HPPD: An extensive review of potential causes and treatments
To research the causes and treatments of HPPD, I made 664 highlights from 193 articles, studies, and forum posts. This article is the result of that research.
As always, this is not medical advice. Also, I'm not a pharmacologist or an academic, so it's possible that I got some things wrong. If you notice an error, please let me know. I wrote this with the intention of it being helpful to others, so I'd like to make sure this is as accurate as possible. Thank you.
This article ended up being much longer than I intended, so I focused on making it skimmable as well. I recommend reading it top-to-bottom to understand the reasoning, but if you don't have the time for that, read this section and the last few sections.
Psychedelics induce strong synaptogenesis, resulting in high synaptic density. EEG scans show less inhibitory activity in the visual cortex both in people on psychedelics and in people with HPPD. Artificially adding inhibitory waves to the brain diminishes hallucinations in people while they're on psychedelics. So a good focus point is substances that increase inhibitory alpha waves. These seem to be tonic GABAergics, likely: GABA itself, emoxypine, neurosteroids, GABA transaminase inhibitors like valproic acid or rosmarinic acid. Also cholinergics — primarily muscarinic — should work. So Huperzine A might be good.
Another focus point might be enhancing neuroplasticity in the direction of pruning excessive synapses, i.e. LTD and autophagy. Lithium might be useful, lifestyle and exercise plays a big role here.
The increase in synaptic density might also be related to an overexpression of AMPA receptors. AMPA inhibitors (which are antiepileptic anticonvulsants) might help with the symptoms, and antiepileptic anticonvulsants seem to be what people on HPPD forums go for (though those are blockers of excitatory ion channels — levetiracetam and lamotrigine). Specific NMDA agonists or antagonists (likely the former, but the glutamatergic system is too complex to simplify this) may be useful too. D-serine or high dose glycine. mGluR2/3 agonists look like an extremely promising type of treatment, but they're not researched enough.
There might be a psychological aspect to HPPD, because LSD is reported to cause HPPD more often than other psychedelics. The thinking is that seeing things pulsate for hours teaches your brain in a Bayesian way (& exacerbated due to high neuroplasticity during the experience) that objects indeed do pulsate. The counterarguments are that nootropics and short-lasting hallucinogens can cause HPPD too, so this likely plays a minor role.
General neuroplasticity agents (Lion's Mane, 7,8-DHF) help some people, and make HPPD worse for some people. It might be wise not to use them when you're in a situation that involves strong perception of HPPD symptoms (solitude, sitting at a desk, dark places), since this might combine with the psychological hypothesis. You want neuroplasticity when you don't see heavy HPPD (in movement and while socializing), similar to how you've learned not to see your nose, because you weren't focusing on it. Again, neuroplasticity should preferably be in the direction of pruning excessive circuits in the brain, rather than creating new neurons and synapses.
The end of this article has a link to a table with a list of potential treatments, and a link to a short survey.
Hallucinogen persisting perception disorder (HPPD) is a disorder that can take place after a hallucinogenic experience.
It's characterized by persisting hallucinogen-type effects.
While common psychedelics are completely non-toxic (both to the brain — they do the opposite of neurotoxicity: neurogenesis — and to the body — they can't kill you), they can have persisting issues: HPPD and traumatic experiences. The latter is greatly dependent on the person's mental state and as such can be affected.
The former — HPPD — seems to be a lot more random, though usually individuals either are susceptible or they are not. But there are cases of people acquiring HPPD after their nth experience, so this is not a fixed rule.
HPPD is typically viewed as a very rare thing, and that's partially true. The definition of HPPD per DSM-5 (the standard psychiatric diagnostic manual in the US) says that "it must cause distress in everyday life". This is a good distinction.
From my research and anecdotal experiences, it seems like a lot of people (two digit %) get some form of HPPD, but not a form that's "true" HPPD since it's typically very mild and causes no distress.
HPPD usually seems to be a long tail-end of the experience. It feels similar to the come-up (psychedelics don't feel like hallucinations, they feel like natural illusions enhanced — objects and reverse-colored afterimages stay in your visual field for longer)
For most people (who get any form of HPPD), it seems to be come-up-level effects stretched out over 1-3 weeks. No negative effect on life, can even be pleasurable as a form of aesthetic enhancement (really depends on one's outlook).
For others, it involves more effects that have a negative impact on their life, and it can be prolonged (months or years).
The symptoms typically include:
palinopsia (objects persisting in vision)
If the object moves, this is trailing (you see a trail of where the object was previously)
If your eyes move, you can see the object in opposite colors in your visual field. These are afterimages.
- dysmetropsia (things looking like they have a different size)
Bolded symptoms are the most common & benign ones.
The bad thing about HPPD is that there's no known treatment, or even cause for that matter. We know some things can help, we have some hypotheses about the cause, but nothing conclusive.
And in this article, I try to do exactly that — find potential causes and treatments. I spent a few days researching this topic, so this will be a summary of that research.
Before looking at physical changes in the brain, it's good to have a theoretical framework which can guide us towards relevant systems in the brain.
So, let's take a look at how psychedelics work. Scott Alexander wrote a few articles that look into very interesting and promising hypotheses about what may be happening.
In the Mental Mountains article, he writes about a model for therapy that involves updating old beliefs with new evidence. Basically, it boils down to the brain giving higher priority to established beliefs than to new perceptions, and some psychiatric illnesses coming from erroneous beliefs being held (I'll get attacked if I speak) and not updated (despite not being attacked a single time for speaking in the past 20 years).
He reviews a therapy book that proposed how life-long trauma-originating delusional fears can be treated by making the patient vividly recall the moment that caused this fear, and then vividly thinking about all the evidence showing that the fear is not rational. It has a biological basis in memories being reconstructed when they're recalled, which can be proved by fear extinction in mice after they're given a protein synthesis inhibitor and made to think about the fear. If you're interested in more details, you're highly encouraged to read the article.
He suggests that this might be how psychedelics work. They decrease the strength of your prior beliefs, making it easier to update them with new evidence. Specifically, he ties it into another article on his blog, which looks at how psychedelics flatten the energy landscape of the brain.
They analogize the same process to “flattening an energy landscape”. Imagine a landscape of hills and valleys. You are an ant placed at a random point in the landscape. You usually slide downhill at a certain rate, but for short periods you can occasionally go uphill if you think it would help. Your goal is to go as far downhill as possible. If you just follow gravity, you will end up in a valley, but it might not be the deepest valley. You might get stuck at a “local minimum”; a valley deep enough that you can’t climb out of it, but still not as deep as other places in the landscape you will never find. F&CH imagine a belief landscape in which the height of a point equals the strength of your priors around that belief. If you settle in a suboptimal local minimum, you may never get out of it to find a better point in belief-space that more accurately matches your experience. By globally relaxing priors, psychedelics flatten the energy landscape and make it easier for the ant to crawl out of the shallow valley and start searching for even deeper terrain. Once the drugs wear off, the energy landscape will resume its normal altitude, but the ant will still be in the deeper, better valley.
The second article continues that this can explain HPPD as well:
In other words, the priors relax and don’t unrelax again after the drug experience.
For example, an especially common HPPD experience is seeing solid objects pulsate, ooze, or sway. It’s not surprising that a noisy visual system would sometimes put the edge of an object in one place rather than another. But usually a strong prior on “solid objects are not pulsating” prevents this from interfering with perception. Relax this prior too far and the pulsating becomes apparent. If the prior stays relaxed after the drug trip ends, you’ll keep seeing the pulsation indefinitely.
This is one of two plausible theories of HPPD, the other being that the hours of seeing objects pulsate makes your brain learn a new prior, “objects do pulsate” and stick to it. This would make more sense in the context of other learned permanent perceptual disorders like mal de debarquement.
These articles mention prior beliefs very often. What's up with that?
Prior and posterior probabilities are part of a mathematical concept called the Bayes theorem. You could say that it's a formula for calculating the probability of things in the presence of a prior probability, i.e. the chance that they'd happen on their own. "Bayesian" is almost a buzzword lately, but it's an extremely important concept in statistics if you want to predict things accurately.
Statistics ... predicting things accurately ... how is this related to the brain? Well, it's almost the same thing. The brain largely works by making weighted predictions and assumptions about the world, otherwise you wouldn't be able to get anything done. Nothing in the world is 100% certain, so we need accurate predictions. Scott has a third article (it's the last one, I promise) that reviews a few studies which try to link this theoretical concept with physical receptors in the brain.
And that's where it gets very relevant for us.
The brain has prior beliefs about the world. When new perceptions come up, it compares them with the prior beliefs. If there's a big mismatch (e.g. there are never gunshot sounds around your house, but now there are), it focuses attention that way to get more information.
You look outside and you see that it's your neighbors practicing shooting at a paper target. You're relieved that no one came to kill you, and you remember that this is a possible explanation of gunshots outside your house.
A week later, you hear the same thing. Again, you're uncertain so you look outside to get more evidence. Just because neighbors were practicing with guns once doesn't mean that all gunshot sounds outside your house are safe. Luckily, it's your neighbors again. This repeats a few times and you eventually learn that there can be gunshot sounds outside your house, perhaps especially on the weekend, and that this is not a thing that requires your attention.
Getting more evidence was critical, since the prior probability of gunshots happening outside your house due to something benign (like neighbors) was extremely low (you never saw them practice shooting guns). On the other hand, your city might have a moderate crime rate. The probability of an evil person with a gun being outside when you hear gunshots is not 100%, but it's also not low enough for you to not care.
And you only changed your belief after being presented with evidence continuously.
In the paper cited by Scott, they argue that the NMDA signaling represents prior beliefs, AMPA signaling represents new perceptions, dopamine represents the confidence interval and other neurotransmitters have some more specific modulatory effects on this system. This sounds very ambitiously specific, but it makes a lot of sense: People with autism have a problem with re-learning (they love their patterns) and they get bothered by inaccuracies.
The top-down model tries to predict the feeling of the shirt on my skin, but tiny changes in the position of the shirt change the feeling somewhat; bottom-up data does not quite match top-down prediction. In a neurotypical with wide confidence intervals, the brain would shrug off such a tiny difference, declare it good enough for government work, and (correctly) ignore it. In an autistic person, the confidence intervals are very narrow; the top-down systems expect the feeling of shirt-on-skin, but the bottom-up systems report a slightly different feeling of shirt-on-skin. These fail to snap together, the perceptual handshake fails, and the brain flags it as important; the autistic person is startled, upset, and feels like stopping what they’re doing in order to attend to it.
A problem with re-learning would indicate too strong prior beliefs, i.e. too much NMDA signaling. And a problem with inaccuracies would indicate a too small confidence interval. Slight mismatches between expectations and perceptions don't let autistic people relax. People with autism also have a very hard time socializing, and it makes sense considering that other people may just well be the most unpredictable thing, so a well-regulated prediction system with wide enough confidence intervals is needed.
They generally react well to stimulants and NMDA antagonists — at least as far as I know — so this would make perfect sense.
It seems like the opposite of autism is schizophrenia. Schizophrenics have weaker prior beliefs, so they believe delusions more easily. And they're typically treated with antidopaminergics.
On top of that, autism has an excess of synapses and mTOR signaling, whereas schizophrenia has a lack of synapses and mTOR signaling. mTOR is important here for synaptogenesis.
And as for dopamine being the confidence interval — we know that stimulant psychosis results in mental states of delusions that seem more real than reality. There's more confidence in them.
The study elaborates that AMPA serves as the feed-forward mechanism (it feeds sensory information forward to the (to simplify it; neuroscientists please bear with me) "logical" parts of the brain), whereas NMDA is the feedback mechanism that imposes structure upon this sensory input.
So schizophrenics believe perceptions even if they don't really match prior beliefs. (This model is not perfect and it gets more complex with delusions that can't be changed with explanations — new input — but those are related to other dysfunctions in the brain etc. If you're interested, further reading). Whereas autists have a hard time understanding that new perceptions indeed match their prior beliefs.
The mask in the picture is concave, ie the nose is furthest away from the camera. But most viewers interpret it as convex, with the nose closest to the camera. This makes sense in terms of Bayesian perception; we see right-side-in faces a whole lot more often than inside-out faces.
Schizophrenics (and people stoned on marijuana!) are more likely to properly identify the face as concave than everyone else. In CFF’s system, something about schizophrenia and marijuana messes with NMDA, impairs priors, and reduces the power of top-down processing. This predicts that schizophrenics and potheads would both have paranoia and delusions of reference, which seems about right.
HPPD is better in movement (severe palinopsisa aside) and light — you can't notice visual snow. Imposing order on order. When sitting still, visual disturbances are more noticeable.
Schizophrenics (and stoned people) are better in stillness, too much sensory stimulation results in delusions due to a lack of top-down order. Schizophrenics also do better in sensory deprivation. (Weed can be bad for sensory deprivation, but I'd argue that it's only the case when weed acts in an anxiogenic way. Weed is otherwise pretty close to schizophrenia in this context.)
Normal people do worse in sensory deprivation than schizophrenics — they feel paranoid. The study argues that it's due to top-down signaling expecting the presence of others, and projecting it onto the empty nothingness.
Enough about autism and schizophrenia, how does all this relate to HPPD? Specific parts of those two illnesses may be relevant to a model of HPPD. I think that schizophrenia is a good mental model for arguing about the Bayesian basis behind HPPD, and ASD-like synaptic excess may be present too. I'll go into synapses a bit later, so let's wrap up all this Bayesian stuff.
So in short:
- delusions (schizophrenia, ketamine, cannabis) are too much bottom-up signaling unrestrained by top-down signaling
- schizophrenia and cannabis might also be too little top-down signaling (related to the mask illusion example)
- hallucinations (LSD, sensory deprivation) are too little bottom-up signaling (small signal-to-noise ratio) upon which order is imposed by top-down signaling
Putting it together
I think that the above models are very useful for finding the causes of HPPD, and by extension the treatments.
However, you may have noticed some inconsistencies in those models.
- The Mental Mountains article talks about psychedelics in a behavioral way: they let you connect new evidence with old beliefs
- The Bayesian model relates this to glutamatergic receptors: AMPA receptors representing perceptions and NMDA receptors representing the top-down influence of prior beliefs
- It also suggests that LSD and sensory deprivation creates hallucinations by decreased perceptions and preserved priors, resulting in structure being projected onto priors:
But then one of the bayesian papers claims that psychedelics decrease top-down priors:
psychedelics “relax” priors, giving them less power to shape experience. Part of their argument is neuropharmacologic: most psychedelics are known to work through the 5-HT2A receptor. These receptors are most common in the cortex, the default mode network, and other areas at the “top” of a brain hierarchy going from low-level sensations to high-level cognitions. The 5-HT2A receptors seem to strengthen or activate these high-level areas in some way
And some of the studies that I go over in the following sections also claim that psychedelics decrease alpha waves (resulting in a less inhibited cross-brain-region excitation) and increase AMPA.
So in my view the study that went over the multiple models of psychosis in the context of Bayesian signaling was wrong about LSD. Scott suggested the same thing. It's probably because they tried to put LSD hallucinations together with sensory deprivation hallucinations, but they have a different mechanism.
Psychedelics indeed increase NMDA signaling, but they don't decrease AMPA, yet still they cause hallucinations. Why? I think it's because they lead to 1) more noise 2) more structure, which really sounds like the perfect mix for hallucinations.
But then how come psychedelics decrease priors? I think it's because their mechanism is less of an NMDA increase and more of an AMPA increase. Priors slightly increase, but sensory input massively increases, resulting in really any sensory input being matched as some sort of a prior.
The difference between priors and perceptions is flatter. Just like the mental mountains.
Scott suggested this:
Consider a slightly different distortion: increased AMPA signaling combined with increased NMDA signaling. You’ve still got a lot of sensory noise. But you’ve also got stronger priors to try to make sense of them. CFF argue these are the perfect conditions to create hallucinations. The increase in sensory noise means there’s a lot of data to be explained; the increased top-down pattern-matching means that the brain is very keen to fit all of it into some grand narrative. The result is vivid, convincing hallucinations of things that are totally not there at all.
LSD is mostly serotonergic, but most things that happen in the brain bottom out in glutamate eventually, and LSD bottoms out in exactly the pattern of increased AMPA and increased NMDA that we would expect to produce hallucinations. CFF don’t mention this, but I would also like to add my theory of pattern-matching based mysticism. Make the top-down prior-using NMDA system strong enough, and the entire world collapses into a single narrative, a divine grand plan in which everything makes sense and you understand all of it. This is also something I associate with LSD.
It's worth mentioning that persistent flattening of these mental mountains does occur post-psychedelics without necessarily being HPPD: Mystical Experiences Occasioned by the Hallucinogen Psilocybin Lead to Increases in the Personality Domain of Openness
Taken together, these results indicate predominantly stable personality traits with specific increases in Openness following the high-dose session.
One previous well-controlled study of LSD (McGlothlin et al., 1967) found evidence for short-term improvements on measures of artistic ability (e.g., figure drawings), aesthetic sensitivity (e.g., compatibility between participant and expert ratings of paintings), and creativity (e.g., generating alternate uses for a common object). However, McGlothin and colleagues failed to find significant improvements in creativity or aesthetic measures at a 6-month follow-up.
(The study then mentions that they found long-lasting increases in openness and creativity, and that it might be due to a different demographic engaging in their study.)
In addition, nearly all of the participants in the present study regularly engaged in spiritual activities such as religious services, prayer, and meditation. It is possible that such individuals are particularly sensitive to the mystical-type effects of psilocybin, which were predictive of increases in Openness.
Maybe the reason why some people don't get HPPD is that their visual cortex wasn't affected, but they still reaped the benefits of a more flexible Default Mode Network in other parts of the brain.
So my conclusion of this theoretical section would be: In HPPD, the difference between priors and posterior beliefs is too flat and we want to make it bigger. Noise is getting accidentally picked up as signal. We want to decrease noise (AMPA) and possibly increase priors (NMDA). This is consistent with AMPA agonists causing visual snow (I'll get into this in the section about synapses) and NMDA agonists possibly improving schizophrenia.
One thing to keep in mind is that the involved glutamatergic receptors are immensely complex, and sometimes there's a thin line between agonists and antagonists. The main point is that modulating glutamatergic activity might be key. If you read the study presenting the Bayesian/glutamatergic model, you'll see that there are a lot of nuances to the core principle, so arguing about what a specific pharmacological intervention will do with regards to HPPD requires a lot of theoretical and neurological nuance.
Another note on agonists/antagonists is that there's a huge difference between presynaptic, postsynaptic, and extrasynaptic receptors, as well as their subtypes and the way the substance binds to the receptor.
Before we get to the neuropharmacological complexities, let's briefly entertain an alternate hypothesis. What if HPPD is psychological?
It's possible that HPPD is more common in bad/traumatizing experiences, and is some light form of PTSD, but that can be mostly disproven, since people who don't have any distress at all during a trip end up getting strong HPPD. So I'll leave that hypothesis at "it likely plays some role, but if there's a link, it's likely a common causation".
In one of the cited Slate Star Codex articles, Scott said:
This is one of two plausible theories of HPPD, the other being that the hours of seeing objects pulsate makes your brain learn a new prior, “objects do pulsate” and stick to it. This would make more sense in the context of other learned permanent perceptual disorders like mal de debarquement.
The French word stands for an HPPD-type condition where people feel like they're floating/flying long after coming back on land. Kind of like you can feel the sense of waves on your skin after diving for a long time, but it lasts months and is a lot stronger.
There's very little explanation for that condition, much like HPPD. If it were that the brain learns "aha, objects do pulsate/waves are hitting me/I am flying", it could explain both HPPD and French-word condition.
That would sound like an issue with learning. A new belief gets internalized with little evidence and then it persists. I guess it makes sense that this can happen more often with hallucinogens than with plane flights, since I haven't seen evidence of plane flights causing neurogenesis.
And after all, the point of the Mental Mountains article and really all of these therapeutic things is that we adapt wrong beliefs and we hold on to them.
And this would be consistent with reports of following hallucinogen experiences fixing HPPD from past hallucinogen experiences.
Some people also pointed out that HPPD seems to be largely an LSD thing, or perhaps a phenethylamine thing. With few reports of DMT causing HPPD. But ayahuasca — much longer lasting DMT — seems to have more HPPD cases than smoked DMT (though that is largely speculative, there's a severe lack of statistics when it comes to HPPD).
So far it makes perfect sense. But:
- Racetams like Noopept and Coluracetam can cause symptoms like HPPD. Other nootropics possibly as well
- The brain being more plastic post-trip should be able to fix wrong beliefs ("objects do pulsate") easier, not harder
But a lot of the arguments that do support this hypothesis seem pretty strong.
So, which hypothesis is correct? Is it physical changes in the brain or a psychological thing?
It's likely a combination of both. The arguments for the psychological hypothesis seem convincing enough that I don't want to discard the hypothesis.
And at the same time, there are real changes in the brain.
- There seems to be a changed expression of receptors
- There might be changes in gene expression
- There is a lot of synaptogenesis taking place
- EEG scans show changes in brain waves similar to the changes that take place during the psychedelic experiences
And of those things, neither one seems to be able to explain or cure HPPD completely on its own.
Also, some substances will look like perfect candidates for some of the pathways described below, but they'll have counterproductive activity in other pathways. So until we know the core mechanism behind HPPD, it seems to be important to look at all these pathways when considering a substance.
There might be a root cause of things, and the root cause might be fixable with a single treatment. But after compiling the information from 664 highlights from 193 articles, studies, and forums, I didn't find anything that would conclusively work.
But, based on the Bayesian model above and information from recent studies on epilepsy, schizophrenia, and autism, I found some experimental things that I'd try if I could get them.
Perhaps this can serve someone who researches HPPD officially, or someone who's a bigger lab rat than me (and is fine with buying overpriced substances from Sigma-Aldrich).
Why epilepsy, schizophrenia, and autism? They share parts of HPPD. Epilepsy might have similar glutamatergic dysregulation, schizophrenia might have similar hallucinatory mechanisms, and autism has a synaptic excess. Speaking of synapses, let's dive into the neuropharmacology of that.
LSD, ketamine, and racetams like noopept induce neuroplasticity through the AMPA receptor, which activates mTORC1, resulting in synaptogensis and neurogenesis.
Lysergic Acid Diethylamide (LSD) Promotes Social Behavior Through mTORC1 in the Excitatory Neurotransmission
Brain imaging studies in humans have shown that the effects of LSD on SB are mediated by mPFC 5-HT2A receptors (16, 17), and that the activation of postsynaptic cortical 5-HT2A receptors increases glutamate release in the synaptic cleft, an effect that can be reversed by AMPA antagonists like LY293558
These data indicate that repeated LSD selectively potentiates AMPA and 5-HT2A excitatory transmission of the mPFC.
These experiments show that the prosocial effects induced by LSD require neurotransmission through mPFC 5-HT2A and AMPA receptors.
The mTOR pathway is activated by several psychoactive drugs, including the hallucinogen ketamine (23, 24) and selective serotonin reuptake inhibitor (SSRI) antidepressants (25). Furthermore, dysregulation of mTORC1 signaling is implicated in social deficit disorders (12, 26, 27). The mTORC1 complex can be activated via AMPA receptors (24) and through the phosphatidylinositol 3-kinase (PI3K) and serine/threonine kinase B (Akt) pathways (12, 28). Thus, we measured the level of the serine-threonine protein kinase Akt S437 and mTOR phosphorylation after repeated administration of LSD. Western blot analysis revealed that LSD had no effect on total Akt (Fig. 3A) and mTOR (Fig. 3C) levels, but significantly increased the phosphorylation levels of the proteins (Fig. 3 B and D, respectively) in the PFC, demonstrating that mTOR signaling is activated by repeated LSD administration in the mPFC.
Psychedelics Promote Structural and Functional Neural Plasticity
Although the molecular targets of ketamine and psychedelics are different (NMDA and 5-HT2A receptors, respectively), they appear to cause similar downstream effects on structural plasticity by activating mTOR
We observed a significant increase in the density of dendritic spines on cortical pyramidal neurons 24 hr after dosing with DMT (Figures 2I and 2J). This effect was comparable with that produced by ketamine at the same dose (Figure 2J)
Treatment with rapamycin, an mTOR inhibitor, completely blocked psychedelic-induced neuritogenesis (Figure 5), thus confirming that mTOR activation plays a role in the plasticity-promoting effects of classical serotonergic psychedelics.
Why am I mentioning racetams? Because they can cause HPPD-like effects too. This contradicts the behavioral hypothesis which states that HPPD is due to psychological effects from the hallucinogen experience.
These synaptic changes underlie the antidepressant effects of these substances. Also, it's worth noting that they cause a growth in synaptic density, not length. LSD especially:
Colocalization of pre- and postsynaptic markers following treatment demonstrated that psychedelics promoted synaptogenesis by increasing the density, but not the size of synapses
LSD nearly doubling the number of spines per 10 μm
Surprisingly, the majority of the psychedelics and entactogens we tested exhibited significantly greater potency than ketamine, with LSD being particularly potent (EC50 = 0.409 nM). In fact, LSD exhibited activity across 8 orders of magnitude into the low picomolar range (Figure S3).
The second study also mentioned 7,8-dihydroxyflavone having the same effect as it's a potent neuroplasticity agent.
Which leads us to the main point: Do other neuroplasticity agents cause HPPD? I think yes, but it's a lot more rare than from psychedelics.
As I mentioned, noopept is relatively well known to cause HPPD-like effects. I believe I got these effects from NSI-189 too (which is also an mTOR-based neuroplasticity-inducing antidepressant) though it may have been the combination with noopept. Coluracetam gives me acute visual snow very comparable to HPPD. Some HPPD users say that Lion's Mane helps a lot, others say that Lion's Mane makes HPPD worse.
So, if it's the case that neuroplasticity agents can cause HPPD-type effects, the synaptic density increase could easily explain most of HPPD.
Psychedelics and especially LSD have a higher rate of causing HPPD possibly due to stronger neuroplasticity effects, which seems to be right. DMT isn't that known to cause HPPD, but neither is ketamine and according to the studies above they cause approximately equal synaptogenesis at equivalent doses (I don't know how they came up with equivalent doses, but I'll assume they did it right).
Another (but not contradictory) explanation might be that psychedelics cause neurogenesis in the visual cortex a lot more than these nootropics. Which seems plausible, since the effects of psychedelics obviously involve a lot of excitatory activity in the parts of the brain responsible for processing visual information. And this might explain the disparity between Noopept and Coluracetam (both of which can acutely change vision) and Lion's Mane, 7,8-DHF, and other supplements which don't have as many reports of HPPD-type effects.
So if the cause really was that we have an excess of synapses in the visual cortex, what to do about that? How do we remove synapses? And isn't that bad?
The answer is that it might be possible, but I wasn't able to find a single substance that could conclusively help.
Some more science: Synaptoplasticity has two types — long term potentiation (LTP) and long-term depression (LTD). The latter sounds bad, but as long as it's not out of balance it's wanted. Basically, LTP is the growth/strengthening of synapses and LTD is getting rid/weakening of synapses.
Ideally, the brain would strengthen the synapses that serve it well, and get rid of the synapses that are of poor use (and are just consuming energy for no reason).
There's also autophagy which is another mechanism of killing off what's useless or counter-productive. We don't know that much about autophagy in this context, but we know that mTORC1 activation inhibits autophagy. I'll cite this one lazily (from Wikipedia):
mTORC1's ability to inhibit autophagy while at the same time stimulate protein synthesis and cell growth can result in accumulations of damaged proteins and organelles, contributing to damage at the cellular level. Because autophagy appears to decline with age, activation of autophagy may help promote longevity in humans. Problems in proper autophagy processes have been linked to diabetes, cardiovascular disease, neurodegenerative diseases, and cancer
mTOR is also overactive in autism, and autism is known to be related to an excess of synapses. And this mechanism is a good way to even replicate autism: Loss of mTOR-dependent Macroautophagy Causes Autistic-Like Synaptic Pruning Deficits
The mTOR inhibitor rapamycin corrected ASD-like behaviors and spine pruning defects
Our findings suggest that mTOR regulated autophagy is required for developmental spine pruning, and activation of neuronal autophagy corrects synaptic pathology and social behavior deficits in ASD models with hyperactivated mTOR
neuronal autophagy is responsible for ∼70% of postnatal net spine elimination
Using an in vitro primary neuronal culture system, we find that autophagy regulates spine elimination but not spine formation during developmental pruning of dendritic spines. Autophagy may remodel dendritic spines by directing internalized postsynaptic membrane neurotransmitter receptors, including GABA-A (Rowland et al., 2006) and AMPAR (Shehata et al., 2012), toward lysosomal degradation. Although autophagy was classically considered an ‘in-bulk’ process, evidence now supports selectivity mediated via recognition of post-translational modifications by molecules that bind cargo and components of the autophagic machinery
TSC inhibition of mTOR is required for postnatal spine pruning
Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects
To our knowledge, our results are the first to show the role of microglial autophagy in the regulation of the synapse and neurobehaviors. We anticipate our results to be a starting point for more comprehensive studies of microglial autophagy in ASDs and the development of putative therapeutics.
So it seems like autophagy is also something we want. Another quote from wiki:
mTOR promotes the protein synthesis required for synaptic plasticity. Studies in cell cultures and hippocampal slices indicate that mTOR inhibition reduces long-term potentiation. mTOR activation can protect against certain neurodegeneration associated with certain disease conditions. On the other hand, promotion of autophagy by mTOR inhibition may reduce cognitive decline associated with neurodegeneration
This is not to say that the neuroplasticity induced by psychedelics is bad. It's a very consistent, rapidly acting antidepressant mechanism that's good for the brain in many ways.
We just don't want too much of it. We want to get rid of stuff too. So, we want to induce LTD/autophagy, preferably in the visual cortex. How do we do it?
There are some substances that might work. Neurosteroids come to mind as reliable neuroplasticity agents, but they might have a preference for LTP.
For example, pregnenolone:
If I'm reading this study correctly (it's possible that I'm not), they're suggesting that the LTP/LTD frequency curve shifts to the left, resulting in LTP happening more frequently and LTD happening less frequently (aside from the highest frequencies)
Increasing α4βδ GABAA receptor current with gaboxadol during puberty decreases dendritic spine density in adulthood.
Decreasing α4βδ GABAA receptor expression with THP during puberty increases dendritic spine density in adulthood.
These findings suggest that α4βδ GABAA receptors are a novel target to normalize spine density in adolescence.
These results may suggest new therapies for autism and schizophrenia where spine density and cognition are abnormal.
Pubertal GBX decreased spine density post-pubertally by 70% (P < 0.05), while decreasing α4βδ expression with THP increased spine density by twofold (P < 0.05), in both cases, with greatest effects on the mushroom spines. Adult relearning ability was compromised in both hippocampus-dependent tasks after pubertal administration of either drug. These findings suggest that an optimal spine density produced by α4βδ GABARs is necessary for optimal cognition in adults
THP being pregnenolone.
That study has a few too specific details.
- Adolescent mice
- Female mice
- CA1 region
I think that this reproduction study was not done during adolescence: Neurosteroid Effects at α4βδ GABAA Receptors Alter Spatial Learning and Synaptic Plasticity in CA1 Hippocampus Across the Estrous Cycle of the Mouse
Here, we show that impairments in both CA1 hippocampal LTP and spatial learning observed on the morning of proestrus are due to increased dendritic expression of α4βδ GABAA
Proestrous levels of 3α-OH-THP reversed the deficits in LTP and spatial learning, an effect prevented by the inactive metabolite 3β-OH-THP (10 mg/kg, i.p.), which antagonizes actions of 3α-OH-THP. In contrast, administration of 3α-OH-THP (10 mg/kg, i.p.) on the morning of proestrus improved spatial learning scores 150-300%. These findings suggest that cyclic fluctuations in ovarian steroids can induce changes in cognition via α4βδ GABARs that are dependent upon 3α-OH-THP
And this is not just CA1 but also CA3: α4βδ GABAA Receptors Trigger Synaptic Pruning and Reduce Dendritic Length of Female Mouse CA3 Hippocampal Pyramidal Cells at Puberty
These data suggest that pubertal α4βδ GABARs alter dendritic morphology and trigger pruning in female CA3 hippocampus
Also one of those studies (can't recall which one now, I think it was the first one) cited that they reproduced the same results in male rats after the reviewers wanted to know this.
So pregnenolone may be good for neuroplasticity but it seems to have a strong preference for LTP rather than LTD. Some neurosteroids will be similar, and other neurosteroids might do the opposite. This may be worth researching further.
I've already went into a lot of depth with neurosteroids and — being an extremely complex topic — there's a lot more to research.
If you're interested in looking more into this topic, you can start with this study: The Neurosteroids, Allopregnanolone and Progesterone, Induce Autophagy in Cultured Astrocytes
As I said in the introduction, HPPD is such a complex topic that saying "yes, this substance will work with 100% certainty based on this research" is extremely difficult. So you can just try these substances and see how they work. They have many other health benefits as well.
Next: You can see that one of the studies in the pregnenolone section mentions that gaboxadol can significantly decrease synaptic density. This one is interesting.
It seems like pregnenolone and gaboxadol interact with the same receptor to regulate synaptic pruning. Gaboxadol seems like a relatively safe sleep aid, but it's pretty obscure. So with regards to gaboxadol, I'll just say that it might be useful, so if you can get it, it's worth trying.
Next, lithium. Lithium is commonly used to treat bipolar personality disorder (BPD), but some people also use it as a nootropic supplement. Lithium can stabilize mood (duh), decrease insulin tolerance, and induce synaptic plasticity. As with many above mentioned substances, lithium induces primarily synaptogenesis, so it might be bad. But it seems to be pretty commonly used in the HPPD community, so there should be some reason for that.
And sure enough, lithium induces autophagy: Antidepressive-Like Effects of Rapamycin in Animal Models: Implications for mTOR Inhibition as a New Target for Treatment of Affective Disorders
Lithium, the prototypic mood stabilizer, was recently demonstrated to enhance autophagy in cells. Recent hypotheses regarding the source of therapeutic effects of lithium as well as other mood stabilizers and antidepressants suggest that they may stem from increased neuroprotection, cellular plasticity and resilience. Hence it is clearly a possibility that enhanced autophagy may be involved in the therapeutic action by contributing to increased cellular resilience. A well-documented mechanism to induce autophagy is by inhibition of mTOR, a negative modulator of autophagy and rapamycin (sirolimus) is a commonly used inhibitor of mTOR
So while lithium may lead to even more synaptogenesis, it could lead to enough autophagy to get rid of the negative effects of this synaptogenesis and ideally the your HPPD-inducing synaptogenesis. To go into a bit more detail, lithium seems to inhibit mTORC1, which means less autophagy and more synaptogenesis (both opposite of what we want), but overall it has a positive effect on autophagy, so there are more mechanisms involved. Worth trying, seems to be pretty low risk (as long as you don't combine lithium with psychedelics, since that has the undesirable side effect of: death).
I'll end this section by saying that I don't want to suggest anything that could lead to an excessive loss of synapses, this is a dangerous game. But it seems like some substances should be relatively safe and mild in their effects and as such could be worth trying.
I guess that the worst case scenario of excessive synaptic pruning is that you just add more mTOR-mediated synaptogenesis.
And a technical note: You may have noticed that the studies cited above mention multiple times that rapamycin does exactly what we want. Unfortunately it's pretty dangerous, unavailable, and we'd preferably use more innocent mTOR inhibitors. In the context of this article mTOR sounds like an asshole, but mTOR inhibitors are immunosuppressants decreasing cell growth, so we just want a slight nudge at most.
There might be an overexpression of AMPA.
LSD's antidepressant effect comes from activating and potentiating AMPA: Lysergic Acid Diethylamide (LSD) Promotes Social Behavior Through mTORC1 in the Excitatory Neurotransmission
These data indicate that repeated LSD selectively potentiates AMPA and 5-HT2A excitatory transmission of the mPFC.
Indeed, in vitro studies have shown that LSD increased the excitatory response of interneurons in the piriform cortex following AMPA
These experiments show that the prosocial effects induced by LSD require neurotransmission through mPFC 5-HT2A and AMPA receptors.
Standard antidepressants increase AMPA expression: Chronic Antidepressant Treatment Increases the Membrane Expression of AMPA Receptors in Rat Hippocampus
Chronic antidepressant treatment increases the membrane expression of AMPA receptors in rat hippocampus
Previously reported modifications in phosphorylating enzymes by chronic antidepressants could perhaps play a role in hippocampal membrane insertion of AMPAR subunits
NMDA antagonists that don't have any AMPA activity are not antidepressants, unless they're selective for the 2B subunit of the NMDA receptor: An Innovative Design to Establish Proof of Concept of the Antidepressant Effects of the NR2B Subunit Selective N-Methyl-D-Aspartate Antagonist, CP-101,606, in Patients With Treatment-Refractory Major Depressive Disorder
Antagonism of the NR2B subtype of the N-methyl-D-aspartate receptor may be a fruitful target for the development of a new antidepressant with more robust effects and a faster onset compared with those currently available and capable of working when existing antidepressants do not
These observations suggest that NR2B signaling limits AMPA receptor incorporation at developing synapses by negatively regulating TARP expression and provide a mechanism to explain the maintenance of low AMPA/NMDA ratio at immature glutamatergic synapses
Our experiments show that NR2B can act to negatively regulate the amount of AMPAR subunits and AMPAR-mediated current at synaptic sites in developing cortical networks.
So: NR2B => less AMPA
Remarkably, it appears this aberrant overabundance of NR2B can be ameliorated by even a single dose of an NR2B-specific or noncompetitive NMDA receptor antagonist (Iafrati et al., 2014). This effect highlights the extremely plastic nature of the juvenile and adolescent brain; a single attempt to normalize the neural environment can indeed result in lasting amelioration of early dysfunction.
A single dose of a NR2B antagonist can decrease NR2B expression, leading to more AMPA. This is what ketamine does, alongside agonizing AMPA directly.
So hypothetically, agonizing NR2B might decrease AMPA expression. But that receptor seems to be responsible for NMDA receptor excitotoxicity:
NR2B-containing receptors, especially those localized at extrasynaptic sites, mediate excitotoxic events that lead to neuronal damage and apoptosis (Hardingham, 2006), whereas NR2A activation stimulates pro-survival pathways
This is consistent with another study which says that synaptic NMDA promotes survival, whereas extrasynaptic NMDA promotes death.
So agonizing NR2B is a good target for us (presuming that the goal is reducing AMPA expression), but it could easily get excitotoxic. Maybe if we agonize NMDA non-selectively (or perhaps selectively to the NR2 subunit — but regardless of if it's A or B) we'll get the AMPA de-expressing effects of NR2B while getting the neuroprotective effects of NR2A?
This is entirely speculative, and caution is needed. But at reasonable doses, or when co-administered with neuroprotective agents, this might work?
Another thing that we might do is simply antagonize AMPA. This seems like the cleanest approach. Unfortunately AMPA agonists seem pretty rare.
Most of the ones I found are used in research only, but Perempanel is one that's prescribed for epilepsy.
As I mentioned, there are reports of racetams, usually noopept, causing changes in vision, close to HPPD. There's not a lot of science on this, but from what I found it seems like noopept initially works on the NMDA receptor and with chronic use on the AMPA receptor. This would make sense, considering the difference between acute tolerance-free noopept effects and daily noopept effects. I'd say that an acute dose makes things look zoomed and chronic use can increase visual snow a bit. This would make sense with the NMDA effects being opposite of dissociatives' effects and with AMPA increasing visual noise.
An interesting case is l-theanine. It has mixed reports, but seems to be usually bad for HPPD. It's technically an NMDA agonist and an AMPA antagonist.
Isn't that exactly what we want? It is, but theanine's effects are opposite to its pharmacology on paper. Or at least its pharmacology in simple words. The thing is that theanine is a competitive NMDAr agonist (= it competes with glutamate at the NMDA receptor) with a lower potency than glutamate. This means that it displaces glutamate from the receptor, and then goes on to activate it weaker than glutamate would have.
This is a good example of why I've said that the things I go over here are how it could work, but there's no guarantee that it will work. The real world has unexpected nuances.
Next: glycine. There have been some studies about glycine in schizophrenia, and it seems like high dose glycine (tens of grams) helps. Might be worth trying with HPPD.
And then you can try some paradoxical things too, like ampakines. In this write-up, I'm assuming that too much AMPA is a likely source of problems, but again the glutamatergic system is complex so only God knows what a specific substance will do with your HPPD. IDRA-21 is an available AMPA PAM if you want to try what that might do.
Aside from the glutamatergic system, we can affect excitation via the GABAergic system.
In the HPPD community, it seems like usually clonazepam and sometimes other benzodiazepines are used, though they don't seem to do much beyond anxiety reduction.
Benzodiazepines can be a bad idea if your HPPD is not severe.
If the dose is tiny and you're using them safely, they can be alright if they work. Seems like they might work sometimes: Hallucinogen Persisting Perception Disorder: Etiology, Clinical Features, and Therapeutic Perspectives
Benzodiazepines may be useful and effective in eliminating benign HPPD I and ameliorating, but not completely eradicating, pervasive HPPD II symptoms
Reading other studies (related to points in next sections), it seems like tonic GABA signaling is what we want the most. Tonic signaling is in the background, and phasic signaling is when synapses send signals.
HPPD has persistent visual disturbances both with eyes open and eyes closed, so it makes sense that tonic currents are what we want.
Interestingly, benzodiazepines don't do much for tonic currents. They seem to work mostly synaptically. Tonic currents are in extrasynaptic GABA receptors.
The reason why clonazepam is the preferred benzodiazepine of choice might be that it seems to be selectively anxiolytic without too many side effects. So it might be helpful if your HPPD is partially caused by anxiety.
Clonazepam seems to be selective for the a2 and a3 subtypes. These seem pretty useless for most seizures, but it's apparently used for myoclinic and absence seizures. Absence seizures in specific seem to have an opposite relation to the GABA system. Most GABAergic antiepileptics increase the tonic current, but this tonic current increase can cause absence seizures. So for those seizures GABAergics which have a more phasic effect are used.
Tonic GABA can be increased by inhibiting GABA transaminase: Looking for GABA in All the Wrong Places: The Relevance of Extrasynaptic GABAA Receptors to Epilepsy
For example, the anticonvulsant vigabatrin (VGB) is a GABA-transaminase inhibitor that leads to an increase in brain GABA levels (27), which was presumed to lead to an increase in the size of IPSPs. Surprisingly, VGB does not increase IPSPs, but instead causes a large increase in tonic GABAergic inhibition (21). It is believed that the anticonvulsant effect of this drug is due to this selective enhancement of tonic inhibition, which would be expected to reduce seizures, for example, by acting on a subset of hippocampal interneurons to regulate network excitability
However vigabatrin requires caution, since it's an irreversible inhibitor. A good safe GABA transaminase inhibitor is rosmarinic acid, found in lemon balm, spearmint, peppermint, rosemary, and related plants. Extracts might be decently potent, teas work too.
Next, you can try supplementing with GABA powder itself. If it were to increase GABA anywhere, it would be tonic currents.
Another way to increase GABA efficiency is to use emoxypine. It seems to increase how receptor membranes can bind to GABA.
Neurosteroids seem like a good candidate for enhancing tonic currents.
In late diestrus (high-progesterone phase), enhanced expression of δGABAARs increases tonic inhibition, and a reduced neuronal excitability is reflected by diminished seizure susceptibility and anxietyThere are thus multiple mechanistic possibilities for pregnenolone as a potential therapeutic agent in schizophrenia, including the amelioration of NMDA receptor hypofunction (via metabolism to pregnenolone sulfate) and the mitigation of GABA dysregulation (via metabolism to allopregnanolone)
There are studies and clinical trials suggesting the use of neurosteroids for schizophrenia, but some metastudy found that when more elaborate statistical analysis is done, one of the clinical trials didn't reach statistically significant results. This doesn't have to mean it's wrong, just that it doesn't confirm the hypothesis as strongly as we'd like.
in mean composite changes in two neurocognitive measures were not significantly different in patients randomized to PREG compared with placebo. Thus, when Bonferroni correction was applied, improvement on any outcome measure did not reach a significant level (negative trial). Over the last few decades, statistical analysis has increasingly been used in medical studies. Nevertheless, the hypothesis test has often been misused and misinterpreted. In adition, the number of subjects required is calculated (power analysis) because without this calculation, reliable conclusions cannot be drawn from the p‐values. For instance, a conclusion in this study (Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia ), based on a small sample and nonsignificant difference after Bonferroni correction between PGEG and placebo groups, can lead to an unsound clinical judgement.
Another thing worth mentioning is that a lot of these schizophrenia studies look at management of negative symptoms which means things like depression, mood issues, etc. The hallucinatory/delusional symptoms are the positive symptoms. So a lot of these studies seem to just show that X improves mood, but they put it in relation with a mental illness to give it a more clinically meaningful use. The same is with ASD studies, they report that some substance decreases irritation but overall that finding may not be really relevant to ASD.
The study Enhanced Tonic GABAA Inhibition in Typical Absence Epilepsy says that gaboxadol (THIP) and GHB increase tonic currents. Caution: they talk about this in the presence of TTX (some toxin) and GHB has excitatory effects too. Also, these are not substances to be used daily.
application of 0.1–10 μM THIP increased tonic current amplitude in TC neurons of the VB
Similarly, in the presence of TTX, application of 0.3–3 mM GHB, concentrations that induce SWDs in vivo27, significantly increased tonic current amplitude in vitro
Phenibut, gabapentin, and pregabalin might work too. I haven't researched that in specific, but I've seen people sue gabapentin, and these are all similar. They're also somewhat similar to GHB. Be very careful with these and don't use them habitually though.
What are alpha waves? Are they even real? I initially thought it's a woo concept made up by yoga bloggers, but seems like alpha waves are real and they have a decent link to HPPD.
LSD and psilocybin cause a huge decrease in alpha power in the visual cortex. This seems to be strongly linked to the hallucinations, because alpha power represents the inhibitory signal that prevents that part of the brain from going crazy. When this inhibitory signal is decreased, we get strong excitation and more connectivity with other parts of the brain: Neural Correlates of the LSD Experience Revealed by Multimodal Neuroimaging
Cortical alpha has been hypothesized to serve a general inhibitory function, filtering out “stimulus-irrelevant” information (34). Thus, reduced alpha power (9, 29, 35) could have disinhibitory consequences, facilitating the release of anarchic patterns of excitation that manifest spontaneously and experientially as visual hallucinations. This hypothesis is leant (indirect) support by two prior studies that found reduced spontaneous visual cortex alpha power under psilocybin alongside reduced evoked visual responses
Increased visual cortex cerebral blood flow (CBF), decreased visual cortex alpha power, and a greatly expanded primary visual cortex (V1) functional connectivity profile correlated strongly with ratings of visual hallucinations, implying that intrinsic brain activity exerts greater influence on visual processing in the psychedelic state, thereby defining its hallucinatory quality
(I had a paragraph here about artificially increased alpha waves decreasing the hallucinatory effects of psilocybin, but I quoted the wrong source, and now I can't find the right source. So either one of the studies I read said this, or I misread and misinterpreted something. Either way, it would be in line with the rest of this section.)
So reduced alpha power leads to unconstrained vision.
eyes-closed fMRI recordings during ayahuasca hallucinations suggest the visual cortex behaves “as if” there is external input when there is none
The present findings of increased visual cortex CBF, expanded V1 RSFC, and decreased alpha power may be seen as consistent with the notion of “seeing with eyes-shut” under psychedelics, because they are all properties normally associated with visual stimulation
Very relevant! We want to increase alpha power then.
There's a lot of valuable information in this study: On the Physiological Modulation and Potential Mechanisms Underlying Parieto-Occipital Alpha Oscillations
As I said in the first few sections, HPPD is more noticeable when you're sitting still, and less noticeable when you're moving. Visual snow and auras around objects only come up when you're looking at things from a static perspective. The alpha wave hypothesis supports this:
when attention is directed to internal representations, such as during visual imagery and retention of working memory, alpha power increases with attention
Alpha waves increase as attention increases. Alpha waves decrease when you're more relaxed. This makes sense with non-hallucinatory vision as well — you see significantly less of your environment when you're focusing on a task.
Extrasynaptic GABA = tonic GABA current = alpha waves
Extrasynaptic GABAARs generate a persistent hyperpolarizing current which makes it less likely to generate an action potential. Even in the case of depolarizing GABAergic currents, the tonic conductance decreases the membrane resistance, making the neuron less sensitive to sharp changes in voltage, thus attenuating the effect of excitatory input at the synapse
These extrasynaptic receptors generate non-desensitizing tonic inhibition currents that are highly sensitive to the extracellular GABA concentration
Interestingly, lorazepam (a benzodiazepine) decreased alpha power:
The increase of GABA efficacy leads two main predictions. First, if alpha is exerting its functional inhibition role through physiological inhibition, GABAergic enhancement should increase tonic alpha power. Second, this alpha power attentional modulations should increase parametrically with drug dosage. We found robust evidence in the opposite direction for both predictions. First, lorazepam strongly decreased both tonic alpha power and attentional power modulations
This might make sense, considering that benzodiazepines (with the interesting exception of clonazepam, as I mentioned in the GABA section) are generally not used for HPPD. I looked into clonazepam and it might be very selective for the anxiety-related subtypes of GABAA, so perhaps its use in the HPPD community is being a semi-sustainable anxiolytic.
I believe that their explanation was that benzodiazepines are also active in other parts of the brain which affect the alpha power, so overall they decrease alpha power.
So this might be why benzos aren't used that much.
Cholinergics, on the other hand, seem great:
Physostigmine (cholinergic enhancer) increases the attentional alpha power modulations in parieto-occipital cortices relative to placebo during the cue interval of a visuo-spatial attention task
It has been reported that while muscarinic blockers like scopolamine diminish the resting parieto-occipital alpha oscillations
Muscarinic activity is better than nicotinic activity, but IME nicotine is good too.
To enhance general cholinergic activity, you can use an acetylcholinesterase inhibitor like Huperzine A. It's a commonly used nootropic, so it's pretty safe (though be warned about the potential GI distress if you're sensitive to it).
We don't know if NMDA or AMPA has an effect on alpha power. The study itself makes contradictory claims:
In line with this hypothesis, blocking excitation by NMDA antagonists reduces alpha power in humans
Finally, a recent ground-breaking monkey study has found that both AMPA and NMDA blockers consistently suppressed alpha power in V1
Surprisingly, the same ketamine and perampanel (AMPA blocker) produced no apparent effect—either in the posterior alpha power, or the frequency in visual stimulation tasks
Seems like glutamatergics do different things in different contexts.
Alpha frequency is typically around 10 Hz and if I'm reading this right, LSD increased the frequency (not power) to 15-20 Hz? Meaning that the frequency might be relevant too. So we'd want higher power and lower frequency — the opposite of LSD effects.
Importantly, these LSD-induced brain activity changes the predicted quality and intensity of the visual hallucinations (Carhart-Harris et al., 2016). This study also found that LSD produced a remarkable increase in alpha frequency Figure Figure1d.1d. What might be the functional relevance of this peak frequency change? LSD users often report dramatic visual disturbances or “visual trails” where they perceive a series of discrete stationary images trailing in the wake of otherwise normally moving objects (Dubois and VanRullen, 2011). To estimate the sampling rate of visual trails, Dubois and VanRullen created 10 short movies of 4 frames each, varying the inter-frame interval from 25 to 250 ms. They released the movies on a website and asked self-declared past LSD users to decide which movie best matched their recollection of psychedelic experiences. Interestingly, LSD users reported visual trail periodicities around 15–20 Hz (Dubois and VanRullen, 2011). Although highly speculative, the alpha power suppression and the frequency increase with LSD consumption might produce the segmentation of visual experiences into visual trails, a pharmacologically-induced form of perceptual cycles (VanRullen, 2016). New experiments are needed to test this possibility
Basically most GABAergics have the opposite effect:
In conclusion, pharmacologically increasing GABA efficacy leads to a decrease in power of the classical alpha—but, what is the underlying mechanism
However, I found that GABA ... itself increases alpha waves. Which is actually pretty intuitive, it preferentially binds to the extrasynaptic receptors which create a tonic current.
Using electroencephalography (EEG), experiment 1 from Abdou et al. (2006) showed that 100 mg GABA in 200 ml water increased changes in (i) alpha waves (compared to water condition) and (ii) alpha/beta ratio (compared to water and theanine condition). They also reported a trend for reduced changes for beta waves in GABA vs. water condition
Maybe combining GABA with neurosteroids which increase tonic GABA currents can make this even stronger. Not sure, might be worth trying.
Slight cautionary note: Don't take high doses of GABA if you haven't used it before. Even though it's a commonly sold supplement, it can give some people shortness of breath and itchy skin.
I tried 130mg GABA a few times and it does decrease palinopsia, auras around objects, and visual snow/CEVs in the dark. In light environments the background visual snow persists, but it doesn't gather around objects. (Worth noting that I have a very mild form of HPPD which usually goes away in a few weeks. It's more on the level of being an aesthetic enhancement.)
I found contradictory evidence about l-theanine's effect on alpha waves. A lot of studies say that it increases alpha power (a nice-sounding value prop shared by clueless fitness bloggers), while others say that it decreases alpha power. Even if it increases it, it's possible that the unfortunate glutamatergic effects overpower any alpha power increase, making theanine counterproductive. That is, if theanine is bad in your case.
Noopept seems to increase alpha activity under some conditions, but I think I've read that it can decrease it as well. Regardless, seems counterproductive for most.
Lost the source for these quotes but it seems like neurotrophins (such as BDNF) are also region-specific in their effects. They can "reduce dendric elaboration" which might be what we want.
Treatment of layer 6 neurons with BDNF and NGF produced an unexpected result. Rather than enhancing dendrites as in layers 4 and 5, BDNF and NGF decreased dendritic growth
Neurotrophins could, in some cases (e.g., NGF and BDNF in layer 6), reduce dendritic elaboration, a phenomenon not previously reported for peripheral neurons. This indicates that, at least in neocortex, the same neurotrophin can regulate dendritic growth in both positive and negative directions.
This explains why some generic neuroplasticity supplements like Lion's Mane, 7,8-DHF, and NSI-189 might work.
Kindling is a concept in epilepsy which refers to how seizures tend to come in waves. Having a seizure increases the chance of having a second seizure, which will then increase the chance of having yet another seizure.
Since seizures are basically excitatory overload, it seems like the mechanism behind kindling is excitation creating more excitatory circuits.
The same term is used for how GABAergic withdrawals can get progressively worse:
Repeated benzodiazepine withdrawal episodes may result in similar neuronal kindling as that seen after repeated withdrawal episodes from alcohol, with resultant increased neuro-excitability. The glutamate system is believed to play an important role in this kindling phenomenon with AMPA receptors which are a subtype of glutamate receptors being altered by repeated withdrawals from benzodiazepines. The changes which occur after withdrawal in AMPA receptors in animals have been found in regions of the brain which govern anxiety and seizure threshold; thus kindling may result in increased severity of anxiety and a lowered seizure threshold during repeated withdrawal.
Kindling might be the mechanism behind psychedelics and racetams inducing prolonged excitatory activity in the visual cortex (and probably other parts of the brain). Mad.Science.Blog originally came up with the term "kindling" in the context of nootropics.
Kindling is formally related to epilepsy, which leads us to anticonvulsants. Anticonvulsants are the first-line treatment of epilepsy. They work by decrease excitatory activity, especially in the parts of the brain that are related to seizures.
We don't really care about seizures, but we care about overexcitation.
So, how do anticonvulsants work?
They are typically blockers of presynaptic excitatory (sodium/calcium) ion channels.
Ketogenic diet has proven useful in epilepsy, this may be due to an increase in things like β-hydroxybutyrate and a decrease in aspartate (closely related to gutamate), and a lot of other things. We don't understand exactly why keto helps with epilepsy, but we know a lot of these small things. They probably add up.
Anticonvulsants seem to be the go-to medication in the HPPD community. Lamotrigine (Lamictal) and Levetiracetam (Keppra).
This is the fun section. Based on all the research above, here's what I think might work very well (but is also experimental and might work terribly).
AMPA antagonists like Perampanel. It's an anticonvulsant antiepileptic, but it's an ion channel blocker. It's specifically an AMPA inhibitor so if my assumption that HPPD is related to an excess of AMPA signaling (which is slightly confirmed by the fact that anticonvulsants are the main medications used in the HPPD community) is true, this class of medications can be great.
Next: mGluR2,3 agonists. mGluR2 and mGluR3 are subtypes of the metabotropic glutamate receptor. Interestingly, agonizing these receptors has an inhibitory effect (but it's important that it's just these two subtypes).
The best studied drug in this class seems to be Eglumegad which, according to Wikipedia:
was found to be as effective as diazepam for treating anxiety symptoms in several standard tests, but without producing any of the negative side effects of diazepam such as sedation and memory impairment.
Tests in humans confirmed that it produced anxiolytic effects without producing sedation.
However it did slightly reduce cognitive performance in tests on monkeys.
Eglumegad has also been found to be effective in relieving the symptoms of withdrawal from chronic use of both nicotine and morphine in animals, as well as inhibiting the development of tolerance to morphine.
Eglumegad and related drugs are neuroprotective and are synergistic with the neuroprotection produced by N-methyl-D-aspartic acid (NMDA) antagonist drugs, which may make these drugs useful in aiding recovery from brain injury.
This class of drugs also interacts with hallucinogenic drugs, with eglumegad reducing the effects of 5HT2A agonist hallucinogens
So it's an anxiolytic, antipsychotic, antiglutamatergic, antiaddictive neuroprotective drug.
Too good to be true? Probably. But it's surprisingly unknown.
There are other drugs in this class, namely LY-404,039; LY-487,379; and LY-379,268. From the research papers that I read, mGluR2,3 agonists seem like a very promising class of drugs. I hope this article raises awareness of them, at least a little bit.
The paper that described the Bayesian NMDA top-down and AMPA bottom-up signaling also mentioned that potassium channels may be the true underlying mechanism behind these drugs.
It's also worth mentioning that the famously obscure sigma-1 receptor seems to interact with potassium channels, and DMT is a sigma-1 agonist. Specifically, DMT opens potassium channels. Might be related to why DMT doesn't cause HPPD that much?
And on that note — potassium channel openers (potassium is inhibitory) are a new class of anticonvulsants. They seem very promising for tinnitus, but they also seem to have bad side effects being so new. Some people reported that they reduced their tinnitus, but gave them visual snow. I think we'll pass on that. But good to keep in mind as a potential future treatment.
A related and possibly useful solution can be a potassium supplement. It seems like most people may be slightly deficient. Potassium is not as important to supplement as magnesium, but still may be worth trying.
I also mentioned autophagy agents and NMDA/AMPA agonists/antagonists (likely AMPA antagonists, maybe NMDA agonists, and unlikely but possibly the opposite). I'm including them here again to make it clear that they're part of the experimental group of substances. Same with gaboxadol.
The rest that I mentioned seem to be mostly incapable of causing great harm, and they're all pretty well studied (i.e. the neurosteroids, GABAergics, neuroplasticity supplements, etc)
There are reports of further single-dose psychedelics or dissociatives fixing HPPD from past experiences.
Of course you don't want to risk this if your HPPD is not benign. You also don't want to risk this if you only used a hallucinogen once and got HPPD from that.
If you decide to do this, I'd probably go with substances in this order:
- Memantine — pretty pure, usually non-recreational, dissociative, not too much AMPA activity
- Ketamine or other dissociatives — dissos cause HPPD infrequently compared to psychedelics. And there are reports of dissociatives fixing psychedelic-induced HPPD.
- DMT — short lasting, seems to cause HPPD infrequently or not at all
- Psilocybin — shorter lasting than LSD, seems to be popular for fixing HPPD and doesn't cause HPPD as often as LSD
- Other psychedelics — proceed with caution
If this approach works, then this indicates that psychedelic neuroplasticity is not strictly more synapses in visual cortex, but a more random effect that simply has a bias towards VC synaptogenesis.
Which means that other neuroplasticity agents with a potential for both LTP and LTD can be useful even if they seem mostly counterproductive.
Also, this is more of food for thought than a recommendation, but I've read that DiPT — an almost purely auditory psychedelic — can cause auditory HPPD. This makes me think that strong neuroplasticity agents with a strong bias towards visual effects are what causes the usual HPPD. That's also in line with the more visual racetams causing HPPD-like symptoms.
Other hypotheses include toxicity or some sort of permanent inhibition.
I think that from the brain scans it's pretty clear that if there's an inhibition, it's an inhibition of inhibition. Parts of the HPPD brain are overactive. Technically the regulatory mechanisms are hypo-active, but the end result is more excitation.
So the psychedelic definitely didn't take anything away from the brain, it most likely strengthened excitatory circuits in parts of the brain (the study on LSD's pro-social effect also mentions that the effect is dependent on excitatory AMPA receptors).
This, combined with the absolute lack of proof of any neurotoxicity of classical psychedelics despite being studied extensively, is in my view a pretty clear indication that there's no toxicity taking place either.
Overview of causes
- Likely: synaptic overgrowth, AMPA overexpression
- Relevant: too low alpha wave power in visual cortex, possibly leading to overexcitation
- Possible: psychological aspect, learned Bayesian beliefs about visual distortions
It's likely a combination of these things.
Overview of treatment
Ideally HPPD could be fixed with a single dose of something, just like a single session of hallucinogens can sometimes fix it.
The point of my research was to look at the causes and hopefully identify such substances. I didn't manage to do that, but I think the pathways I outlined above have a reliable effect on HPPD and can be a good framework for experimenting with supplements.
In my opinion, these are the best treatment options, in this specific order:
- Don't delay this, treat it as soon as you can. Also don't stress that you didn't treat it earlier, now is fine. Just sooner is better. Also, if any step makes your HPPD consistently worse, skip it.
- If you're taking any nootropics, stop. Take a break for a few days and establish a baseline state without them.
- Follow principles in the section below — drug-free treatment including the supplements
- Supplements to suppress the symptoms: cholinergics (Huperzine A > nicotine), tonic GABAergics (lemon balm/spearmint/peppermint/rosemary extract or tea), GABA powder, smell lavender aroma
- If you know what you're doing, neurosteroids (progesterone > pregnenolone). Probably taken before bed.
- Lithium, gaboxadol if you can get it (you likely can't), possibly curcumin. They should help with pruning excessive synapses.
- Try glycine (possibly high dose), d-serine, emoxypine.
- Low dose clonazepam or another benzo. See if it decreases the symptoms without causing many side effects. If yes, look up how to take tiny doses safely.
- If your symptoms haven't diminished much, try the commonly used anticonvulsants — Levetiracetam and Lamotrigine
- If these things did make the symptoms better, or at least didn't make them worse, try adding neuroplasticity agents. Probably Lion's Mane > 7,8-DHF > NSI-189. Drop them if they make it worse.
- Carry on being healthy and wait it out.
The rationale of this treatment is to get rid of the HPPD while it's still new and I'd assume it's easier for the brain to reject it. When seeing auras around people is what you're used to, you'll probably have a harder time getting rid of it — similarly to if you were used to seeing your nose, like you do now because I suggested it. Pretty annoying, but because you weren't focusing on it, you learned to ignore it.
So the goal is to create a lifestyle that gives the least power to HPPD and then trying neuroplasticity regimens to adapt to the low-HPPD state.
It's definitely not a bulletproof approach and you'll encounter paradoxical interactions, but from all the research I've read on this topic I think that this is a good framework to use.
I also made a table with these substances. It lists popularity, safety, potential efficiency, mechanism of action, and notes for each substance. https://airtable.com/shr56w3DEjfbpw5BS
If I were to treat HPPD without drugs, I'd try to:
- have an active lifestyle that doesn't involve staring at static objects
- avoid dark places, go to sleep early
- RELAX. If one of the causes is lack of inhibitory brain waves in the visual cortex, you should be
- living a low-stress life. Meditation is said to help with HPPD. Breathe well and get sunlight
- have a lifestyle that supports neuroplasticity without biasing for growth, i.e. exercise, fasting, possibly keto and avoiding overeating
- have enough minerals, especially magnesium, since that's the one everyone is deficient in
- social contact helps, it's easier for trippiness to creep in when you're alone
(Now that I mentioned fasting I remembered that some people had success with this and almost felt like it was their gut microbiome having issues. Fasting supports autophagy.)
If I were to add non-drug supplements to this, I'd add NAC, vitamins (C, B, D — not CBD, though you can try), acetyl-l-carnitine, and possibly magnesium, glycine, taurine, zinc, GABA, potassium.
If you're organized, you can try doing self-blinded experiments with these substances. Some of the effects are mild, some days have natural fluctuations that can result in misattribution, and then there's of course placebo. Nothing wrong with placebo reducing your HPPD, but you don't want to falsely believe that it reduced your HPPD if it didn't (perception and belief can be separate).
Once you have enough data, you can calculate the correlations etc.
If you're currently experiencing HPPD, I'd appreciate if you filled out this survey.
It will take less than 3 minutes.
Most of the questions are related to HPPD extent and what substances worked and didn't work for you. That way I can compare real world results with the theoretical pharmacology above, and the results (which will be public) can help others see what treatments worked best for others.
I wrote this article, I let it sit for around a week, and now I'm publishing it.
During that time I dropped all racetams, exercised, avoided too much stress, slept well — and my symptoms largely disappeared. (My symptoms were slight auras, visual snow, and palinopsia — not severe in any sense, I did this research only to be capable of fixing HPPD in the future and to help others who have it worse.)
By this I want to emphasize the treatment steps of: dropping all nootropics and living a healthy lifestyle.
A week ago I published the survey on reddit and the HPPD forum and I got 54 responses. You may view the responses here
When there's more data, I'll clean it and do summaries of the effects of specific substances.
Thanks for reading this, I hope it helps, at least a little bit.