor mediated cellular modulation with multiple neurotransmitters interactions. The molecular mechanisms underlying the action of NPS are more complex than expected, with a wide range of overlap among activated receptors and neurotransmitter systems. The peculiar action profile of single compounds does not necessarily reflect that of the structural class to which they belong, accounting for possible unexpected toxic reactions.
... The use of SCs is constantly growing, particularly among adolescents, and is posing major medical and psychiatric risks. Acute and chronic consumption of SCs have been linked to numerous reports of emergency department admissions for adverse health effects, including signs of addiction and withdrawal, and central and peripheral toxicity (e.g., headache, vomiting, paranoia, tachycardia, hypertension, seizures, agitation, psychosis, extreme anxiety/panic, and hallucinations) [5][6][7][8], and even fatalities. As consumers obtain SCs mainly through unknown sources (i.e., the deep and dark web), they are usually not aware of the identity and purity of these substances. ...
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Since the early 2000s, herbal mixtures containing synthetic cannabinoids (SCs), broadly known as Spice/K2, have been marketed as a legal marijuana surrogate and have become very popular among adolescents. Adolescence is a critical period of development, which is associated with an increased vulnerability to the central effects of drugs. Despite growing concerns about the negative effects of the use of SCs, newly synthetized compounds are increasingly detected in drugs seized by the authorities, posing a serious threat to public health. 5F-MDMB-PICA has been recently detected and classified as a highly potent agonist of CB1 and CB2 cannabinoid receptors. Here, we first investigated the rewarding properties of 5F-MDMB-PICA in C57BL/6 adolescent and adult mice by in vivo brain microdialysis. Data showed that acute administration of a selected dose of 5F-MDMB-PICA (0.01 mg/kg i.p.) stimulates the release of dopamine in the nucleus accumbens shell of adolescent, but not of adult, mice. To further investigate the consequences of repeated exposure to this dose of 5F-MDMB-PICA, a separate group of adolescent mice was treated for 14 consecutive days and evaluated for behavioral abnormalities at adulthood, starting from 7 days after drug discontinuation. Data showed that this group of adult mice displayed an anxiety-like and compulsive-like state as revealed by an altered performance in the marble burying test. Our study suggests an alarming vulnerability of adolescent mice to the effects of 5F-MDMB-PICA. These findings provide a useful basis for understanding and evaluating both early and late detrimental effects that may derive from the use of SCs during adolescence.
... New-onset psychosis in otherwise healthy young men ( Hurst et al., 2011 ;Theunissen et al., 2018 ;Roberto et al., 2016 ). Perceptual alterations including: hallucinations and distortion of spatial perception are typical acute effects following use ( Blevins et al., 2016 ;Every-Palmer, 2011 ). Chronic use may increase the risk for developing psychotic disorders ( Fattore, 2016 ;Weinstein et al., 2017 ;van Amsterdam et al., 2015 ). ...
The objective of the present study was the development and validation of the method for determining AMB-FUBINACA and its metabolite - AMB-FUBINACA O-desmethyl acid – in blood samples, followed by verification of the method in toxicological judicial and forensic medicine practice employing the example of post-aggression suicide. Most likely in consequence of development of adverse effects resulting in psychotic symptoms, a male being under the influence of the synthetic cannabinoid AMB-FUBINACA and the new synthetic opioid U-47700, mortally wounded his female partner and subsequently committed suicide. Identification and determination of the afore-mentioned xenobiotics in blood samples collected from the male and female victims were performed employing high performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). The analytes were isolated from blood samples using the solid phase extraction (SPE) method. The blood samples collected from the male and female demonstrated respectively 110 and 196 ng/mL of AMB-FUBINACA O-desmethyl acid metabolite, 1935 and 357 ng/mL of U-47700, 250 and 200 ng/mL of N-desmethyl-U-47700, as well as 410 and 200 ng/mL of N,N-didesmethyl-U-47700. The concentration values of new psychoactive substances (NPS’s) in blood samples originating from the male and female were within the ranges encountered in cases of poisoning, including these resulting in death. Nevertheless, the evident signs of exsanguination proof that the woman was alive when she sustained lethal injuries. The presented cases illustrate the difficult to be anticipated effect exerted on the users by NPS’s.
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Background: On the current psychopharmacological panorama, the variety of substances able to provoke an episode of acute psychosis is rapidly increasing. Such psychotic episodes are classified according to the major category of symptoms: positive, negative, or cognitive psychotic episodes. On one hand, the abuse of methamphetamines, cannabis, and cocaine plays a big role in increasing the incidence of episodes resembling a psychotic disorder. On the other hand, the progress in terms of pharmacodynamics knowledge has led to the synthesis of new drugs, such as cannabinoids and cathinone's, which have rapidly entered into the common pool of abusers' habits. Regarding these newly synthesized substances of abuse, further clinical studies are needed to understand their psychogenic properties. The topic of this review is complicated due to the frequent abuse of psychotomimetic drugs by patients affected by psychotic disorders, a fact that makes it extremely difficult to distinguish between an induced psychosis and a re-exacerbation of a previously diagnosed disorder. Methods: The present narrative review summarizes results from clinical studies, thus investigating the psychotogenic properties of abused substances and the psychotic symptoms they can give rise to. It also discusses the association between substance abuse and psychosis, especially with regards to the differential diagnosis between a primary vs. a substance-induced psychotic disorder. Findings: Our findings support the theory that psychosis due to substance abuse is commonly observed in clinical practice. The propensity to develop psychosis seems to be a function of the severity of use and addiction. Of note, from a phenomenological point of view, it is possible to identify some elements that may help clinicians involved in differential diagnoses between primary and substance-induced psychoses. There remains a striking paucity of information on the outcomes, treatments, and best practices of substance-induced psychotic episodes.
Full-text available
Background Synthetic cannabinoids (SCs) are the largest class of novel psychoactive substances (NPS) and are associated with an increased risk of overdosing and adverse events such as psychosis. JWH-018 is one of the earliest SCs and still widely available in large parts of the world. Controlled studies to assess the safety and behavioural profiles of SCs are extremely scarce. Aim The current study was designed to assess the psychotomimetic effects of a moderate dose of JWH-018. Methods Twenty-four healthy participants (10 males, 14 females) entered a placebo-controlled, double blind, within-subjects trial and inhaled vapour of placebo or 75μg/kg bodyweight JWH-018. To ascertain a minimum level of intoxication, a booster dose of JWH-018 was administered on an as-needed basis. The average dose of JWH-018 administered was 5.52 mg. Subjective high, dissociative states (CADSS), psychedelic symptoms (Bowdle), mood (POMS) and cannabis reinforcement (SCRQ) were assessed within a 4.5-h time window after drug administration. Results JWH-018 caused psychedelic effects, such as altered internal and external perception, and dissociative effects, such as amnesia, derealisation and depersonalisation and induced feelings of confusion. Conclusion Overall, these findings suggest that a moderate dose of JWH-018 induces pronounced psychotomimetic symptoms in healthy participants with no history of mental illness, which confirms that SCs pose a serious risk for public health.
Background In contrast to delta-9-tetrahydrocannabinol, the phytocannabinoid cannabidiol does not exert psychotomimetic effects. Cannabidiol was suggested a re-uptake inhibitor of anandamide and potential antipsychotic properties have been hypothesized for it. We therefore performed a clinical trial to investigate thesis hypothesis and to clarify the underlying link to the neurobiology of schizophrenia. Methods We performed an explorative, 4-week, double-blind, controlled clinical trial on the effects of purified cannabidiol in acute schizophrenia compared to the antipsychotic amisulpride. The antipsychotic properties of both drugs were the primary target of the study. Furthermore, side-effects and anxiolytic capabilities of both treatments were investigated. Results 42 patients fulfilling DSM-IV criteria of acute paranoid schizophrenia participated in the study. Both treatments were associated with a significant decrease of psychotic symptoms after 2 and 4 weeks as assessed by BPRS and PANSS. However, there was no statistical difference between both treatment groups. In contrast, cannabidiol induced significantly less side effects (EPS, increase in prolactin, weight gain) when compared to amisulpride. Conclusions Cannabidiol revealed substantial antipsychotic properties in acute schizophrenia. This is in line with our suggestion of an adaptive role of the endocannabinoid system in paranoid schizophrenia, and raises further evidence that this adaptive mechanism may represent a valuable target for antipsychotic treatment strategies. The Stanley Medical Research Institute (00-093 to FML) and the Koeln Fortune Program (107/2000 + 101/2001 to FML) funded this study.
The N-1 alkyl side chain of the aminoalkylindole analogues (AAI) has been implicated as one of a three-point interaction with the cannabinoid CB1 receptor. In this study, the morpholinoethyl of WIN 55,212-2 was replaced with carbon chains of varying lengths ranging from a methyl to heptyl group. Additional groups were added to the naphthoyl and the C2 positions of the molecule. These structural changes revealed that high affinity binding to the CB1 and CB2 receptors requires an alkyl chain length of at least three carbons with optimum binding to both receptors occurring with a five carbon side chain. An alkyl chain of 3–6 carbons is sufficient for high affinity binding; however, extension of the chain to a heptyl group results in a dramatic decrease in binding at both receptors. The unique structure of the cannabimimetic indoles provides a useful tool to define the ligand-receptor interaction at both cannabinoid receptors and to refine proposed pharmacophore models.
Δ9-Tetrahydrocannabinol from Cannabis sativa is mimicked by cannabimimetic analogs such as CP55940 and WIN55212-2, and antagonized by rimonabant and SR144528, through G-protein-coupled receptors, CB1 in the brain, and CB2 in the immune system. Eicosanoids anandamide and 2-arachidonoylglycerol are the “endocannabinoid” agonists for these receptors. CB1 receptors are abundant in basal ganglia, hippocampus and cerebellum, and their functional activity can be mapped during behaviors using cerebral metabolism as the neuroimaging tool. CB1 receptors couple to Gi/o to inhibit cAMP production, decrease Ca2+ conductance, increase K+ conductance, and increase mitogen-activated protein kinase activity. Functional activation of G-proteins can be imaged by [35S]GTPγS autoradiography. Post-synaptically generated endocannabinoids form the basis of a retrograde signaling mechanism referred to as depolarization-induced suppression of inhibition (DSI) or excitation (DSE). Under circumstances of sufficient intracellular Ca2+ (e.g., burst activity in seizures), synthesis of endocannabinoids releases a diffusible retrograde messenger to stimulate presynaptic CB1 receptors. This results in suppression of γ-aminobutyric acid (GABA) release, thereby relieving the post-synaptic inhibition. Tolerance develops as neurons adjust both receptor number and cellular signal transduction to the chronic administration of cannabinoid drugs. Future therapeutic drug design can progress based upon our current understanding of the physiology and pharmacology of CB1, CB2 and related receptors. One very important role for CB1 antagonists will be in the treatment of craving in the disease of substance abuse.