The New Janus?


Do we really have another antipsychotic in the offing, one with a completely different mechanism than existing agents? Here: existing evidence regarding the effects of cannabidiol.

THC is pro-psychotic, but is cannabidiol antipsychotic? Do we really have another antipsychotic in the offing, one with a completely different mechanism than existing agents?

Oregon’s legalization of marijuana, enacted by a statewide referendum, is just now going into effect (July 2015). Ironically, recent case-control data have increased the certainty that cannabis use is associated with psychosis. The risk of individuals having a psychotic disorder showed a roughly 3-times increase in users of high potency cannabis compared with those who never used cannabis.1 “Skunk-like” cannabis has high concentrations of Δ-9-tetrahydrocannabinol (THC), compared with hash-type (resin) marijuana.2

Into this changing landscape of marijuana use, which has raised realistic alarm about preventable psychosis in youth, comes new evidence for potential benefits from another marijuana component, cannabidiol (CBD). In a remarkably thorough review of existing evidence regarding the effects of cannabidiol, Drs Iseger and Bossong3 examine:

1. The impact of the TSH/CBD ratio in the marijuana used on its pro-psychotic effects (8 studies)

2. Effects of CBD on healthy volunteers, who were also given THC (7 studies)

3. Neuroimaging after CBD in healthy volunteers (9 studies)

4. Effects of CBD in patients with psychosis (5 studies)

All of the findings are of interest, as is the authors’ review of the brain’s endocannabinoid system. But the use of CBD as an antipsychotic is of particular interest, of course. Do we really have another antipsychotic in the offing, one with a completely different mechanism than existing agents?

Unfortunately, it is too early to raise significant hopes for a new tool. Of the 5 studies of CBD in patients with psychosis, 3 are case reports or small cases series. The first dates back to 1995: a 19-year-old improved on CBD after not improving on haloperidol. But in a follow-up study from the same group, treatment-resistant schizophrenia in 3 patients was treated using CBD for 4 weeks and only one of the 3 showed (limited) improvements on the Brief Psychiatric Rating Scale (BPRS).

However, one of the studies was in patients with Parkinson’s disease who were experiencing psychosis (brilliant idea, no?). In that study, significant BPRS reductions were found, with no adverse effects. In particular, there was no worsening of motor control, the routine problem with conventional antipsychotics.

Finally, there was a small randomized trial which I am embarrassed to admit I had never heard of, given the findings: 40 patients with schizophrenia were randomized to CBD or amisulpride. Improvements were significant in BPRS and also the PANSS (Positive and Negative Syndrome Scale). Here’s the kicker: improvements were equal in both groups, but the CBD group had significantly smaller changes in extrapyramidal symptoms, weight gain, and prolactin levels.4 So maybe there is hope?


Dr Phelps is Director of the Mood Disorders Program at Samaritan Mental Health in Corvallis, Ore. He is the Bipolar Disorder Section Editor for Psychiatric Times. [full bio]


1. Di Forti M, Marconi A, Carra E, et al. Proportion of patients in south London with first-episode psychosis attributable to use of high potency cannabis: a case-control study. Lancet Psychiatry. 2015;2:233-238. [pdf:]
2. Freeman T. Potent questions about cannabis and mental health. Lancet Psychiatry. 2015;2:195-196.
3. Iseger TA, Bossong MG. A systematic review of the antipsychotic properties of cannabidiol in humans. Schizophr Res. 2015;162:153-161.
4. Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012;2:e94. Accessed July 1, 2015.

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