Location bias

Location bias:  no this isn’t about real estate or red lining.  It’s about how drugs act differently depending on where they’re able to get.  If this sounds too abstract, location bias may explain why dimethyl tryptamine (DMT) is a hallucinogen (it is the main psychoactive component of ayahuasca) and why serotonin (5 hydroxy tryptamine) is not.

The psychoactive effects of many drugs (LSD, DMT) are explained by their binding to one of the many (> 13) subtypes of serotonin receptors, namely 5HT2AR.

Well serotonin certainly binds to 5HT2AR, so why doesn’t it produce hallucinations?  This is where [ Science vol. 379 pp. 700 – 706 ’23 ] (and local bias) comes in.

We tend to think of receptors for neurotransmitters (like serotonin) as being on the outer membrane of the cell (the plasma membrane).  This makes sense as neurotransmitters are released from neurons into the extracellular space.  However it is now known that some neurotransmitter receptors (such as 5HT2AR) are found inside the cell where they are found on endosomes and the Golgi apparatus.

The article claims that the hallucinogenic effects of DMT, LSD etc. etc. are due to their binding to 5HT2ARs found inside the cell, not those on the plasma membrane. Serotonin with its free OH and NH2 groups is simply too water soluble (hydrophilic) to pass through the lipids of the plasma membrane.   DMT and LSD are not.   Unfortunately we are a long way from understanding how activation of 5HT2ARs inside the cell leads to hallucinations, but if the authors are right, it’s time to look.

We don’t know if animals hallucinate, and use things like head twitch and effects on dendritic branching and size in tissue culture as markers for hallucinations as LSD, DMT produce these things,.

The authors do show that putting a serotonin transporter into neuronal cultures so serotonin gets inside, produces similar effects on dendritic branching and size.  While fascinating, these effects are  pretty far removed from clinical reality.

The authors do raise a fascinating point at the end of their paper.  Perhaps there are endogenous intracellular ligands for intracellular 5HT2AR which differ from serotonin.   Perhaps the hallucinations and mental distortions of schizophrenia and other psychiatric disease are due to too much of them.