HPPD and the Specter of Permanent Side Effects

I recently worked with a man who took LSD once in college and never stopped hallucinating. It's been ten years now and it's still going. We can control it with medication, but take the meds away and it starts right back up again.

This is a real disease – hallucinogen persisting perception disorder. Most descriptions of the condition emphasize that it's just some the visual effects and doesn't involve distorted reality perception. I'm not sure I believe this – my patient has some weird thoughts sometimes, and 65% of HPPD patient have panic attacks related to their symptoms. Maybe if you can see the walls bubbling, you're going to be having a bad time whether you believe it's "really true" or not.

Estimates of prevalence vary. It seems more common on LSD and synthetic cannabinoids, less common (maybe entirely absent) on psilocybin and peyote. Some people say about 1-4% of LSD users will get some form of this, which seems shockingly high to me – why don't we hear about this more often? If I were a drug warrior or DARE instructor, I would never shut up about this. But if most people just get some mild visual issues – by all accounts the most common form of the condition – maybe they never tell anybody. Maybe 1-4% of people who have tried LSD are walking around with slightly distorted perception all the time.

There's a lot to say about this from an epidemiological or cultural perspective. But I want to talk about the pharmacology. How can this happen? Why should a drug with a half-life of a few hours have permanent effects on your psyche?

It can't be that the LSD sticks around. That doesn't make metabolic sense. And a study discussed here using radio-labeled LSD definitively finds that although a few molecules might stay in the body up to a week or so, there's no reason to think the drug can last longer than this. I like this study, both for its elegant design and because it implies that somewhere someone got a consent form saying "we're going to give you radioactive LSD" and thought "sure, why not?"

But then why does it have permanent effects? I know very few other situations where this happens, aside from obvious stuff like "it gives you a stroke and then you're permanently minus one lobe of your brain". The only other open-and-shut case 100% accepted by every textbook is a movement disorder called tardive dyskinesia. If you take too many antipsychotics for too long, you can get involuntary tremors and gyrations that never go away, even off the antipsychotic. Although traditionally associated with very-long-term antipsychotic use, in a few very rare cases you can get it from a single dose. On the other hand, most people can take antipsychotics for decades without developing any problems.

Some other possibilities are controversial but plausible. The sexual side effects of SSRIs almost always stop within a few months of stopping the medication, but a few people have reported cases where they can last years or decades. Psychedelics may permanently increase openness and hypnotizability, though it's unclear if this is biochemical or just that drug trips are a life-changing experience – see my discussion here for more. Also, for every drug that has a mild week-long withdrawal syndrome in the average population, you can find a handful of people who claim to have had a five-year protracted nightmare of withdrawal symptoms that never go away.

So, again, how does this happen?

Every discussion of HPPD etiology I've seen is speculative and admits it doesn't know what it's talking about. Also, most of them are in gated papers I can't access. But a few papers seem to gesture at a theory where LSD kills an undetectably small number of very important neurons. Hermle et al talk about "the excitotoxic destruction of inhibitory interneurons that carry serotonergic and GABAergic receptors on their cell bodies and terminals, respectively". Martinotti seems to be drawing from the same inaccessible source in mentioning "an LSD-generated intense current that may determine the destruction or dysfunction of cortical serotonergic inhibitory interneurons with gamma-Aminobutyric acid (GABAergic) outputs, implicated in sensory filtering mechanisms of unnecessary stimuli".

This would require some extra work to explain the coincidence of why the effects of HPPD are so similar to the effects of an LSD trip itself. In particular, if we're talking excitotoxicity, shouldn't the neurons be stimulated (ie more active) in the tripper, but dead (ie less active) in the HPPD patient? Maybe the tripper's neurons are just so overwhelmed that they temporarily stop working? Or maybe you could interpret the comments above to be about LSD exciting some base population of neurons, the relevant inhibitory neurons having to work impossibly hard to inhibit them, and then the inhibitory neurons die of exhaustion/excitotoxicity.

Against cell death based explanations, some people seem to recover from HPPD after a while. But this could just be the same kind of brain plasticity that eventually lets people recover from strokes that kill off whole brain regions. The body is usually pretty good at routing around damage if you give it long enough.