Serotonin, Hallucinations & Psychosis

Serotonin, as every newspaper reader knows, is the brain's "feel good chemical". Of course, it's a little bit more complicated than that. A lot more complicated, in fact. But even amongst scientists who are aware of the complexity of serotonin pharmacology, the functions of serotonin are still generally thought of in the context of mood and emotion.
What everyone tends to forget is that serotonin has a wild side. There's a long line of research, stretching back to the 40s, on the role of serotonin in perception and hallucinations.

It all started on Bicycle Day - the 1943 day that Albert Hofmann first experienced the psychedelic effects of LSD ("acid") while riding his bike home from the lab where he first synthesized the drug. Serotonin was discovered in 1948. It was soon noticed that the chemical structure of LSD bears a striking similarity to serotonin - as does psilocybin, the major psychoactive ingredient in "magic mushrooms":You don't need to be a chemist to appreciate the resemblance. So it would be a very reasonable assumption that hallucinogenic drugs work by interfering with the brain's serotonin pathways, and therefore that the serotonin system is somehow involved in regulating thought and perception. Somehow, LSD inteferes with the serotonin system in the brain to cause profoundly altered states of conciousness. That's pretty important.That's also the easy bit. What's been difficult has been working out what hallucinogens actually do in the brain specifically, and how this produces their psychoactive effects. Trends in Pharmacological Sciences has a nice review article on this. To cut a long story short, we still don't know how LSD works, although since research has mostly dried up since the 1970s (everyone's studying happy pills now) this isn't all that surprising.

What has emerged is that LSD and similar compounds all activate the 5HT2A receptor. Interestingly, so do drugs which are chemically rather different, but with similar hallucinogenic effects, such as mescaline, favored by Native Americans and Matrix fans alike. The more potent a drug is at activating the receptor, the less of it you need to take to trip out.

So, does this mean that 5HT2A = hallucinogenic effects? The problem with this nice simple theory is lisuride, a potent 5HT2A agonist with no hallucinogenic effects at all. This troublesome result might not disprove the 5HT2A theory, however, in the light of a 2007 experiment finding that LSD has different effects on target cells from lisuride, despite them both binding to the same receptor. Presumably LSD and lisuride do subtly different things to the same receptors (read the paper for a more detailed account).

There's loads more to be said about hallucinogen pharmacology, and I'll be covering some of it in the future. What's interesting - and frustrating - is how few psychopharmacologists are aware of the field. A lot of hallucinogen research is really groundbreaking; the finding that two different agonists of the same receptor can have quite different effects is a really important one. It's certainly a humbling result. After Hallucinogens Recruit Specific Cortical 5-HT2A Receptor-Mediated Signaling Pathways to Affect Behavior, it's impossible not to get to wondering whether other receptors in the brain might have equally complex lives. Hallucinogen research underlines how imperfect our current understanding of the brain is. Plus, hallucinogens are really a lot sexier than antidepressants. Given all of which, it's a shame so few scientists are studying them. Acid - it's not just for ageing hippies.

Link Erowid.org has made available Hofmann's personal archive of over 4,000 papers relating to LSD. A dream come true if that kind of stuff floats your boat & well worth a browse for historical interest.

M GEYER, F VOLLENWEIDER (2008). Serotonin research: contributions to understanding psychoses Trends in Pharmacological Sciences, 29 (9), 445-453 DOI: 10.1016/j.tips.2008.06.006

González-Maeso, J., Weisstaub, N., Zhou, M., Chan, P., Ivic, L., Ang, R., Lira, A., Bradley-Moore, M., Ge, Y., & Zhou, Q. (2007). Hallucinogens Recruit Specific Cortical 5-HT2A Receptor-Mediated Signaling Pathways to Affect Behavior Neuron, 53 (3), 439-452 DOI: 10.1016/j.neuron.2007.01.008