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I recently worked with a man who took LSD once in college and never stopped hallucinating. It\\u2019s been ten years now and it\\u2019s 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 \\u2013\\xa0hallucinogen persisting perception disorder. Most descriptions of the condition emphasize that it\\u2019s just some the visual effects and doesn\\u2019t involve distorted reality perception. I\\u2019m not sure I believe this \\u2013 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\\u2019re going to be having a bad time whether you believe it\\u2019s \\u201creally true\\u201d 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 \\u2013 why don\\u2019t 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 \\u2013 by all accounts the most common form of the condition \\u2013 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\\u2019s 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\\u2019t be that the LSD sticks around. That doesn\\u2019t make metabolic sense. And\\xa0a study\\xa0discussed here\\xa0using radio-labeled LSD definitively finds that although a few molecules might stay in the body up to a week or so, there\\u2019s 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 \\u201cwe\\u2019re going to give you radioactive LSD\\u201d and thought \\u201csure, why not?\\u201d

But then why\\xa0does\\xa0it have permanent effects? I know very few other situations where this happens, aside from obvious stuff like \\u201cit gives you a stroke and then you\\u2019re permanently minus one lobe of your brain\\u201d. 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\\xa0openness\\xa0and\\xa0hypnotizability, though it\\u2019s unclear if this is biochemical or just that drug trips are a life-changing experience \\u2013 see\\xa0my discussion here\\xa0for 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\\u2019ve seen is speculative and admits it doesn\\u2019t know what it\\u2019s talking about. Also, most of them are in gated papers I can\\u2019t access. But a few papers seem to gesture at a theory where LSD kills an undetectably small number of very important neurons.\\xa0Hermle et al\\xa0talk about \\u201cthe excitotoxic destruction of inhibitory interneurons that carry serotonergic and GABAergic receptors on their cell bodies and terminals, respectively\\u201d.\\xa0Martinotti\\xa0seems to be drawing from the same inaccessible source in mentioning \\u201can 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\\u201d.

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\\u2019re talking excitotoxicity, shouldn\\u2019t the neurons be stimulated (ie more active) in the tripper, but dead (ie less active) in the HPPD patient? Maybe the tripper\\u2019s 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\\xa0inhibitory\\xa0neurons 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.