Psychological Medicine (2009), 39, 1607–1616.

f Cambridge University Press 2009 O R I G IN AL A R T IC L E

doi:10.1017/S0033291709005522 Printed in the United Kingdom

The acute effects of synthetic intravenous

D9-tetrahydrocannabinol on psychosis, mood
and cognitive functioning

P. D. Morrison1*, V. Zois1, D. A. McKeown2, T. D. Lee2, D. W. Holt2, J. F. Powell1, S. Kapur1

and R. M. Murray1
1
Institute of Psychiatry, The Biomedical Research Centre, King’s College London, UK
2
Analytical Unit, St George’s, University of London, UK

Background. Recent work suggests that heavy use of cannabis is associated with an increased risk of schizophrenia-
like psychosis. However, there is a dearth of experimental studies of the effects of the constituents of cannabis, such
as D9-tetrahydrocannabinol (THC). In a study of intravenous (i.v.) synthetic THC in healthy humans, we aimed to
study the relationship of the psychotic symptoms induced by THC to the consequent anxiety and neuropsychological
impairment.

Method. Twenty-two healthy adult males aged 28¡6 years (mean¡S.D.) participated in experimental sessions in
which i.v. THC (2.5 mg) was administered under double-blind, placebo-controlled conditions. Self-rated and in-
vestigator-rated measurements of mood and psychosis [the University of Wales Institute of Science and Technology
Mood Adjective Checklist (UMACL), the Positive and Negative Syndrome Scale (PANSS) and the Community
Assessment of Psychic Experiences (CAPE)] were made at baseline and at 30, 80 and 120 min post-injection.
Participants also completed a series of neuropsychological tests [the Rey Auditory Verbal Learning Task (RAVLT),
Digit Span, Verbal Fluency and the Baddeley Reasoning Task] within 45 min of injection.

Results. THC-induced positive psychotic symptoms, and participant- and investigator-rated measurements of these
were highly correlated. Participants showed an increase in anxiety ratings but there was no relationship between
either self- or investigator-rated positive psychotic symptoms and anxiety. THC also impaired neuropsychological
performance but once again there was no relationship between THC-induced positive psychotic symptoms and
deficits in working memory/executive function.

Conclusions. These findings confirm that THC can induce a transient, acute psychotic reaction in psychiatrically
well individuals. The extent of the psychotic reaction was not related to the degree of anxiety or cognitive impair-
ment.

Received 30 September 2008 ; Revised 4 February 2009 ; Accepted 8 February 2009 ; First published online 1 April 2009

Key words : Psychosis, schizophrenia, D9-tetrahydrocannabinol.

Introduction 2007), and those patients who continue to use cannabis

exhibit earlier and more frequent relapses compared
Since the nineteenth century there have been descrip-
to non-users (Linszen et al. 1994 ; Caspari, 1999 ; Grech
tions of acute schizophrenia-like psychotic symptoms
et al. 2005). Furthermore, there is now considerable
in healthy subjects who had taken cannabis (Moreau
evidence that regular cannabis use is associated with
de Tours, 1845 ; Ames, 1958 ; Talbott & Teague, 1969 ;
an increased risk of schizophrenic illness (Arseneault
Chopra & Smith, 1974). The prevalence of cannabis
et al. 2004 ; Barnes et al. 2006 ; Hall, 2006 ; Moore et al.
use in psychotic patients presenting to psychiatric
2007 ; Murray et al. 2007).
services for the first time is approximately double that
It is clear that the major psychoactive properties
found in the general population (Hambrecht &
of cannabis are attributable to the molecule D9-
Hafner, 2000 ; Van Mastrigt et al. 2004 ; Barnett et al.
tetrahydrocannabinol (THC), which acts as a partial
agonist at cannabinoid CB1 receptors in the brain
(Mechoulam et al. 1970 ; Pertwee, 2006). Several recent
* Address for correspondence : Dr P. D. Morrison, Institute of
studies have investigated the acute pharmacological
Psychiatry, The Biomedical Research Centre, King’s College London,
De Crespigny Park, Denmark Hill, London SE5 8AF, UK. effects of marijuana, plant-derived THC extracts or
(Email : paul.morrison@iop.kcl.ac.uk) synthetic THC under laboratory conditions, either in
1608 P. D. Morrison et al.
healthy controls (Curran et al. 2002 ; D’Souza et al.
2004 ; Henquet et al. 2006 ; Koethe et al. 2006 ;
Ramaekers et al. 2006 ; Juckel et al. 2007) or in schizo-
phrenic patients (D’Souza et al. 2005), using a variety
of drug administration routes.
Studies using smoked marijuana, although highly
informative of herbal drug effects, are compromised
by the presence of at least 60 other cannabinoid mol-
ecules, some of which are CB1 receptor antagonists
(Pertwee, 2006, 2008 ; Ryan et al. 2006). Orally admin-
istered cannabinoids have the disadvantage of poor,
irregular absorption and marked inter-individual vari-
ation in plasma concentrations (Grotenhermen, 2003).
By contrast, intravenous (i.v.) administration of syn-
thetic THC offers a rapid and reliable delivery method
with low inter-individual variation in bioavailability
and a pharmacokinetic time-course that mirrors that of
smoked marijuana (Ohlsson et al. 1980 ; Grotenhermen,
2003 ; Naef et al. 2004). Previous studies of the effects
of IV THC have used doses ranging from 2 to 5 mg,
which approximate the levels of THC from smoking
a standard cannabis ‘ joint ’ containing 1–3.5 % THC
(16–34 mg) (Ohlsson et al. 1980 ; Volkow et al. 1991 ;
D’Souza et al. 2004, 2005). Using this route, it was
shown that THC elicited psychotic symptoms and
cognitive impairments in a proportion of healthy sub-
jects (D’Souza et al. 2004) and worsened psychotic
symptoms in schizophrenic patients (D’Souza et al.
2005). This work used the Positive and Negative Syn-
drome Scale (PANSS ; Kay et al. 1989), an investigator-
rated scale, to measure THC psychosis (D’Souza et al.
2004).
Although the work by D’Souza and colleagues
shows that THC induces an elevation of PANSS posi-
tive scores, it is to be recognized that the PANSS is a
scale developed and validated in patients with chronic
psychosis, is rated by the observer, and was not de-
signed for immediate repeated administration (i.e. re-
peatedly within a few hours). Thus, we thought that
it would be informative to obtain the subjective per-
spective on the THC-induced experience by adminis-
tering a subjective scale previously used in healthy
subjects : the Community Assessment of Psychic Ex-
periences – state version (CAPE-state ; Henquet et al.
2006). Furthermore, to fully explore the phenomen-
ology of THC-induced acute psychosis as a possible
‘ model ’ for schizophrenia, we thought it crucial that
its effects on mood and anxiety be explored con-
currently ; therefore, we included a validated struc-
tured instrument that is known to be sensitive to
change : the University of Wales Institute of Science
and Technology Mood Adjective Checklist (UMACL ;
Matthews et al. 1990). We hypothesized that i.v.
THC would be anxiogenic and aimed to explore
the relationship between THC-elicited psychosis and
THC-elicited anxiety. Finally, we wanted to further
characterize the effect of THC on cognitive function
and the relationship between psychotic symptoms and
cognitive impairment. Deficits in cognitive function
are regarded as a potential intermediate phenotype
in schizophrenia and predict outcome (reviewed in
Solowij & Michie, 2007). We hypothesized that cogni-
tive performance would be poorer under THC com-
pared to placebo conditions.
Method
The study was carried out at the Institute of Psychi-
atry following approval by the South London and
Maudsley (SLAM) Regional Ethics Committee.
Design
The psychological properties of i.v. THC (2.5 mg) were
investigated in an experimental study using a within-
subject, double-blind, placebo-controlled design. Par-
ticipants attended two experimental sessions, at least
2 weeks apart, in which either THC or placebo was
given in a random, counterbalanced order.
Participants
Healthy male participants were recruited by way of
email advertisements delivered to the staff and stu-
dents of King’s College London. Prospective partici-
pants, assessed by a trained psychiatrist at baseline,
were required to be aged between 21 and 50 years ; to
have previously taken cannabis on at least one oc-
casion ; to score <15 on the General Health Ques-
tionnaire (GHQ-12 ; Goldberg & Blackwell, 1970) ; and
be willing to provide written informed consent. Ex-
clusion criteria were a history of mental illness, sub-
stance dependence (excluding nicotine), current or
past severe medical disorders or a history of major
mental illness in a first-degree family member. Al-
cohol and drug dependence were excluded using the
Michigan Alcohol Screening Test (MAST ; Selzer, 1971)
and the Drug Abuse Screening Test (DAST ; Skinner,
1982). The nature and risks of the study were dis-
cussed. Participants were alerted to the possibility of
transient anxiety and psychosis following THC and
were made aware that they would be able to stop the
experimental sessions at any stage without sanction
and that rescue medication (lorazepam tablets 1–4 mg)
would be available. Participants were asked to avoid
alcohol and drugs for 24 h before, and to abstain from
driving for 24 h after, experimental sessions. Partici-
pants were followed up by telephone the following
day and a small monetary reimbursement was made
at the end of their involvement in the study.

Pharmaceuticals
Dronabinol (THC) was supplied by THC Pharm
GmbH (Frankfurt am Main, Germany) and prepared
as (1 mg/ml) vials for i.v. injection by Bichsel Lab-
oratories (Interlaken, Switzerland) according to the
method of Naef et al. (2004). Placebo and active vials
were identical in composition (except for THC) and
identical in appearance. After dilution in normal sa-
line, preparations for injection contained 2.5 % (v/v)
absolute ethanol.
Experimental sessions
A psychiatrist assessed participants and a brief physi-
cal examination was conducted at the beginning of
each session. Urine was taken for drug testing. Sterile
cannulae (20G) were inserted into veins in the ante-
cubital fossa of both arms, one for administration of
pharmaceuticals and one for blood sampling. Partici-
pants were asked to sit comfortably on a clinical couch
and given free access to water. Pharmaceuticals were
administered in pulses at 1 ml/min over 5 min (total
5 ml).
Outcome measures
Psychological assessments and self-rated scales were
administered at baseline (30 min prior to injection)
and at 30, 80 and 120 min following the final injected
pulse. Participants were instructed to complete rating
scales as applied to the present moment. A trained
psychiatrist conducted all assessments.
Positive psychotic symptoms
Momentary positive psychotic symptoms were as-
sessed using the positive subscale of the PANSS and
the CAPE-state. The CAPE-state is a validated 42-item
self-reported questionnaire, derived from the Peters
Delusions Inventory (PDI), which generates a positive,
a negative and a depressive dimension score (Henquet
et al. 2006). In the current study, the CAPE-state fre-
quency score (0=never, 1=sometimes, 2=often, 3=
nearly always) was collapsed to a yes/no response
option.
Affect
The UMACL was used to assess changes in affect.
Three dimensions of affect are measured : hedonic
tone, energetic arousal and tense arousal (Matthews
et al. 1990). It has been suggested that a three-
dimensional model of affect with separate pleasure–
displeasure, awake–tiredness and tension–relaxation
dimensions provides a more informative description
of core affect (compared to one- and two-dimensional
Acute effects of THC 1609
models) and fits better with experimental data
(Matthews et al. 1990 ; Schimmack & Grob, 2000). For
each dimension, subjects rated their level of agreement
with four emotionally positive and four emotionally
negative adjectives. The total score in each dimension
was calculated by subtracting negatively valenced
from positively valenced items. For each subject the
total score in each dimension at baseline, 30, 80 and
120 min post-injection was a value between x12
and +12.
Cognitive testing
Cognitive assessments began 10 min post-injection.
The order of tests was consistent across both sessions :
(1) the Rey Auditory Verbal Learning Task (RAVLT)-
immediate recall ; (2) Digit Span ; (3) Verbal Fluency ;
(4) RAVLT-20 min recall ; and (5) the Baddeley Rea-
soning Task. Cognitive testing was complete within
45 min post-injection.
RAVLT
The standard administration format of the RAVLT
was used. Immediate recall of a 15-word list was as-
sessed over five trials. Two different, but equivalent,
word lists were used. Free recall was assessed follow-
ing a 20-min delay. (The interference component, List
B, was included but the data are not reported here.)
Digit Span
The Digit Span task evaluates the capacity of attention
and working memory. Participants were tested in their
immediate recall of a sequence of digits ; and given
two attempts at each level of difficulty. In the reverse
digit span condition, participants were required to re-
call the sequence in the reverse order.
Verbal fluency
The verbal fluency task evaluates speed of retrieval
from semantic memory. Participants were given 60 s
to generate words beginning with a specific letter of
the alphabet and instructed that proper nouns and
plurals did not score. The mean number of words
generated from four trials was recorded as the total
score.
The Baddeley Reasoning Task
Participants were given 3 min in which to verify the
truth of 32 logical statements containing one of four
grammatical constructs such as : ‘ B does not precede
A … AB ’. The highest obtainable score was 32. This
task evaluates the performance of the central execu-
tive.
1610 P. D. Morrison et al.

Pharmacokinetic analysis (a)

Blood (5 ml) was collected at baseline and at 1, 5, 15,

14

PANSS positive subscale

30, 60 and 120 min post-injection. Immediately af-
ter collection, samples were stored at 2–5 xC, prior 12
to being centrifuged. Plasma was stored at x70 xC
until analysis. The samples were extracted using 10
solid phase extraction (SPE), then THC and its pri-
mary metabolite 11-OH-THC were derivatized and 8
measured using gas chromatography with mass-
spectrophotometric detection (GC–MS) as described 6
previously (Steinmeyer et al. 2002).
0 30 80 120
Time (min)
Statistical analyses
(b)
All analyses were performed in SPSS version 15.0
5
(SPSS Inc., Chicago, IL, USA). Data were assessed for
normality using Kolmogorov–Smirnov test statistics.

CAPE positive subscale

Because of absence of variance in positive psychotic 4
scores under placebo conditions, Friedman’s test,
a non-parametric repeated-measures test, was used 3
to compare positive psychotic scores under THC
and placebo conditions. Two-way repeated-measures 2
ANOVA was used to compare immediate recall in the
RAVLT, with Trial (1–5) and Treatment (placebo ver- 1
sus THC) as within-subject factors. The Greenhouse–
Geisser corrected F ratio was used because there was 0
0 30 80 120
a violation of sphericity. For the remaining cognitive
Time (min)
tasks and the UMACL, differences between placebo
and THC were compared using paired t tests. Re- Fig. 1. Mean positive psychotic symptoms as measured by
lationships between normally distributed variables (a) the Positive and Negative Syndrome Scale (PANSS) and
were analysed using Pearson’s product moment cor- (b) the Community Assessment of Psychic Experiences
relation. Relationships between non-parametric vari- (CAPE) scale following intravenous D9-tetrahydrocannabinol
(THC) (2.5 mg). Error bars show ¡95 % confidence interval.
ables were tested using Spearman’s rank correlation
coefficient. Significance was accepted at p values


– –, Placebo ; –&–, THC.

<0.05. All comparisons were two-tailed.

Results
Of 24 volunteers, 22 attended both sessions. Partici-
pants were aged 28¡6 years (mean¡S.D.). All partici-
pants were Caucasian. Estimated lifetime exposure to
cannabis ranged from 2 to about 1000 episodes. Self-
reported last previous use of cannabis ranged from
12 h to 10 years (mean¡S.D.=2¡3.3 years). In urine
drug screens, one participant tested positive for THC,
but this was the case prior to both experimental
sessions, thus the data were included in the main ana-
lyses. No participants tested positive for other com-
mon drugs of abuse (opiates, cocaine, amphetamines,
methamphetamine, methadone, benzodiazepines) at
either session.
Of the 22 participants, three subjects were unable to
complete all parts of the protocol. One experienced
nausea during the THC arm ; another refused to
participate in cognitive testing or to complete
self-rated scales under THC ; and one participant ex-
perienced profound anxiety during the THC arm and
requested ‘ rescue medication ’ (lorazepam 3 mg) ; sym-
ptoms resolved completely within 30 min.
THC-induced positive psychotic symptoms
Scores on the PANSS positive subscale were increased
from baseline following THC but not placebo admin-
istration (Friedman’s x2=62, df=7, n=21, p<0.001).
At 30 min post-THC, PANSS positive scores had in-
creased by a mean of 3.7 points (range 0–17), returning
to baseline levels by 120 min (Fig. 1 a). Similarly, sub-
ject-rated positive psychotic symptoms as measured
by the CAPE-state increased from baseline following
THC but not placebo (Friedman’s x2=20, df=7, n=17,
p=0.005). By 80 min post-injection, CAPE-state scores
had returned to baseline (Fig. 1 b). Investigator-rated
(PANSS) and subject-rated (CAPE-state) positive
 Acute effects of THC 1611

psychotic scores at 30 and 80 min post-THC admin- (a)

istration were correlated (Spearman’s r=0.62, p<
10
0.001). Participants who had taken cannabis more ex-
tensively in the past were less likely to exhibit positive
5

Hedonic tone
psychotic symptoms as rated by the PANSS under
THC conditions at 30 min post-injection (Spearman’s
0
r=x0.45, p<0.05).

The impact of THC on core affect –5

Hedonic tone
–10
IV THC elicited transient feelings of dysphoria. Under
0 30 80 120
THC conditions, self-rated hedonic tone as measured
by the UMACL was decreased compared to placebo Time (min)
at 30 min post-injection [THC, mean=4.3, 95 % confi- (b)
dence interval (CI) 2.9–5.8 ; placebo, mean=8.7, 95 %
10
CI 7.3–10.1, t(17)=3.24, p=0.005] and at 80 min post-
injection [THC, mean=7.2, 95 % CI 6.3–8.1 ; placebo,

Energetic arousal
5
mean=9.3, 95 % CI 8.5–10.2, t(15)=2.62, p<0.05]. By
120 min, there was no significant difference in hedonic
0
tone between THC and placebo conditions (Fig. 2 a).

Energetic arousal –5

On the UMACL awake–tiredness dimension, THC in-

–10
duced feelings of tiredness at 30 min [THC, mean=
0.3, 95 % CI x1.8 to 2.4 ; placebo, mean=4.6, 95 % CI 0 30 80 120
3.3–5.8, t(17)=4.09, p=0.001], at 80 min [THC, mean= Time (min)
x1.0, 95 % CI x3.0 to 1.1 ; placebo, mean=5.5, 95 % CI
4.3–6.7, t(15)=4.74, p<0.000] and at 120 min post- (c)
injection [THC, mean=x0.2, 95 % CI x1.6 to 1.3 ; 10
placebo, mean=5.1, 95 % CI 3.7–6.6, t(9)=3.60,
p<0.01] (Fig. 2 b). 5
Tense arousal

Tense arousal 0
On the UMACL tension–relaxation dimension, THC
induced feelings of tense arousal at 30 min [THC, –5
mean=x0.7, 95 % CI x3.2 to 1.9 ; placebo, mean=
x7.3, 95 % CI x8.5 to x6.1, t(17)=x3.93, p=0.001] –10
and at 80 min post-injection [THC, mean=x3.3, 95 %
0 30 80 120
CI x5.7 to x1.0 ; placebo, mean=x8.3, 95 % CI x9.4
Time (min)
to x7.2, t(15)=x3.2, p<0.01]. By 120 min, there was
no significant difference in tense arousal between THC Fig. 2. Mean scores of (a) hedonic tone, (b) energetic arousal
and placebo conditions (Fig. 2 c). and (c) tense arousal as measured by the University of
Notably, there was no relationship at 30 and 80 min Wales Institute of Science and Technology Mood
Adjective Checklist (UMACL) following intravenous
post-injection between the degree of THC-elicited
D9-tetrahydrocannabinol (THC) (2.5 mg). Error bars show
tense arousal and positive psychotic symptoms whe-
ther measured using the PANSS (Spearman’s r=0.19,


¡95 % confidence interval. – –, Placebo ; –&–, THC.

p=0.30) or the CAPE-state (Spearman’s r=0.28, p=

0.12).
The impact of THC on cognitive performance
RAVLT
Immediate recall under THC or placebo conditions
(Treatment) was compared in successive trials A1–A5
(Trial) of the RAVLT. There was a significant main
effect of drug [F(1, 19)=16.6, p<0.005] and a signifi-
cant main effect of trial [F(2.71, 51.49)=85.3, p<0.000]
but only a trend towards a drugrtrial interaction
[F(3.04, 57.82)=2.24, p=0.09]. Whereas THC signifi-
cantly decreased immediate recall, there was only a
1612 P. D. Morrison et al.
18
16
14
Correct responses
12
10
8
6
4
2
0 0
A1 A2 A3 A4
Trial
Fig. 3. Performance in the Rey Auditory Verbal
Learning Task (RAVLT) following intravenous
D9-tetrahydrocannabinol (THC) (2.5 mg) or matched placebo.
Mean scores are shown for consecutive trials of working
memory (A1–A5) and for free recall at 20-min post-encoding.
Error bars show ¡95 % confidence interval. – –, Placebo ;
–&–, THC.
trend towards a difference in free recall (at 20 min
post-encoding) between placebo (mean¡S.D.=11.1¡
3.3) and THC (9.7¡3.5) conditions [t(17)=1.75,
p=0.10] (Fig. 3).
Under THC conditions, the total diminution in
immediate recall (sum of trials A1–A5) showed no
relationship to PANSS positive scores at 30 min
(Spearman’s r=x0.29, p=0.20). Similarly, delayed
free recall performance under THC conditions was
unrelated to PANSS positive scores at 30 min
(Spearman’s r=x0.39, p=0.12).
Digit Span
THC decreased performance in the forward [mean
raw score¡S.D. : THC=7.0¡1.2, placebo=7.8¡0.9,
t(18)=2.62, p<0.05] and reverse digit span task
[THC=5.1¡1.4, placebo=6.2¡1.1, t(18)=3.3, p<
0.005]. Diminished performance under THC condi-
tions was unrelated to the magnitude of PANSS posi-
tive scores at 30 min post-injection, both for the
forward (Spearman’s r=0.11, p=0.61) and reverse
(Spearman’s r=0.30, p=0.20) arms.
Verbal fluency
Participants showed no difference in performance
between THC (mean¡S.D.=19.3¡3.2) and placebo
(18.9¡4.2) conditions [t(15)=x0.3, p=0.7].
Baddeley Reasoning Task
Performance in the Baddeley Reasoning Task under
THC (mean¡S.D.=22.3¡7.6) was significantly poorer
than under placebo conditions (26.9¡5.9) [t(15)=3.6,
200
175
THC conc. (ng/ml)
150
125
100
75
50
25
0
15 30 45 60 75 90 105 120
A5 20-min recall
Time (min)
Fig. 4. Mean plasma concentrations following intravenous
administration of D9-tetrahydrocannabinol (THC) (2.5 mg).
Error bars show ¡95 % confidence interval.
p=0.003]. There was no relationship between per-

formance in the Baddeley Reasoning Task and work-
ing memory scores as indexed by the Digit Span task
(r=x0.1, p=0.7), indicating that poorer executive
function was not driven by the effect of THC on
working memory. The magnitude of poorer perform-
ance in the Baddeley under THC conditions was
unrelated to PANSS positive scores at 30 min post-
injection (Spearman’s r=0.08, p=0.77).
Pharmacokinetics
Following IV THC (2.5 mg over 5 min), plasma con-
centrations reached a maximum and then decreased
rapidly over 15 min. Thereafter, concentrations de-
creased at a slower rate (Fig. 4).
At 1 min post-injection the plasma concentration of
THC ranged between 96.1 and 206.6 ng/ml (mean¡
S.D.=176.7¡33.7). Peak plasma concentrations of the
main psychoactive metabolite of THC (11-OH-THC)
occurred at 5 min post-injection and ranged from 1.5
to 7.8 ng/ml (mean¡S.D.=4.4¡2.1). THC area under
the curve from time 0 to infinity (AUC0–1) ranged
from 1110.1 to 2995.4 ng min/ml (mean¡S.D.=
2047.3¡423.7).
There was no relationship between positive psycho-
tic symptoms, as measured by the PANSS, and plasma
concentrations of THC at 5 min, or 11-OH-THC con-
centrations at 5 min. Similarly, PANSS positive scores
following THC administration and AUC0–1 were un-
related.
Discussion
The observed plasma concentrations and time-course
of THC in the present study are in a similar range to
those from previous studies in which individuals
smoked cannabis cigarettes. In a study of healthy

males, mean plasma levels of THC immediately after
10 puffs from cannabis cigarettes containing 1.75 % or
3.55 % THC were respectively 56.2 and 146.6 ng/ml
(Azorlosa et al. 1995). Ramaekers et al. (2006) inves-
tigated the properties of high-potency marijuana
cigarettes containing 13 % THC in a sample of rec-
reational cannabis users. The mean (S.D.) serum THC
concentration at 5 min post-smoking was 93.6 (63.9)
ng/ml. In the present study, the mean (S.D.) plasma
THC concentration at 5 min post-injection was 68.0
(14.1) ng/ml.
Psychological responses to THC began during the
redistribution phase (about 5–10 min post-injection)
when the plasma concentration of THC had already
fallen sharply (Fig. 4). The majority of the psycho-
logical effects tapered off between 60 and 120 min
post-THC, despite the relatively small change in the
absolute plasma concentration during that period
(Fig. 4). Thus, in agreement with previous reports,
the onset, peak and termination of psychological re-
sponses to THC were not related to concurrent plasma
concentrations (Grotenhermen, 2003).
Psychotic symptoms
There was wide inter-individual variation in psy-
chosis scores. At 30 min post-injection, 50 % of subjects
had increases in the PANSS positive subscale score
o4, and similarly, 47 % of subjects endorsed positive
subscale items from the CAPE-state. Under THC con-
ditions there was a significant correlation between
increases in PANSS and CAPE-state positive scores at
30 and 80 min. This suggests that phenomena that
were categorized as psychotic were likely to be ‘ true ’
psychotic experiences. THC psychosis as measured by
the PANSS or the CAPE-state did not correlate with
THC-elicited anxiety, suggesting that THC-elicited
acute anxiety and THC-elicited acute psychosis are
separable psychological effects. The most commonly
endorsed items on the CAPE-state under THC condi-
tions at 30 min post-injection were : Q.2 Do you feel as if
people seem to be dropping hints about you or saying things
with a double meaning ? and Q.30 Do you hear your own
thoughts being echoed back to you ? We find this aspect of
THC-induced phenomenology particularly interesting
from the point of view of a model psychosis, as ideas
of reference are one of the commonest symptoms in
schizophrenia (Mass, 2000 ; Startup et al. 2003). An
influential hypothesis holds that delusional ideas
emerge from a psychological state in which mundane
events are attributed with inappropriate motivational
salience (Kapur, 2003). Aberrant salience is thought to
reflect pathological hyperdopaminergia in the ventral
striatum. Recent work has shown that the dopamine
and endocannabinoid systems are intimately linked
Acute effects of THC 1613
throughout the reward system and it has become clear
that some important effects of dopamine are mediated
by downstream endocannabinoid signalling at CB1
receptors (Shen et al. 2008). The pro-psychotic effects
of THC observed here may have arisen from direct
overstimulation of CB1 receptors in the striatum.
Affect
As hypothesized, THC elicited pronounced changes
in core affect. Overall, participants were more likely to
rate themselves on the UMACL as dysphoric and an-
xious in the first hour following THC. (Anecdotally,
many subjects gave verbal reports of feeling more re-
laxed following THC but in the majority of cases their
verbal reports were in contradiction to their self-rated
scores on the tense–arousal dimension of the UMACL
and the overall clinical impression. Perhaps this re-
flects an underlying, widely held assumption that
cannabis has tranquillizing properties.) Dysphoria and
anxiety peaked in the early stages following i.v. THC
and subsided more rapidly than subjective feelings
of tiredness, which peaked later and were more per-
sistent.
Cognitive function
In the 30 min following THC administration, there
were marked deficits in working memory and execu-
tive functioning and a trend towards impaired epi-
sodic memory, all of which are largely consistent with
previous studies (Curran et al. 2002 ; D’Souza et al.
2004 ; Ramaekers et al. 2006). It is well established that
schizophrenia is associated with deficits in tasks of
working memory, executive functioning and episodic
memory (Barch & Smith, 2008 ; Ranganath et al. 2008).
Several recent reviews have drawn attention to the
similarities between the cognitive deficits elicited by
cannabis/THC and the cognitive deficits of schizo-
phrenia and suggested a shared underlying neuro-
biology (Fletcher & Honey, 2006 ; Solowij & Michie,
2007). In the current study we found no suggestion
of any relationship between the extent of positive
psychotic symptoms and working memory/executive
function.
Most human studies that have explored the acute
effects of THC and cannabis on mood have used visual
analogue scales and have focused on vague concepts
such as ‘ stoned ’ or ‘ high ’. To our knowledge, this is
the first study to incorporate a validated, sensitive in-
strument to investigate the effects of cannabis/THC
on the three core dimensions of mood. Animal and
human work suggests that the effects of THC on an-
xiety is biphasic, with lower doses being anxiolytic
and higher doses being anxiogenic (Ashton, 2001 ;
1614 P. D. Morrison et al.
Iversen, 2003 ; Viveros et al. 2005 ; Rubino et al. 2008).
The anxiety response observed here and in the study
by D’Souza et al. (2004) may be attributable to high
plasma levels of THC. Clearly, the setting and drug-
delivery method are far removed from the naturalistic
way of taking cannabis and may have facilitated an
anxiety response. Furthermore, the purely synthetic
preparation used in the present study was devoid
of cannabidiol (CBD), which has known anxiolytic
properties (Pertwee, 2008). This is of interest because it
has been suggested that CBD inhibits the anxiogenic
properties of THC in humans (Zuardi et al. 1982).
Recent work shows that CBD can potently inhibit the
pharmacological effects of CB1 agonists despite having
low affinity for the orthosteric site of the CB1 receptor
(Pertwee, 2008). It is possible that the anxiogenic ef-
fects of THC observed here (and also the pro-psychotic
effects) emerge from the unopposed actions of THC,
rather than being a function of the plasma levels of
THC per se. This may have relevance to cannabis con-
sumption in more typical settings, and not be merely a
laboratory phenomenon, given that CBD concentra-
tions are almost undetectable in some ‘ street ’ forms of
cannabis such as sinsemilla (Potter et al. 2008).
In agreement with a previous study (D’Souza et al.
2008), participants who had taken cannabis more ex-
tensively in the past were less likely to exhibit positive
psychotic symptoms following i.v. THC. However,
because people who had used more cannabis in the
past were also more likely to report having taken other
substances, the finding here of a relationship between
previous cannabis use and psychotic symptoms fol-
lowing i.v. THC may be attributable to other sub-
stances taken previously or to polydrug use rather
than cannabis alone.
Limitations
A limitation of this study is that only a single dose of
THC was used. Animal work has shown that the
properties of THC are highly dose dependent and bi-
directional effects are common (Iversen, 2003). To
date, human studies have characterized the effects
of THC within a narrow dose range. Despite the
methodological difficulties, more extensive dose–
response studies are required. Furthermore, the pres-
ent study does not address the important question
of why some individuals are more susceptible than
others to experience psychotic symptoms following
THC/cannabis.
The use of intravenous preparations is clearly dif-
ferent from the use of cannabis in a more natural set-
ting. However, it can be argued that this is balanced by
the pharmacokinetic advantages of the i.v. route and
the pharmacodynamic advantage of a pure synthetic
preparation, devoid of other active cannabinoid mol-
ecules. The plasma concentrations and time-course
of THC in this study are in the same range as those
observed following inhalational cannabis use.
In conclusion, in a sample of healthy male sub-
jects, a pure, synthetic i.v. preparation of THC elicited
acute positive psychotic symptoms, anxiety, dys-
phoria, working memory/executive deficits and, sub-
sequently, feelings of tiredness. Our findings suggest
that THC-induced positive psychotic symptoms are
neither secondary to high levels of anxiety nor a cause
of anxiety.
Acknowledgements
This study was supported by the Psychiatry Research
Trust. We thank M. Diforti, S. Luzi and E. Barkus for
helpful advice and suggestions.
Declaration of Interest
None.
References
Ames F (1958). A clinical and metabolic study of acute
intoxication with Cannabis sativa and its role in the model
psychoses. Journal of Mental Science 104, 972–999.
Arseneault L, Cannon M, Witton J, Murray RM (2004).
Causal association between cannabis and psychosis :
examination of the evidence. British Journal of Psychiatry
184, 110–117.
Ashton CH (2001). Pharmacology and effects of cannabis :
a brief review. British Journal of Psychiatry 178, 101–106.
Azorlosa JL, Greenwald MK, Stitzer ML (1995). Marijuana
smoking : effects of varying puff volume and breathhold
duration. Journal of Pharmacology and Experimental
Therapeutics 272, 560–569.
Barch DM, Smith E (2008). The cognitive neuroscience of
working memory : relevance to CNTRICS and
schizophrenia. Biological Psychiatry 64, 11–17.
Barnes TR, Mutsatsa SH, Hutton SB, Watt HC, Joyce EM
(2006). Comorbid substance use and age at onset of
schizophrenia. British Journal of Psychiatry 188, 237–242.
Barnett JH, Werners U, Secher SM, Hill KE, Brazil R,
Masson K, Pernet DE, Kirkbride JB, Murray GK,
Bullmore ET, Jones PB (2007). Substance use in a
population-based clinic sample of people with
first-episode psychosis. British Journal of Psychiatry 190,
515–520.
Caspari D (1999). Cannabis and schizophrenia : results of a
follow-up study. European Archives of Psychiatry and Clinical
Neuroscience 249, 45–49.
Chopra GS, Smith JW (1974). Psychotic reactions following
cannabis use in East Indians. Archives of General Psychiatry
30, 24–27.

Curran HV, Brignell C, Fletcher S, Middleton P, Henry J
(2002). Cognitive and subjective dose-response effects of
acute oral delta 9-tetrahydrocannabinol (THC) in
infrequent cannabis users. Psychopharmacology (Berlin) 164,
61–70.
D’Souza DC, Abi-Saab WM, Madonick S, Forselius-Bielen
K, Doersch A, Braley G, Gueorguieva R, Cooper TB,
Krystal JH (2005). Delta-9-tetrahydrocannabinol effects in
schizophrenia : implications for cognition, psychosis, and
addiction. Biological Psychiatry 57, 594–608.
D’Souza DC, Perry E, MacDougall L, Ammerman Y,
Cooper T, Wu YT, Braley G, Gueorguieva R, Krystal JH
(2004). The psychotomimetic effects of intravenous
delta-9-tetrahydrocannabinol in healthy individuals :
implications for psychosis. Neuropsychopharmacology 29,
1558–1572.
D’Souza DC, Ranganathan M, Braley G, Gueorquieva R,
Zimolo Z, Cooper T, Perry E, Krystal J (2008). Blunted
psychotomimetic and amnestic effects of delta-9-
tetrahydrocannabinol in frequent users of cannabis.
Neuropsychopharmacology 33, 2505–2516.
Fletcher PC, Honey GD (2006). Schizophrenia, ketamine
and cannabis : evidence of overlapping memory deficits.
Trends in Cognitive Sciences 10, 167–174.
Goldberg DP, Blackwell B (1970). Psychiatric illness in
general practice. A detailed study using a new method of
case identification. British Medical Journal 1, 439–443.
Grech A, Van Os J, Jones PB, Lewis SW, Murray RM (2005).
Cannabis use and outcome of recent onset psychosis.
European Psychiatry 20, 349–353.
Grotenhermen F (2003). Pharmacokinetics and
pharmacodynamics of cannabinoids. Clinical
Pharmacokinetics 42, 327–360.
Hall W (2006). Is cannabis use psychotogenic ? Lancet 367,
193–195.
Hambrecht M, Hafner H (2000). Cannabis, vulnerability, and
the onset of schizophrenia : an epidemiological
perspective. Australian and New Zealand Journal of Psychiatry
34, 468–475.
Henquet C, Rosa A, Krabbendam L, Papiol S, Fananas L,
Drukker M, Ramaekers JG, van Os J (2006). An
experimental study of catechol-O-methyltransferase
Val(158)Met moderation of delta-9-tetrahydrocannabinol-
induced effects on psychosis and cognition.
Neuropsychopharmacology 31, 2748–2757.
Iversen L (2003). Cannabis and the brain. Brain 126,
1252–1270.
Juckel G, Roser P, Nadulski T, Stadelmann AM, Gallinat J
(2007). Acute effects of Delta9-tetrahydrocannabinol and
standardized cannabis extract on the auditory evoked
mismatch negativity. Schizophrenia Research 97, 109–117.
Kapur S (2003). Psychosis as a state of aberrant salience :
a framework linking biology, phenomenology, and
pharmacology in schizophrenia. American Journal of
Psychiatry 160, 13–23.
Kay SR, Opler LA, Lindenmayer JP (1989). The Positive and
Negative Syndrome Scale (PANSS) : rationale and
standardisation. British Journal of Psychiatry (Suppl.) 59–67.
Koethe D, Gerth CW, Neatby MA, Haensel A, Thies M,
Schneider U, Emrich HM, Klosterkotter J,
Acute effects of THC 1615
Schultze-Lutter F, Leweke FM (2006). Disturbances of
visual information processing in early states of psychosis
and experimental delta-9-tetrahydrocannabinol
altered states of consciousness. Schizophrenia Research 88,
142–150.
Linszen DH, Dingemans PM, Lenior ME (1994). Cannabis
abuse and the course of recent-onset schizophrenic
disorders. Archives of General Psychiatry 51, 273–279.
Mass R (2000). Characteristic subjective experiences of
schizophrenia. Schizophrenia Bulletin 26, 921–931.
Matthews G, Jones DM, Chamberlain AG (1990). Refining
the measurement of mood : the UWIST Mood Adjective
Checklist. British Journal of Psychology 81, 17–42.
Mechoulam R, Shani A, Edery H, Grunfeld Y (1970).
Chemical basis of hashish activity. Science 169, 611–612.
Moore TH, Zammit S, Lingford-Hughes A, Barnes TR,
Jones PB, Burke M, Lewis G (2007). Cannabis use and risk
of psychotic or affective mental health outcomes :
a systematic review. Lancet 370, 319–328.
Moreau de Tours JJ (1845). Hashish and Insanity [in French].
Fortin, Masson et Cie : Paris.
Murray RM, Morrison PD, Henquet C, Di Forti M (2007).
Cannabis, the mind and society : the hash realities. Nature
Reviews Neuroscience 8, 885–895.
Naef M, Russmann S, Petersen-Felix S, Brenneisen R (2004).
Development and pharmacokinetic characterization of
pulmonal and intravenous delta-9-tetrahydrocannabinol
(THC) in humans. Journal of Pharmacological Sciences 93,
1176–1184.
Ohlsson A, Lindgren JE, Wahlen A, Agurell S, Hollister LE,
Gillespie HK (1980). Plasma delta-9 tetrahydrocannabinol
concentrations and clinical effects after oral and
intravenous administration and smoking. Clinical
Pharmacology and Therapeutics 28, 409–416.
Pertwee RG (2006). Cannabinoid pharmacology : the first
66 years. British Journal of Pharmacology 147 (Suppl. 1),
S163–S171.
Pertwee RG (2008). The diverse CB1 and CB2 receptor
pharmacology of three plant cannabinoids :
delta9-tetrahydrocannabinol, cannabidiol and
delta9-tetrahydrocannabivarin. British Journal of
Pharmacology 153, 199–215.
Potter DJ, Clark P, Brown MB (2008). Potency of delta 9-THC
and other cannabinoids in cannabis in England in 2005 :
implications for psychoactivity and pharmacology. Journal
of Forensic Science 53, 90–94.
Ramaekers JG, Kauert G, van Ruitenbeek P, Theunissen
EL, Schneider E, Moeller MR (2006). High-potency
marijuana impairs executive function and inhibitory motor
control. Neuropsychopharmacology 31, 2296–2303.
Ranganath C, Minzenberg MJ, Ragland JD (2008). The
cognitive neuroscience of memory function and
dysfunction in schizophrenia. Biological Psychiatry 64,
18–25.
Rubino T, Guidali C, Vigano D, Realini N, Valenti M,
Massi P, Parolaro D (2008). CB1 receptor stimulation in
specific brain areas differently modulate anxiety-related
behaviour. Neuropharmacology 54, 151–160.
Ryan D, Drysdale AJ, Pertwee RG, Platt B (2006).
Differential effects of cannabis extracts and pure plant
1616 P. D. Morrison et al.
cannabinoids on hippocampal neurones and glia.
Neuroscience Letters 408, 236–241.
Schimmack U, Grob A (2000). Dimensional models of core
affect : a quantitative comparison by means of structural
equation modeling. European Journal of Personality 14,
325–345.
Selzer ML (1971). The Michigan alcoholism screening test :
the quest for a new diagnostic instrument. American Journal
of Psychiatry 127, 1653–1658.
Shen W, Flajolet M, Greengard P, Surmeier JD (2008).
Dichotomous dopaminergic control of striatal synaptic
plasticity. Science 321, 848–851.
Skinner HA (1982). The drug abuse screening test. Addictive
Behaviours 7, 363–371.
Solowij N, Michie PT (2007). Cannabis and cognitive
dysfunction : parallels with endophenotypes of
schizophrenia ? Journal of Psychiatry and Neuroscience 32,
30–52.
Startup M, Owen DM, Parsonage RK, Jackson MC
(2003). Anomalous experiences and the contents of
persecutory delusions during acute psychotic episodes.
Psychology and Psychotherapy : Theory, Research and Practice
76, 315–322.
Steinmeyer S, Bregel D, Warth S, Kraemer T, Moeller MR
(2002). Improved and validated method for the
determination of Delta(9)-tetrahydrocannabinol (THC),
11-hydroxy-THC and 11-nor-9-carboxy-THC in serum,
and in human liver microsomal preparations using gas
chromatography-mass spectrometry. Journal of
Chromatography B : Analytical Technologies in the Biomedical
and Life Sciences 772, 239–248.
Talbott JA, Teague JW (1969). Marihuana psychosis. Acute
toxic psychosis associated with the use of cannabis
derivatives. Journal of the American Medical Association 210,
299–302.
Van Mastrigt S, Addington J, Addington D (2004).
Substance misuse at presentation to an early psychosis
program. Social Psychiatry and Psychiatric Epidemiology 39,
69–72.
Viveros MP, Marco EM, File SE (2005). Endocannabinoid
system and stress and anxiety responses. Pharmacology
Biochemistry and Behaviour 81, 331–342.
Volkow ND, Gillespie H, Mullani N, Tancredi L, Grant C,
Ivanovic M, Hollister L (1991). Cerebellar metabolic
activation by delta-9-tetrahydro-cannabinol in human
brain : a study with positron emission tomography
and 18F-2-fluoro-2-deoxyglucose. Psychiatry Research 40,
69–78.
Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG (1982).
Action of cannabidiol on the anxiety and other effects
produced by delta 9-THC in normal subjects.
Psychopharmacology (Berlin) 76, 245–250.