Thursday, 26 March 2009

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.

ResearchBlogging.orgM 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

13 comments:

pj said...

I'm a little unconvinced that they rule out actions at other receptors - for instance they claim that there is no additional signalling at the 5-HT1A receptor because in 5-HT1A knockouts they don't find a significant effect of genotype on the behavioral response to either R-lisuride or LSD - I think their behavioural data is unimpressive in this regard - and they don't look at any of the markers of downstream signalling which would be what I'd be interested in.

Neuroskeptic said...

The behavioural data being Figure 5C I assume? - that looks kosher to me. Although it would be nice to have some molecular data to go along with the behaviour, to be sure.

pj said...

Well - although they list results of their behavioural measure (head twitch) in Fig 1A if you look at their supplementary material you can see they selected their behavioural measure of 'hallucinogenic' 5-HT2A agonists from a panel of six - and the data is very very messy (some behaviours are affected by some, but not all the hallucinogens but appear to be prevented in 5-HT2A knockouts; others are completely non-discriminatory and unaffected by 5-HT2A knockouts). Note that there was no attempt at dose finding in this section of the study so we have no idea if they just used low doses of the non-hallucinogenic drugs - this is important because the responses vary widely between different hallucinogenic drugs and there appears to be a dose effect in DOI.

Secondly, if you look at figure 5C where they compare the 5-HT1A knockouts to the wildtypes on head twitch we can see that there is in fact a trend towards reduced effect in the knockouts.

I would regard their behavioural findings as highly speculative - first they have asserted on the basis of very little evidence that head twitch is a defining and discriminatory measure of whether a drug is a hallucinogenic or non-hallucinogenic compound. Even if you accept that 5-HT1A knockouts don't differ in their head twitch response to LSD that tells us nothing about whether the differential expression findings are due to activity at 5-HT1A since they aren't really testing that question - even if action at 5-Ht1A receptors doesn't explain why the non-hallucinogenic agonists are non-hallucinogenic, and even if you accept that the head twitch assay is a way to test this (by finding that head twitch doesn't increase in 5-HT1A knockout mice) this tells us nothing about whether the downstream gene expression differences between hallucinogenic and non-hallucinogenic drugs are due to 5-HT1A activity - to test that you would need to actually look at downstream activity in the 5-HT1A knockout mice - the behavioural phenotype tells us sweet FA on this question.*

So, in summary, they have no by any stretch of the imagination established that any of these downstream gene expression differences between hallucinogenic and non-hallucinogenic 5-HT2A agonists are due to differential signalling at the 5-HT2A receptor. All they've demonstrated is that there are different expression pathways activated by the two drug classes.

Sorry for banging on about this, but it is an interesting claim that two drugs with the same agonist action initiate different downstream signalling, and I think it needs much more robust evidence than this study which is purely speculation as far as that substantive question is concerned.

* And, as always in science, if someone does something odd to answer an obvious question, and doesn't do the obvious experiment to answer the obvious question, you begin to wonder why - perhaps they did do the experiment and it didn't show what they wanted?

Neuroskeptic said...

"Sorry for banging on about this, but it is an interesting claim that two drugs with the same agonist action initiate different downstream signalling"

it certainly is - that's why I linked to the paper. In fact AFAIK this is the only paper to make such a claim regarding monoamine receptors (although there may well be other papers from other fields).

your comments are extremely good ones. What do you make of their claim that "Lisuride and LSD Compete for the Same Receptor Target"?

pj said...

I think that claim is more tenable from their data - but it is only really addressed by the competition curves - the rest could be mediated via other receptor signalling.

Anonymous said...

IT is important to note that not ALL the psychedelics/entheogens affect the 5-HT receptors, Salvia Divinorum contains a diterpenoid 'Salvnorin A' which is a k-Opioid receptor agonist.

Salvia is classed by erowid as an 'atypical psychedelic', there is an undeniably 'psychedelic' quality about a Salvia trip, but at the same time it is very different from ALL the other psychedelics

Neuroskeptic said...

max: Quite right, but that's a whole different kettle of fish.

Certainly there are plenty of drugs which have "hallucinogenic" effects which aren't LSD-like, e.g. ketamine (at certain doses), cannabis (sometimes), etc.

But AFAIK Salvia is fairly unique and not really a classical psychedelic. I've never taken it but I've been present when people have & the effects seemed pretty unique, and dramatic.

Anonymous said...

Thought-provoking piece and discussion in the comments (about to let the side down by just saying, "Up with this sort of thing and more of it").

Anonymous said...

Salvia is not alone.
Butorphanol, another k-opoid agonist, also has distinct hallucinogenic qualities separate from the classical hallucinogens.
Is this common to kappa agonists?

Neuroskeptic said...

Well - according to Wikipedia's pages on kappa agonists (Wikipedia is generally pretty good on psychopharmacology) they cause "dysphoria and hallucinations".

Of course, that could mean a lot of things. But it suggests that the kappa receptor mediates some kind of non-LSD-like hallucinogenic response

Anonymous said...
This comment has been removed by a blog administrator.
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Anonymous said...

I am no scientist. However, I have tried quite a few of the above mentioned drugs and find that the psychological effect, no matter the activation mechanism, can be, and usually is - the very same.

Mood can be a factor, but the hallucinations are very similar to those experienced while sober. Perhaps they should be studying the comorbidity of those with highly functioning psychological disorders and those without.

It isn't only the phantasms the drug produces, but the incessant and overpowering cognitive tricks it's plays. One can have euphoria and the entire universe is perfect, and order is easily attributed to everything, as if one is a Texan sharpshooter. The reverse is also true, the Nadir can take hold, and the shit hawks come home to roost. Entropy is all one experiences.

These symptoms mirror those with serve forms of a plurethra of DSM-V recognized psychological disorders. Psychosis, a prevalent symptom of both drug abuse and mood or thought disorders may share the very same root.

Considering that the hallucinations depend in content, wholly on the cognitive predisposition of the individual, further study may prove invaluable to creating a healthier lifestyle for those afflicted.

Perhaps one that doesn't involve sedation and eventual depression.