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

Aragona, Massimiliano MD*; Onesti, Emanuela MD; Tomassini, Valentina MD; Conte, Antonella MD; Gupta, Shiva MD§; Gilio, Francesca MD; Pantano, Patrizia MD; Pozzilli, Carlo PhD; Inghilleri, Maurizio PhD, MD

doi: 10.1097/WNF.0b013e3181633497
Original Articles

Objectives: 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).

Methods: 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.

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 Δ-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.

Conclusions: 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 Δ-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.

*Chair of Philosophy of Psychopathology, "Sapienza" University; †Division of Neurology, Neurological Centre of Latium; ‡Department of Neurological Sciences, "Sapienza" 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'Università 30, 00185 Rome, Italy; E-mail:

© 2009 Lippincott Williams & Wilkins, Inc.