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Friday, February 12, 2010

Dope, Dope, Dopamine

When you smoke pot, you get stoned.
Simple. But it's not really, because stoned can involve many different effects, depending upon the user's mental state, the situation, the variety and strength of the marijuana, and so forth. It can be pleasurable, or unpleasant. It can lead to relaxed contentment, or anxiety and panic. And it can feature hallucinations and alterations of thinking, some of which resemble psychotic symptoms.

In Central nervous system effects of haloperidol on THC in healthy male volunteers, Liem-Moolenaar et al tested whether an antipsychotic drug would modify the psychoactive effects of Δ9-THC, the main active ingredient in marijuana. They took healthy male volunteers, who had moderate experience of smoking marijuana, and gave them inhaled THC. They were pretreated with 3 mg haloperidol, or placebo.

They found that haloperidol
reduced the "psychosis-like" aspects of the marijuana intoxication. However, it didn't reverse the effects of THC of cognitive performance, the sedative effects, or the user's feelings of "being high".

This makes sense, if you agree with the theory that the psychosis-like effects of THC are related to
dopamine. Like all antipsychotics, haloperidol blocks dopamine D2 receptors, and increased dopamine transmission has long been implicated in psychosis; some studies have found that THC causes increased dopamine release in humans (although others have not.)

Heavy marijuana use probably raises the risk of psychotic illnesses, like schizophrenia, although this is still a bit controversial, but it's accepted that some people do experience psychotic-type symptoms while stoned. So Liem-Moolenaar et al's conclusion that "psychotic-like effects induced by THC are mediated by dopaminergic systems" while the other aspects of being stoned are mediated by other brain systems, is not unreasonable, and this study is a nice example of the 'pharmacological dissection' of drug effects.

Still, like most papers of this kind, this leaves me wanting to know more about the subjective effects experienced by the volunteers. What did it feel like to get stoned on haloperidol? The paper tells us that
THC caused a significant increase of 2.5 points in positive PANSS, which was significantly reduced by 1.1 points after pre-treatment with haloperidol... Haloperidol completely reversed THC-induced increases in ‘delusions’ and ‘conceptual disorganization’ and almost halved the increase in ‘hallucinatory behaviour’. Although not statistically significant, haloperidol seemed to increase the items ‘conceptual disorganization’, ‘suspiciousness/persecution’ and ‘hostility’ compared with placebo.
The PANSS being a scale used to rate someone's "psychotic symptoms". On the other hand haloperidol had no significant effect on the users' self-rated Visual Analogue Scales (VAS) scores for things like "altered external perception" and "feeling high".

But surely the haloperidol must have changed what it felt like in some way. It must have changed how people thought, felt, perceived, heard, and so forth. These kinds of rating scales are useful for doing statistics with, but they can no more capture the full depth of human experience than a score out of 5 stars substitutes for a full Roger Ebert movie review.

This matters, because it's not clear whether haloperidol really reduced "psychosis-like experiences", or whether it just sedated people to the extent that they were less likely to talk about them. In other words, its not clear whether the scores on the rating scales changed in "specific" or a "non-specific" way. This is no criticism of Liem-Moolenaar, though, because it's a general problem in psychopharmacology. For example, a sleeping pill could reduce your score on most depression rating scales, even if it had no effect on your mood, because insomnia is a symptom of depression.

There are various ways to try to work around these issues, but ultimately I suspect that there's no substitute for personal experience, with direct observation of other people taking the drugs coming second, and rating scales a distant third. Of course, direct observation is unsystematic, and prone to bias, and few would say it was practical for psychopharmacologists to go around drugging themselves and each other... but life is more than a series of numbers.

Link: On Being Stoned (1971) by Charles Tart is a classic book which used a very detailed questionnaire to investigate what it's like to be stoned, although the methodology was hardly rigorous.

ResearchBlogging.orgLiem-Moolenaar, M., Te Beek, E., de Kam, M., Franson, K., Kahn, R., Hijman, R., Touw, D., & van Gerven, J. (2010). Central nervous system effects of haloperidol on THC in healthy male volunteers Journal of Psychopharmacology DOI: 10.1177/0269881109358200

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