Psychopathological and Cognitive Effects of Therapeutic Cannabinoids in Multiple Sclerosis: A Double-Blind, Placebo Controlled, Crossover Study

Abstract

To study possible psychopathological symptoms and cognitive deficits, abuse induction, as well as general tolerability and effects on quality of life, fatigue and motor function in cannabis-naïve patients with multiple sclerosis (MS) treated with a free-dose cannabis plant extract (Sativex).
In an 8-week, randomized, double-blind, placebo-controlled, parallel group crossover trial, 17 cannabis-naïve patients with MS were assessed at baseline and at the end of the cannabis and placebo phases of the trial (each of 3 weeks) by means of Symptom Checklist-90 Revised, Self-rating Anxiety Scale, Multiple Sclerosis Functional Composite (of which 1 dimension is the Paced Auditory Serial Additional Test that was used to evaluate cognition), Visual Analogue Scale on health-related quality of life, Multiple Sclerosis Impact Scale-29, and Fatigue Severity Scale.
Postplacebo versus postcannabinoid scores showed that no significant differences could be detected on all the variables under study. A significant positive correlation was found between Delta-9-tetrahydrocannabinol blood levels and scores at the General Symptomatic Index and at the "interpersonal sensitivity," "aggressive behaviour," and "paranoiac tendencies" subscales of the Symptom Checklist-90 Revised. No serious adverse events, abuse tendencies, or direct withdrawal symptoms were reported. Increased desire for Sativex with secondary depression was reported in 1 subject.
Cannabinoid treatment did not induce psychopathology and did not impair cognition in cannabis-naïve patients with MS. However, the positive correlation between blood levels of Delta-9-tetrahydrocannabinol and psychopathological scores suggests that at dosages higher than those used in therapeutic settings, interpersonal sensitivity, aggressiveness, and paranoiac features might arise, although greater statistical power would be necessary to confirm this finding.

Full text

Psychopathological and Cognitive Effects of Therapeutic
Cannabinoids in Multiple Sclerosis: A Double-Blind, Placebo
Controlled, Crossover Study
Massimiliano Aragona, MD,* Emanuela Onesti, MD,ÞValentina Tomassini, MD,þ
Antonella Conte, MD,þShiva Gupta, MD,§ Francesca Gilio, MD,þPatrizia Pantano, MD,þ
Carlo Pozzilli, PhD,þand Maurizio Inghilleri, PhD, MDþ
Objectives: To study possible psychopathological symptoms and cog-
nitive deficits, abuse induction, as well as general tolerability and effects
on quality of life, fatigue and motor function in cannabis-naBve patients
with multiple sclerosis (MS) treated with a free-dose cannabis plant
extract (Sativex).
Methods: In an 8-week, randomized, double-blind, placebo-controlled,
parallel group crossover trial, 17 cannabis-naBve patients with MS were
assessed at baseline and at the end of the cannabis and placebo phases of
the trial (each of 3 weeks) by means of Symptom ChecklistY90 Revised,
Self-rating Anxiety Scale, Multiple Sclerosis Functional Composite
(of which 1 dimension is the Paced Auditory Serial Additional Test
that was used to evaluate cognition), Visual Analogue Scale on health-
related quality of life, Multiple Sclerosis Impact Scale-29, and Fatigue
Severity Scale.
Results: Postplacebo versus postcannabinoid scores showed that
no significant differences could be detected on all the variables under
study. A significant positive correlation was found between $-9-
tetrahydrocannabinol blood levels and scores at the General Symp-
tomatic Index and at the Binterpersonal sensitivity,[Baggressive
behaviour,[and Bparanoiac tendencies[subscales of the Symptom
ChecklistY90 Revised. No serious adverse events, abuse tendencies,
or direct withdrawal symptoms were reported. Increased desire for
Sativex with secondary depression was reported in 1 subject.
Conclusions: Cannabinoid treatment did not induce psychopa-
thology and did not impair cognition in cannabis-naBve patients with
MS. However, the positive correlation between blood levels of $-9-
tetrahydrocannabinol and psychopathological scores suggests that at
dosages higher than those used in therapeutic settings, interpersonal
sensitivity, aggressiveness, and paranoiac features might arise, although
greater statistical power would be necessary to confirm this finding.
Key Words: cannabinoids, psychosis, anxiety, cognition, multiple
sclerosis
(Clin Neuropharm 2009;32: 41Y47)
Psychopathological symptoms and cognitive impairment are
often reported as possible side effects of recreational
cannabis use. In population surveys, anxiety and psychotic
symptoms are commonly experienced after cannabis use.
1,2
The
psychotomimetic effect of cannabis, which was proved in ex-
perimental studies reporting transient positive and negative
psychotic symptoms together with other psychopathological
phenomena,
3
is greater in subjects predisposed for psychosis
4,5
and probably in adolescent smokers due to a greater vulnera-
bility of the developing brain.
6
On the other hand, cannabis use
has been frequently reported in anxiety disorders
7
; it might
precipitate psychosis,
5,8
and the overall risk of developing
psychotic symptoms has been described as increasing 3-fold in
cannabis users.
6
The acute administration of cannabis was reported to
produce transient effects on several neuropsychological func-
tions (eg, attention, memory, visual-motor coordination, verbal
fluency, and psychomotor speed).
3,9,10
In Bheavy users[(eg,
subjects smoking several joints per day, during periods of
many years), a long-term, mild cognitive impairment was
reported.
11,12
Although no significant cognitive deficits were
reported in frequent but moderate users of cannabis,
13
the
persistent effects of cannabis on cognition remain uncertain.
14
Cannabinoids have recently been suggested for the treat-
ment of neurodegenerative disorders, vascular and inflamma-
tory diseases, cancer, and central pain,
15
and they are currently
suggested for the treatment of spasticity and chronic pain in
multiple sclerosis (MS). In the light of this potential therapeutic
role, studies focusing on psychological and cognitive tolera-
bility of cannabinoids in MS are eagerly awaited.
16
At the
moment, some studies on general tolerability of cannabis treat-
ment in MS are available,
17
whereas, at least in our knowledge,
no specific data have been published on its cognitive and psy-
chopathological tolerability.
Consequently, the aims of this study were (i) to characterize
the effects of a 3-week cannabinoid treatment with a cannabis
plant extract containing $-9-tetrahydrocannabinol ($-9-THC)
and cannabidiol (CBD) in equal proportions on several psycho-
pathological dimensions, including psychotic symptoms and
anxiety, and cognitive performances in cannabis-naBve patients
with MS; (ii) to evaluate the tolerability and possible abuse
induction; and (iii) to study the effects of cannabis on quality of
lifeYrelated dimensions, on fatigue and motor function.
MATERIALS AND METHODS
Subjects
Seventeen patients with MS were recruited from the MS
Outpatient Clinic at BSapienza[University. After obtaining
written informed consent, subjects underwent a baseline
neurological and psychiatric assessment. To be eligible for
inclusion into this study, patients had to fulfill the following
criteria: male or female subjects between 18 and 60 years of
age; right-handed with normal right-hand function; a baseline
Expanded Disability Status Scale
18
score ranging from 3.5 to
ORIGINAL ARTICLE
Clinical Neuropharmacology &Volume 32, Number 1, January/February 2009 41
*Chair of Philosophy of Psychopathology, BSapienza[University; †Division
of Neurology, Neurological Centre of Latium; ‡Department of Neuro-
logical Sciences, BSapienza[University, Rome, Italy; and §Department
of Radiology, Westchester Medical Center, Valhalla, NY.
Address correspondence and reprint requests to Maurizio Inghilleri, PhD,
MD, Dipartimento di Scienze Neurologiche, Viale dell_Universita
`30,
00185 Rome, Italy; E-mail: maurizio.inghilleri@uniroma1.it
Copyright *2009 by Lippincott Williams & Wilkins
DOI: 10.1097/WNF.0b013e3181633497

6.5; a stable disease for at least 30 days before study entry and
nosystemic corticosteroid therapy within 4 weeks of randomi-
zation; significant spasticity in at least 2 muscle groups;
antispastic and immunomodulatory agents (dosage, frequency,
and route of administration) stable, before the study entry, for at
least 1 and 6 months, respectively; no history of epilepsy of
alcohol or substance abuse and no major medical illnesses;
absence of psychiatric disorders or cognitive impairment at first
evaluation; no history of psychiatric disorders; no concomitant
therapy with psychoactive drugs; no female patient who was
pregnant, lactating, or planning pregnancy during the course of
the study; and no previous use of cannabis. This study was
approved by the local Ethical Committee. Patients were in-
formed about the potential for psychosis, anxiety, and panic, and
they gave their informed consent to be included into the trial.
Study Drug
Patients received cannabis-based medicine extract (Sativex,
GW Pharma, UK) presented in a pump action sublingual spray.
Sativex is composed of whole cannabis plant extract, contain-
ing $-9-THC (27 mg/mL) and CBD (25 mg/mL), in ethanol/
propylene glycol (50:50) excipient. Each actuation delivers
100 KL of spray, containing THC 2.7 mg and CBD 2.5 mg.
Placebo had the appearance, smell, and taste of the active
formulation in ethanol/propylene glycol (50:50) excipient but
contained no active components.
Study Design
This 8-week, randomized, double-blind, placebo-controlled,
crossover trial was part of a larger study on functional mag-
netic resonance imaging and electrophysiological correlates
of cannabinoid effect in MS patients experiencing spasticity
(Pozzilli C et al, personal communication).
Patients taking immunomodulatory, antispastic, and/or any
other pharmacological treatment were admitted in the study if
therapy intake was stable for at least 6 and 1 months, respec-
tively, before the study entry and were requested to maintain the
intake of these pharmacological agents at fixed dosage, route,
and time of administration. Trial assessments were scheduled
at fixed times to be performed under standardized identical
conditions (eg, daytime, interval to the last administration of
antispastic, immunomodulatory compounds, and others).
Screening assessment was followed by randomization and
dose introduction. Patients were randomly assigned to 2 counter-
balanced groups starting either with Sativex or with placebo as
the first drug. After 3 weeks, the first treatment was discon-
tinued, and patients entered a washout phase of 2 weeks, before
starting the second treatment phase of 3 weeks. During each
treatment period, all patients had to reach the optimal, individ-
ualized dosage to subjectively relief spasticity. The number of
daily actuations was recorded.
As shown in Figure 1, all patients completed the psycho-
pathological and cognitive measures before starting therapy and
at the end of both Sativex and placebo treatment phases. A
withdrawal was done at the end of each treatment phase to
evaluate the THC and CBD levels in the blood. Patients were
recontacted and asked to estimate their desire for cannabis and
whether they had noted any new medical or psychiatric problem
twice after the end of the study, 2 weeks, and 2 months later,
respectively.
Outcome Measures
At each visit, all patients were asked to complete rating
scales to assess fatigue, disability, psychopathology, cognitive
functioning, and the physical and psychological impact of MS
on quality of life.
Specifically, psychopathological symptoms were assessed
using 2 self-reporting devices: the Symptom ChecklistY90
Revised (SCL-90-R)
19
and the Self-rating Anxiety Scale
(SAS).
20
The SCL-90-R is a 90-item symptom inventory; the
subject rates each item on a 5-point scale of distress, from 0
Bnot-at-all[to 4 Bextremely.[The 90 items are scored and
interpreted in terms of 9 primary symptom dimensions and 1
global severity index of distress named General Symptomatic
Index. The dimensions are labeled as somatization, obsessive-
compulsiveness, interpersonal sensitivity, depression, anxiety,
hostility, phobic anxiety, paranoid ideation, and psychoticism.
The SAS is a 20-item symptom inventory specifically designed
to study anxiety; the subject rates each item on a 4-point scale
of distress, from 1 Bnone or a little of the time[to 4 Bmost or all
of the time.[
Cognitive performances were evaluated using the Paced
Auditory Serial Additional Test (PASAT), 1 of the 3 dimensions
of the Multiple Sclerosis Functional Composite (MSFC).
21
PASAT is a measure of cognitive function that assesses audi-
tory information processing speed and flexibility, as well as
calculation ability. The dependent variable is the sum of cor-
rect answers given by the subject (out of 60 possible). The
other 2dimensions of the MSFC are the Timed 25-Foot Walk
(T25FW), which is a quantitative measure of leg function and
ambulation, and the 9-Hole Peg Test (9HPT), a quantitative
measure of arm and hand function. To calculate the overall
MSFC, scores for each component are converted to zscores
using a specific formula. All these 3 independent clinical
dimensions contribute equally to the overall MSFC score.
Quality of life and physical and psychological impact of
MS from the patients_perspective were studied by means of
3instruments: the Visual Analogue Scale on health-related
quality of life,
22
the Fatigue Severity Scale,
23
and the 29-item
Multiple Sclerosis Impact Scale.
24
Visual Analogue Scale on
health-related quality of life consists of a straight line of a spec-
ified length with verbal descriptors at each end consisting of
short and easily understood phrases that describe the variable
being measured. Fatigue Severity Scale is a 9-item questionnaire
that assesses the effect of fatigue on daily living. Each item is a
FIGURE 1. Study design. 1 = Screening assessment and
randomization; administration of clinical, cognitive, and
psychopathological questionnaires; first-phase treatment
introduction. 2 = First-phase treatment discontinuation;
administration of clinical, cognitive, and psychopathological
questionnaires; first blood withdrawal; assessment of possible side
effects. 3 = Administration of clinical, cognitive, and
psychopathological questionnaires; second-phase treatment
introduction. 4 = Second-phase treatment discontinuation;
administration of clinical, cognitive, and psychopathological
questionnaires; second blood withdrawal; assessment of possible
side effects. 5 = Clinical assessment; evaluation of possible
long-lasting side effects and of possible desire/craving for
cannabinoids. 6 = Clinical assessment; evaluation of possible
long-lasting side-effects and of possible desire/craving for
cannabinoids.
Aragona et al Clinical Neuropharmacology &Volume 32, Number 1, January/February 2009
42 *2009 Lippincott Williams & Wilkins

statement on fatigue that the subject rates from 1 Bcompletely
disagree[to 7 Bcompletely agree.[Patients with a mean score
of 4 or more were defined as suffering from significant fatigue.
The 29-item Multiple Sclerosis Impact Scale is an instrument
measuring the physical (20 items) and psychological (9 items)
impact of MS. The 2 summary scores are generated by sum-
ming individual items and then transformed to a 0 to 100 scale.
High scores indicate worse health.
THC and CBD Plasma Measurement
Tetrahydrocannabinol and CBD levels in the plasma were
measured according to the LC-MS/MS spectrometric method
(Liquid Chromatography with tandem Mass Spectrometer
detection) of Valiveti and Stinchcomb,
25
with slight modifi-
cations. Chromatographic analyses were carried out using a
High-Performance Liquid Chromatography with tandem Mass
Spectrometer detection (HPLC-MS/MS) system. Negative elec-
trospray ionization was used and all analyses were performed
in Multiple Reaction Monitoring (MRM) mode. The transition
were m/z313V245 for THC and CBD. The limit of quantita-
tion was 0.1 ng/mL for $-9-THC and CBD.
Statistical Analysis
We assigned patients to treatment sequence by using an
independent statistician-generated randomization code. Investi-
gators allocated patients consecutively by time of inclusion at
the study site.
9HPT task periods were averaged over the 2 trials for each
hand, averaging together both the dominant and nondominant
hand trials. T25FW trial periods were averaged over the 2 trials.
MSFC scores were calculated using test results from the baseline
visit from all patients. Analyses for MSFC were conducted
without replacing data values as well.
For all variables measured except for MSFC PASAT, 9HPT,
and T25FW, Wilcoxon_s matched pairs signed-rank tests were
used to compare variables measured at the end of each 3-week
treatment period (postplacebo vs post-Sativex) given that all
variables except those listed above are defined by finite scoring
systems that do not fit a normal distribution. For MSFC PASAT,
9HPT, and T25FW, paired ttests were conducted to compare
the variables postplacebo versus post-Sativex levels, given that
these 3 variables are defined by a continuous, normally dis-
tributed time scale.
For correlations with CBD and $-9-THC serum levels, all
dependent variables except for MSFC PASAT, 9HPT, and
T25FW measured during the post-Sativex period were corre-
lated using Spearman rank correlations given the nonparamet-
ric nature of these variables as stated above. For MSFC PASAT,
9HPT, and T25FW values measured during post-Sativex pe-
riods, Pearson correlations were evaluated to correlate with CBD
and $-9-THC serum levels.
All tests are reported with their local Pvalues, thus iden-
tifying differences that would have potential statistical sig-
nificance (PG0.05), if chosen as the primary efficacy criterion.
For the correlation statistics, Bonferroni correction was not
used because the comparisons did not fall within a single joint
family of comparisons by definition.
RESULTS
All the 17 patients who entered the study completed the
trial and were included in the analysis.
Baseline demographic and clinical characteristics are re-
ported in Table 1. Baseline assessment did not reveal significant
cognitive problems. All the included patients had taken
antispastic and immunomodulatory compounds in their clin-
ical history, with generally poor results. During the study,
only 5 patients were taking immunomodulatory compounds
(interferon-beta, copolymer-1, or azatioprine) and 10 were tak-
ing antispastic drugs (baclofen, dantrolene sodium, chlorohyd-
rate tizanidina, or botulinum toxin). All patients maintained the
intake of these pharmacological agents at fixed dosages, route,
and time of administration in relation to the assessment points
of the trial.
The number of daily actuations used was significantly
higher during the placebo than during the Sativex period
(15.16 + 4.51 vs 8.20 + 3.15; t= 5.31, PG0.001).
Postplacebo versus post-Sativex scores are reported in
Table 2. It is shown that neither psychopathological nor
cognitive scores differed between the Sativex and the placebo
period. Although objective measures did not reveal any
cognitive impairment, 11 patients during the Sativex admin-
istration and 2 subjects during the placebo period reported
subjective drowsiness and sense of Bslower-thinking[;1of
the 11 subjects who reported this symptom experienced tran-
sient mental confusion with temporal and spatial disorientation.
Measures of fatigue, leg and arm function, quality of life, and
TABLE 1. Baseline Demographic and Clinical Characteristics
(n = 17)
Characteristics Mean (TSD)
Age (range) 49.8 (T6.64)
Sex (Female/Male) 11:6
Disease duration, yr 20.76 (T8.42)
Disease course 17 SP
EDSS score 6.1 (T0.3)
MSFC (PASAT) 35.76 (T13.22)
MSFC (9HPT) 29.66 (T8.21)
MSFC (T25FW) 26.85 (T14.51)
MSIS-29 (physical items) 53.64 (T11.83)
MSIS-29 (psychological items) 36.54 (T20.51)
FSS 5.61 (T0.97)
VAS QoL 4.29 (T2.08)
SAS 36.38 (T6.42)
SCL-90 GSI 0.63 (T0.28)
SCL-90 Somat 10.61 (T4.17)
SCL-90 Obsess 6.61 (T4.36)
SCL-90 Sens 4.46 (T4.31)
SCL-90 Depr 12.76 (T6.59)
SCL-90 Anx 4.46 (T3.45)
SCL-90 Aggr 2.46 (T1.66)
SCL-90 Phob 4.3 (T3.32)
SCL-90 Para 2.92 (T3.61)
SCL-90 Psychosis 4.23 (T2.42)
SP indicates secondary progressive MS; EDSS, Expanded Disability
Status Scale; MSFC, Multiple Sclerosis Functional Composite; PASAT,
Paced Auditory Serial Additional Test; 9HPT, 9-Hole Peg Test; T25FW,
Timed 25-Foot Walk; MSIS-29, Multiple Sclerosis Impact Scale; FSS,
Fatigue Severity Scale; VAS QoL, Visual Analogue Scale for Quality of
Life; SAS, Self Rating Anxiety Scale; SCL-90, Symptom Checklist-90
Revised; GSI, General Symptomatic Index; Somat, somatized anxiety;
Obsess, obsessive-compulsive features; Sens, sensitivity; Depr, depres-
sion; Anx, anxiety; Aggr, aggressive behaviour; Phob, phobic anxiety;
Para, paranoiac tendencies; Psychosis, psychotic symptoms.
Clinical Neuropharmacology &Volume 32, Number 1, January/February 2009 Effects of Therapeutic Cannabinoids in MS
*2009 Lippincott Williams & Wilkins 43

physical and psychological impairment due to MS did not
differ between the 2 treatment periods.
Correlation between clinical scores and plasma levels of
CBD and $-9-THC are reported in Table 3. A significant
positive correlation was found between the $-9-THC blood
levels and scores at the General Symptomatic Index and at
the BInterpersonal sensitivity,[BAggressive behaviour,[and
BParanoiac tendencies[of the SCL-90-R. No correlations were
found between the other major component of Sativex (CBD)
and the studied variables.
No serious adverse events (hospitalization, death) occurred
during the study. Side effects reported during the placebo
and Sativex phases were generally mild (Table 4). During the
Sativex administration, 1 patient required treatment in the
emergency department because of transient mental confusion
with temporal and spatial disorientation, tachycardia, increased
blood pressure, and mydriasis. Symptoms recovered in few
hours without requiring hospitalization, and the patient was able
to continue the study without further problems.
All patients were recontacted twice after the end of the
study, 2 weeks, and 2 months later, respectively. At the 2-week
but not at the 2-month visit, one 56-year-old lady reported
intense desire to reintroduce Sativex after withdrawal and
developed depressive symptoms (successfully treated with
sertraline 50 mg/die), probably related to the impossibility to
keep taking Sativex. None of the other patients reported
craving for cannabis, dependence, and withdrawal effects, as
well as any new medical or psychiatric problems.
DISCUSSION
The primary aim of this study was to explore the onset
of psychopathological symptoms and cognitive deficits in
cannabis-naBve patients with MS treated with a cannabis plant
extract (Sativex) for relieving their spasticity. General toler-
ability, possible abuse induction, and the effects of canna-
binoids on quality of life, fatigue, and motor function were
also studied.
Our study evaluated the effects of cannabinoids on
cognition by means of PASAT, which is widely used to test
sustained attention, divided attention, concentration, and infor-
mation processing speed in MS patients.
26
We found no
significant differences between Sativex and placebo in the
PASAT scores, although we found a higher frequency of
subjective drowsiness and sense of Bslower-thinking[in the
cannabinoid phase of the study. Tacking into consideration the
TABLE 2. Postplacebo Versus Post-Sativex Clinical Scales Scores (n = 17)
Scales Postplacebo (mean TSD) Post-Sativex (mean TSD) Statistic
MSFC (PASAT) 43.0 (T11.8) 42.4 (T13.6) t= 0.28, P= 0.79
MSFC (9HPT) 28.4 (T8.66) 28.75 (T9.37) t=j0.33, P= 0.75
MSFC (T25FW) 26.2 (T16.9) 25.1 (T15.1) t = 0.51, P= 0.62
MSIS-29 (physical items) 63.0 (T16.8) 62.3 (T13.1) z= 0.57, P= 0.57
MSIS-29 (psychological items) 47.8 (T17.8) 46.3 (T15.9) z=j0.47, P= 0.64
FSS 5.58 (T1.50) 5.89 (T0.93) z=j0.16, P= 0.88
VAS QoL 3.65 (T2.29) 4.00 (T2.00) z= 1.01, P= 0.31
SAS 37.7 (T8.67) 35.7 (T7.69) z=j1.26, P= 0.21
SCL-90 GSI 0.76 (T0.43) 0.77 (T0.43) z=j0.12, P= 0.91
SCL-90 Somat 12.11 (T7.25) 12.94 (T5.62) z= 0.60, P= 0.55
SCL-90 Obsess 7.94 (T6.2) 8.11 (T5.39) z=j0.19, P= 0.85
SCL-90 Sens 4.52 (T4.62) 4.76 (T4.57) z=j0.03, P= 0.98
SCL-90 Depr 16 (T9.13) 15.58 (T8.65) z=j0.45, P= 0.65
SCL-90 Anx 5.41 (T4.78) 6.05 (T5.65) z= 0.65, P= 0.52
SCL-90 Aggr 3.11 (T3.01) 2.29 (T1.89) z=j0.92, P= 0.36
SCL-90 Phob 6.11 (T4.97) 6.64 (T4.85) z= 0.25, P= 0.81
SCL-90 Para 2.88 (T3.46) 3.17 (T3.74) z= 0.36, P= 0.72
SCL-90 Psychosis 5 (T3.8) 4.23 (T3.63) z=j0.46, P= 0.65
Refer to Table 1 for the explanations of abbreviations.
TABLE 3. Relationship Between Plasma Levels of CBME
Components and Clinical Scores
Indexes CBD, ng/mL $-9-THC, ng/mL
MSFC (PASAT) j0.23 (P= 0.37) j0.17 (P= 0.52)
MSFC (9HPT) 0.06 (P= 0.82) j0.01 (P= 0.97)
MSFC (T25FW) 0.07 (P= 0.80) 0.26 (P= 0.33)
MSIS-29 (physical items) 0.14 (P= 0.59) 0.34 (P= 0.19)
MSIS-29 (psychological
items)
0.11 (P= 0.68) 0.17 (P= 0.51)
FSS 0.14 (P= 0.60) 0.24 (P= 0.35)
VAS QoL 0.20 (P= 0.44) j0.01 (P= 0.96)
SAS j0.02 (P= 0.93) 0.19 (P= 0.47)
SCL-90 GSI 0.17 (P= 0.52) 0.52 (P= 0.03)
SCL-90 Somat 0.19 (P= 0.47) 0.46 (P= 0.06)
SCL-90 Obsess 0.23 (P= 0.37) 0.43 (P= 0.09)
SCL-90 Sens 0.42 (P= 0.09) 0.67 (PG0.01)
SCL-90 Depr 0.03 (P= 0.91) 0.36 (P= 0.16)
SCL-90 Anx 0.19 (P= 0.46) 0.44 (P= 0.07)
SCL-90 Aggr 0.30 (P= 0.24) 0.57 (P= 0.02)
SCL-90 Phob j0.19 (P= 0.47) 0.06 (P= 0.81)
SCL-90 Para 0.27 (P= 0.30) 0.59 (P= 0.01)
SCL-90 Psychosis j0.05 (P= 0.86) 0.29 (P= 0.25)
Refer to Table 1 for the explanations of abbreviations.
Aragona et al Clinical Neuropharmacology &Volume 32, Number 1, January/February 2009
44 *2009 Lippincott Williams & Wilkins

high sensitivity of PASAT for revealing cognitive deficits, we
are prone to interpret this finding as of no significant impact
on cognition in our cohort. Although a previous study reported
an improvement on PASAT performances during a period of
2 weeks,
27
our results are in accordance with a 4-week study,
which did not find any difference compared with placebo.
28
Our
findings support the hypothesis that cannabinoids taken as a
treatment for MS symptoms do not affect cognition, at least in
the short term. Note that research on long-term recreational
cannabis users (mean length of regular use 910.3 years) showed
that slower cognitive processing rates in PASAT performances
are more common among long-term rather than short-term
users,
11
suggesting that although cognitively safe, a note of
caution is needed in the long-term administration. Another
aspect to be considered as of potential impact on cognition is
the dosage. Our findings suggest that in the range of thera-
peutic dosages (mean daily puffs 8.20 + 3.15, approximately
corresponding to 22 mg of $-9-THC), cannabinoids do not
significantly affect cognition, and this is in accordance with re-
sults from a study reporting no significant cognitive deficits in
frequent but moderate users of cannabis.
13
Although we did not
find any significant correlation between $-9-THC and CBD
plasma levels and PASAT scores at the end of the Sativex
treatment, which suggests that at these moderate dosages, there
is no dose effect on cognition; cognitive tolerability at higher
dosages cannot be predicted on the basis of our data because the
study was not designed to detect such an effect.
The other major element under study was the effect of
cannabinoid treatment on psychopathology. Psychopathological
symptoms were often found in recreational cannabis users,
1,2
and cannabis use had been frequently reported in anxiety
7
and
psychotic disorders.
29
Our finding that psychopathological
scores did not differ between cannabinoids and placebo ap-
parently contrasts with the report of transient Bpositive[and
Bnegative[psychotic symptoms, perceptual alterations, eupho-
ria, and anxiety in healthy volunteers.
3
However, in that study,
the authors evaluated the acute effect of 2 fixed dosages of
intravenously injected $-9-THC in subjects who had previously
smoked cannabis, whereas in our study patients were cannabis
naBve, they took a free-dosage oral-administered cannabis
extract that also contains CBD, and the effects on psychopa-
thology were evaluated after 3 weeks of treatment. These
differences in the study design make a direct comparison of
these 2 studies difficult. To our knowledge, there was no pre-
vious study specifically focused on the evaluation of psycho-
pathological phenomena in MS patients. However, a few
psychiatric disturbances were reported among other side ef-
fects. In particular, euphoria was the most frequently reported
symptom, ranging from 3.2% to 26.6% of the treated
subjects,
30Y34
whereas other phenomena were found sporad-
ically (hyperactivity,
30
dissociation,
32
feeling Bparanoid,[and
hallucinations
34
).
In our study, euphoria was reported only by 1 patient in the
treatment group (5.8%), and its rate was comparable to that
reported in the placebo group. This finding does not differ
considerably from previous studies. However, neither our nor
previous studies used standardized questionnaires to measure
euphoria, and further studies with more objective and sensitive
measures are thus required.
Having found no differences in the SCL-90 and SAS
scores, our study suggests that in the short term, Sativex ad-
ministered to cannabis-naBve patients for therapeutic purposes
does not increase the risk of main psychopathological symp-
toms. However, we found a moderate but significant positive
correlation between the plasma levels of $-9-THC (the principal
active ingredient of cannabis) and some of the SCL-90 scales.
This suggests that although at the low therapeutic levels used in
this study, cannabinoids do not induce the onset of psycho-
pathological symptoms, at higher dosages, the risk of worsen-
ing interpersonal sensitivity (eg, the tendency of experiencing
feeling of inadequacy in the relationship with others), aggres-
siveness, and paranoiac thoughts cannot be excluded. This
possibility, together with previous reports of sporadic symptoms
like feeling Bparanoid[and hallucinations
34
in patients with MS
treated with cannabinoids, suggests that a careful evaluation of
history of psychosis should be done in all patients addressed
to cannabinoids treatment. Finally, the correlation between
$-9-THC and aggressiveness found in our study contrasts
with a previous research that excluded aggressive feelings in
50 MS patients treated with cannabis-derived drug.
31
Consid-
ering that the relationship between cannabis use and aggres-
siveness is still debated,
35,36
future studies on larger samples
of patients taking cannabinoids as a therapy are needed.
Another aim of the study was the evaluation of the impact
of cannabinoid treatment on some physical problems related to
MS (eg, reduced leg and arm function, fatigue), as well as on
quality of life and physical and psychological impairment. Our
findings suggest that in the short term, none of these variables
changed significantly. These results are in line with current
literature showing that administered for a 2- to 4-week treat-
ment period, cannabis does not significantly improve arms and
legs mobility
27
and fatigue,
37
whereas they differ from those of
Killestein and colleagues,
37
who found a significant worsening
in the total MSFC and 9HPT scores. Our findings also confirm
previous studies showing how cannabis use did not covary with
general scores on quality of life,
37Y39
whereas a positive slight
trend benefit was found on legs motility (T25FW) in long-term
studies.
39
More promising results have been previously reported
with subjective reports: cannabis was reported to relief fatigue
and dysfunction of walking and balance and to improve emo-
tional dysfunction.
40
However, the fact that findings with objec-
tive measurements are mostly conflicting suggests that studies
on larger cohorts are needed to evaluate the impact of canna-
binoid treatment on these variables.
Another issue to be evaluated was the general tolerability.
All subjects included in the study completed the 3 weeks of
trial, and no serious adverse events occurred during the study.
Side effects were slightly more frequent during active treatment
than during placebo. No clinically relevant changes were ob-
served in physical examinations, with the exception of transient
TABLE 4. Side Effects Reported During the 2 Treatment
Periods
Sativex Phase
(n = 17)
Placebo
Phase
(n = 17)
Mouth dryness or burning 5 0
Depression 1 1
Fatigue 6 3
Euphoria 1 1
Headache 3 3
Nausea and vomiting 2 1
Drowsiness and/or slower thinking 11 2
Dizziness and vertigo 8 0
Tremor 1 0
Lower limb weakness 3 0
Clinical Neuropharmacology &Volume 32, Number 1, January/February 2009 Effects of Therapeutic Cannabinoids in MS
*2009 Lippincott Williams & Wilkins 45

increased blood pressure in 1 patient. No changes were found in
hematology or biochemistry parameters. Finally, although some
possible effects of Sativex are similar to those reported with
antispastics (eg, drowsiness, mouth dryness, dizziness, vertigo,
and fatigue) and consequently could have been responsible of
a summatory effect, this was not found in our study.
Taken together, these findings suggest that Sativex was
well tolerated. Long-term studies confirm the good tolerability
profile of cannabinoids for therapeutic use.
17,39
Finally, a crucial point that is usually a matter of concern
when the therapeutic use of cannabinoids is proposed is the
possibility that cannabis may induce dependence and abuse. At
this regard, our study was in a good position to observe these
possible phenomena, being on cannabis-naBve subjects and
allowing for free dosages. Interestingly, none of the patients
abused the use of Sativex during the treatment phase, the mean
daily dosage being quite low (23Y25 mg) and the number of
daily actuations being significantly higher in the placebo than
in the cannabis phase (suggesting that when patients had
reached the therapeutic daily dosage, they spontaneously inter-
rupted the dosage augmentation of Sativex without craving
induction, whereas in the case of placebo, they continued to
increase the number of daily actuations trying to reach active
effects). Different motivations of the user (recreational vs
therapeutic) might partially explain our findings that cannabi-
noid treatment in MS does not induce tolerability and dosage
increase. However, in the case of other psychoactive sub-
stances (eg, benzodiazepines, tramadol, and zolpidem), some
tendency to induce tolerability is also found in therapeutic
settings with consequent increased risk of dosage augmenta-
tion and dependence,
41Y44
suggesting that our findings may be
not com pletely due to the above-mentioned factor. A related
but different factor is that in recreational use of cannabis, the
route of administration (inhalation) usually maximizes the
Cmax and shortens the Tmax in order to increase the psy-
choactive effect, whereas Sativex (sublingual/oromucosal
administration) reaches a low Cmax and has a fairly long
Tmax.
45
Different pharmacokinetics might be responsible for
less gratifying subjective experiences due to the delayed
psychoactive effect of Sativex, thus explaining (at least in
part) why patients were not driven to increase the dosage.
Furthermore, direct withdrawal symptoms were not
reported, as expected.
17
However, some days after the end of
the trial, 1 patient experienced desire to reintroduce Sativex.
Whether this desire was driven by a perceived effective treat-
ment (she explained it as a reaction to the impossibility to
continue the treatment that she considered very helpful, and in
effect, she presented a significant leg mobility improvement,
with a 57% drop of T25FW scores) or whether it represented
a withdrawal symptom cannot be addressed by a single case.
Two months after the termination of the study, all the subjects
included in the study had not increased desire to be treated
again with Sativex and did not present any new medical or
psychiatric problem. However, long-term studies are needed in
larger samples to evaluate the possible dependence induced
by cannabinoid therapy.
There are some limitations in our study, which need to
be considered in the interpretation of our findings. The sample
size was quite small to address completely all the questions
arising from a study evaluating the psychopathological impact
of cannabinoids. However, the power of the study was though
to evaluate the effect of Sativex on physical symptoms (eg,
spasticity) and its electrophysiological and imaging counter-
part. The study duration of treatment was relatively short,
again aimed to provide pilot information about the study drug.
As a consequence, direct generalization of these data to larger
clinical populations is not viable, and more focused studies are
needed to investigate the safety of cannabinoids on cognitive
and psychopathological domains in patients with MS. Cog-
nitive performances were studied with 1 test (PASAT), and
no other information about cognition in this cohort was avail-
able. More detailed test batteries should be included in future
studies. Finally, the oromucosal route of administration of
cannabis might have induced unpredictable interindividual and
intraindividual variability in plasma $-9-THC levels, not
detectable with blood tests.
In conclusion, cannabinoids prescribed for therapeutic
reasons to cannabis-naBve patients with MS did not induce
onset of psychotic or anxiety symptoms and did not impair
cognition. Safety and tolerability were generally good, drug
tolerance and dose increasing were not reported during the
trial, and desire for Sativex or abuse was not present at follow-
up. However, the positive correlation between blood levels
of $-9-THC and psychopathological scores suggests that at
dosages higher than those used in therapeutic settings, inter-
personal sensitivity, aggressiveness, and paranoiac features
might arise. Finally, the effects of cannabinoids on quality of
life, fatigue, and motor function of MS patients were non-
significant, suggesting that the effective impact of cannabi-
noids in these patients as well as the most proper target
symptoms remain to be better ascertained.
ACKNOWLEDGMENTS
Sativex was kindly provided by GW Pharma Ltd, Salisbury,
England. The grant has been supported as the Project of
University Research (ex-quota 60%)Vyear 2004Vby the
University BSapienza[of Rome.
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*2009 Lippincott Williams & Wilkins 47