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 of 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.

What about tardive dyskinesia? When I was in medical school, I was told that the drugs “permanently hypersensitized dopamine receptors”, which is kind of a cop-out – why do they permanently hypersensitize receptors? How come all the other drugs don’t permanently hypersensitize the receptors they antagonize? Apparently now the story is more nuanced. From here:

The pathophysiology of TD is complex and remains unclear. Multiple models have been proposed to explain this unpleasant and sometimes disabling side-effect. One of the first widespread and popular explanations was the theory of dopamine-receptor hypersensitivity. It was suggested in 1970; however, it cannot completely explain the clinical findings, because TS does not generally appear among all dopamine receptor-blocking drugs users. To date, several neurochemical hypotheses have been proposed for the explanation of TD development. These theories include: (i) a disturbed balance between dopamine and cholinergic systems; (ii) noradrenergic dysfunction; (iii) dysfunctions of striatonigral, γ-aminobutyric acid (GABA)ergic neurons; and (iv) excitotoxicity. Recently, the role of oxidative stress and structural abnormality in the pathophysiology of TD has gained impetus. Induction of free radicals by neuroleptic drugs leading to oxidative stress and resultant structural abnormality could be the key factor in the pathogenesis of TD. The studies by Lerner et al. and Libov et al. support the neurotoxicity hypothesis. This hypothesis has also been supported by reports that chronic neuroleptic treatment increases free radical production and causes structural damage. In 2005, Tan et al. reported that a brain-derived neurotrophic factor appears to exert a protective effect in the nervous system against TD in patients with schizophrenia. There is solid evidence of a genetic predisposition to TD. A study performed by Souza et al. suggests that GSK-3B polymorphism may play a role in the genetic vulnerability to TD manifestation in individuals with schizophrenia.

There also seems to be some sort of role of acetylcholine:

Several studies in animals have reported that cholinergic cells (or the marker enzyme choline acetyl transferase) in the striatum are lost or reduced in amount after prolonged regimes of haloperidol and fluphenazine (49,50). Recently, Grimm and others showed that prolonged haloperidol treatment in rats led to cholinergic cell loss in the specific areas of the striatum related to oral movements (51). This result may provide an animal model to explain why TD in humans is most commonly a motor disorder of orofacial musculature. Proton magnetic resonance spectroscopy provides supporting evidence for the cholinergic hypothesis. This method allows quantification of choline, the precursor of acetylcholine, in specific brain structures. Choline reuptake leads to the accumulation of choline in cholinergic neurons before its conversion to the transmitter; an excess of choline in brain tissue will signify a loss of cholinergic neurons. Using this method, investigators have shown that, in schizophrenia, choline levels in the basal ganglia are greater than normal (52). Ando and others produced further results with this method (53), implying that choline levels in the lenticular nucleus are higher in schizophrenia patients with TD than in those without the syndrome. Apart from such methods for assessing cholinergic processes in the striatum, clinical trials with cholinergic agents in patients with TD could provide indirect evidence related to the cholinergic hypothesis (44). Caroff and colleagues showed that the anticholinesterase donepezil was effective against the symptoms of TD (54,55). Since choline, the precursor of acetylcholine, was not effective, Caroff and others regarded their evidence as support for the hypothesis of Miller and Chouinard. However, a recent metaanalysis concluded that trials of cholinergic agents in the treatment of TD conducted to date have insufficient statistical power to reach a firm conclusion about the drugs’ effectiveness (56). This area of research may be clarified when cholinergic agents effective against specific muscarinic receptors are tested in patients with TD.

So apparently it’s a conflict between a receptor hypersensitivity hypothesis and a killing-off-interneurons hypothesis that resembles some of the work around HPPD?

I’m biased in favor of killing-off-neurons hypotheses because they’re comfortable and they make sense. Of course if a drug kills something, it’s going to permanently impair function. This makes the idea of “drugs with permanent side effects” a little bit less scary, restores us to the “some medications cause strokes and then you’re screwed” realm of everyday life.

The alternative is thinking of the body as a chaotic system which settles into various attractors. Take the wrong drug and you can push yourself into a different attractor state, which will persist until something shifts it. This definitely seems true of some things, and is one of the ways I think about depressive episodes – which can last months or years, and which can be precipitated by some sort of obvious stressor (getting fired, breaking up, being bullied) but last long after the stressor is gone. If this explains permanent drug side effects, it seems somehow scarier to me than the other option. It’s not just that you have to make sure not to accidentally kill any cells. It’s more that nobody has any idea what the underlying mechanisms look like, anything can happen, and you just have to hope you don’t screw up.