Cannabis (Cannabis sativa)
Does olanzapine inhibit the psychomimetic effects of Δ9-tetrahydrocannabinol?
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Δ9-Tetrahydrocannabinol (THC) produces transient psychomimetic effects in healthy volunteers, constituting a pharmacological model for psychosis. The dopaminergic antagonist haloperidol has previously been shown to reduce these effects. This placebo-controlled, cross-over study in 49 healthy, male, mild cannabis users aimed to further explore this model by examining the effect of a single oral dose of olanzapine (with dopaminergic, serotonergic, adrenergic, muscarinergic and histaminergic properties) or two oral doses of diphenhydramine (histamine antagonist) on the effects of intrapulmonarily administered THC. Transient psychomimetic symptoms were seen after THC administration, as measured on the positive and negative syndrome scale (20.6% increase on positive subscale, p<0.001) and the visual analogue scale for psychedelic effects (increase of 10.7 mm on feeling high). Following the combination of THC and olanzapine, the positive subscale increased by only 13.7% and feeling high by only 8.7 mm. This reduction of THC effects on the positive subscale failed to reach statistical significance (p=0.066). However, one-third of the subjects did not show an increase in psychomimetic symptoms after THC alone. Within responders, olanzapine reduced the effects of THC on the positive subscale (p=0.005). Other outcome measures included pharmacokinetics, eye movements, postural stability, pupil/iris ratio, and serum concentrations of cortisol and prolactin.
1 . THC PK (id=NPDI-xU8LWA)
In Vivo Pharmacokinetics Study
As per Table 3.
Two-compartment linear model with zero-order absorption.
Diphenhydramine was used a positive control.
Results
Table 3. Estimated values
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Double-blind
Placebo-controlled
Randomized crossover
Multiple dosing
Healthy volunteers
Males
33
Healthy male subjects aged between 18 and 45 years (inclusive) and with a body mass index between 18 and 30 kg/m2 (inclusive). [...] More specific a personal history of attention deficit disorder without the use of medication was allowed; a per- sonal history of depression or psychotic symptoms was not allowed; a family history of psychosis in first or second-degree relatives and bipolar disorder in first-degree relatives was not allowed. The use of medication and agents (including recreation- ally used drugs such as cannabis) that were expected to affect CNS performance or the pharmacokinetics of the study medica- tion was not allowed during the study period. Subjects were tested for the use of recreational drugs (in urine) and alcohol (in breath) before each study day. Following the medical screening, subjects were trained for the study procedures.
0, 1, 2, 3, 4 h
Drug or Natural Product Administration
Inhalation
Nebulizer
2, 4, 6 mg
90 min intervals
Not specificied
Used VolcanoTM vaporizer
Pharmacodynamics (PD) & Adverse Events
"Psychomimetic symptoms were measured using the PANSS, as described by Kay et al. (1987). [...] To determine other potentially confounding CNS effects, an extensive test battery (NeuroCart) was used, which included VAS, eye movements, postural stability, pupil/iris ratio, Stroop colour word test and the visual verbal learning test (VVLT), extended with measurements of serum cortisol and prolactin. All these measurements were performed repeatedly throughout the study day, including two baseline measurements. The timing of meas- urements was very similar to the scheme used by Liem-Moolenaar et al."
All of the aforementioned are described in further detail in the Outcome Measures section in the text.
Eye disorders
35600000
Psychiatric disorders
36900000
"Transient psychomimetic symptoms were seen after THC administration, as measured on the positive and negative syndrome scale (20.6% increase on positive subscale, p<0.001) and the visual analogue scale for psychedelic effects (increase of 10.7 mm on feeling high). Following the combination of THC and olanzapine, the positive subscale increased by only 13.7% and feeling high by only 8.7 mm. This reduction of THC effects on the positive subscale failed to reach statistical significance (p=0.066). However, one-third of the subjects did not show an increase in psychomimetic symptoms after THC alone. Within responders, olanzapine reduced the effects of THC on the positive subscale (p=0.005). Other outcome measures included pharmacokinetics, eye movements, postural stability, pupil/iris ratio, and serum concentrations of cortisol and prolactin."
Further information can be be found under the Results section of the text.