Adverse Drug Reactions in Autism

Have you ever heard that autistic people often have adverse or unexpected reactions (or total lack of response) to prescription and over-the-counter medications? Well, it could be genetics, pharmacogenetics, that is!

Topics discussed also include:

• Ultra-rapid and very slow drug metabolizers
• How medication sensitivity is not hypochondria
• Mast cell activation syndrome and medication fillers
• Autistic folks' reactions to psychotropic drugs

If you'd like to know more about topics discussed in this episode, check out:

"Pharmacogenomics of Autism Spectrum Disorder" by Brown et al.

"Pharmacogenetic Influences on the Response to Pharmacological Treatment in Autism Spectrum Disorders" by Hervas et al.

"Get to Know an Enzyme: CYP2D6" by Horn and Hansten

"What is Pharmacogenomics?" —National Institute of General Medical Sciences

"The Medications Used to Treat Symptoms of Autism Spectrum Disorder" by Regan

"Recognition and Management of Medication Excipient Reactivity in Patients With Mast Cell Activation Syndrome" by Schofield and Afrin

Episode intro and outro music: "Hachimantai Snow" by Maarten Schellekens (no changes or modifications were made)

Theme music: "Everything Feels New" by Evgeny Bardyuzha.

All episodes written and produced by Kristen Hovet.

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The views, opinions, and experiences shared by guests on this podcast are their own and do not necessarily reflect those of the host or production team. The content is intended for informational purposes only and should not be taken as medical or professional advice. Please consult with a qualified healthcare provider before making any decisions related to your health, fitness, or wellness.

Transcript

Today we're answering a listener question about medications and side effects in autistic people. Specifically, this listener talked about very pronounced and unexpected unpleasant reactions to common medications. And, in some cases, these reactions lasted for weeks. So let's explore some possible reasons for why this happens. Before we get into that, I have a couple announcements. First of all, the microphone drama continues, but it ends today. I still heard microphone popping in the last episode when I was editing, even with my fancy podcaster trick that I learned from Reddit. So I went out and bought a pop filter or pop screen for my microphone. It was the very last one in the store. If this doesn't work, I'm going to throw my computer across the room. Not really, but popping sounds drive me bonkers. So I'm sorry to have driven others bonkers, too, if that's something that bothers you. Anyhoo, I hope today marks the end of popping sounds for good. I hope today also marks the start of being able to get worked up without fear. And second announcement is, there's a new feature on the podcast's website, on Buzzsprout, that allows you to become a supporter of the show. You can find a link to the supporter page that details all of this in the show notes. The link is at the very bottom and says become a supporter of the show for as little as $3 a month. Your support will help keep the number of ads in the episodes to a minimum and will help me produce more and better content. What's cool about the supporter page is that you get to choose a little emoji to represent yourself as a fan. I think that's pretty cute. I'm also thinking of some ways to produce content, especially and solely for supporters of the show. If you have some good ideas as to what that content could be, let me know. Maybe you want a shout out, maybe you want to send a message to a loved one via my voice on this podcast. I don't know. You tell me. Email address is, as always, in the show notes. This is a long ass intro, so I think it's time for some music.

I'm excited to talk today about autism and pharmacogenomics. In simple terms, we're talking about drug metabolism and the fact that many autistic people have adverse or unexpected reactions to medications. I'm going to use the word drug in this episode. It's a common term in medical research. I'm referring to prescription medications, not street drugs. In some sections, I'm also referring to over the counter medications. So these adverse or unexpected drug reactions can include either reacting to even small doses of certain medications or having zero reactions or responses to large doses of other medications. And, of course, everything else in between those two extremes. Anecdotally, these types of adverse reactions are well known, although it's hard to find good, solid research on this, and specifically I'm talking about within the autism community. 

Pharmacogenomics is the word for the field of study that looks at how a person's genetics affect how they respond to or metabolize medications. The term pharmacogenomics is sometimes used interchangeably with pharmacogenetics. I love how the National Institute for General Medical Sciences' website discusses pharmacogenomics. They give the example of how genes determine our hair and eye color. Well, our genes also determine how we process or metabolize medication. For some classes of medications, depending on what biological pathway is responsible for breaking them down, a person can be an ultra rapid metabolizer while they can be poor or very slow metabolizers of other classes of medication. And there's, of course, a spectrum of drug metabolism. 

One example of a key player in drug metabolism is a liver enzyme called CYP2D6, which acts on or breaks down approximately a quarter of all prescription medication. I've also heard this enzyme pronounced SIP-two-D-six. And I kind of prefer that. It's faster. There are 160 variants of the CYP2D6 gene in humans. While most of these variants don't impact drug response, some of them do, and very much so. Certain variants are associated with super fast drug metabolism, for example, or super slow drug metabolism. For some enzymes, the breaking down of medication very rapidly is associated with the medication having very little or almost no effect. In other words, the person can take a large dose, and the medication will do hardly anything at all. For other medications, however, an enzyme might have to convert the drug into a different form. For example, codeine is broken down and converted into morphine, by the CYP2D6 enzyme, otherwise, there would be no analgesic or pain killing effect. In this example, with codeine converted to morphine, super fast metabolism can lead to actually way excess morphine in the body, which means potentially scary overdose situation. For these folks, even a standard dose of codeine can be dangerous. 

It appears that autistic people may have more genetic variants associated with drug metabolism speed or rate, leading to a collection of adverse or unexpected responses. Anecdotally, I hear about this all the time from others in the autism community. It's definitely a thing. And I can say with certainty that it's not about us being more sensitive to the effects of medication or something like that, like being more aware of what the medications are doing. What I mean is that the adverse reaction is not some kind of hypochondria, or hyper awareness of somatic or body based effects, but is a real genetically based set of differences. And the reason I say this is because a lot of us have stories where we have gone to doctors about something, about a reaction that we've noticed, and we've been questioned or told it's in our mind, or straight up told that we're overreacting or something like that. So a lot of us have become scared of actually talking to medical professionals when these things happen. And that's not good either. So anyway, that's why I mentioned that. 

I can tell you that I definitely have adverse responses to medications, and some of these responses appear to be associated with mast cell activation syndrome. For example, for me, salicylic acid and acetylsalicylic acid in aspirin cause a severe set of reactions, including anaphylactic reactions. I'm so sensitive that even naturally occurring salicylates in some foods cause reactions and toxicity. If I have enough, we're talking emergency room level stuff. Before I knew what I was reacting to, or before anyone else knew what I was reacting to, I carried an EpiPen. Now that I know what I'm reacting to, now that I know that salicylates are one of the triggers in my mast cell activation syndrome, and now that I avoid high salicylate products like the plague, and I'm on daily medication to take the edge off of basically ongoing reactions, I don't need to carry one around anymore. But all that to say, these reactions can be quite something, dramatic and potentially dangerous. I'd love to know if this is due to some funky genetic variant or set of variants. I'm sure it is, but I'd love to know exactly which variants, which genes, which chromosomes and all that. We do know that mast cell activation problems are often seen alongside autism and connective tissue disorders like Ehlers Danlos. So it's definitely all looking genetic to me. And I've talked about this before in other episodes, but I have been diagnosed with all three: mast cell activation, type three Ehlers Danlos, and autism. And my geneticist told me that she sees these three co-occurring in so many patients. 

Also, I react oddly or unexpectedly to most medications, not just those with salicylic acid or salicylates. For example, it takes me forever to wake up from general anesthesia, yet I required double or triple local anesthetic, like lidocaine, during dental procedures. Clearly, I process some drugs very, very slowly and others very, very quickly. I don't think there's a middle ground with any medication for me. Even natural supplements like melatonin leave me comatose, even with the lowest dose available on the market. This is all frustrating and scary because I never know how I'm going to react to a new medication. And I hope one day I can get a whole genome test done specifically looking at all the potential drug metabolism related genetic variants. But of course, a lot of these variants haven't been detected. And if they have been, they don't know exactly like what they are associated with. And in many cases, a specific reaction or syndrome is based on many variants working together all at once. So it's never a super easy, clear picture when it comes to this stuff, or often it isn't anyway. 

Interestingly, I did 23andMe and one of the things they tested for is caffeine metabolism. Turns out I'm a very slow metabolizer of caffeine. Caffeine is metabolized by the CYP1A2 enzyme, a member of the cytochrome P 450 super family of enzymes, for anyone keeping track. Now CYP1A2 is responsible for breaking down many food additives, too, including food colorings, preservatives, and so on. This may be why I can't have food with these things added to them. I get hives, I sometimes have trouble breathing, I get angioedema, which is swelling below the skin. If anyone knows, are there ways to increase CYP1A2 activity, any drugs, any supplements? I mean, I'm hoping for a CRISPR-Cas9 gene editing cure, but I don't think that'll be happening anytime soon, unfortunately. 

This all leads me to wonder if researchers are looking in the wrong place sometimes when they're studying specific drugs. What I mean is that research participants could be reacting to the fillers in medications, the artificial colorings, the starches, the binders, the preservatives, and all of those things. In industry terms, these are called excipients. I've included an article on mast cell activation and excipients in the show notes, for those interested. 

Now, most studies looking at adverse drug reactions in autistic people have focused on antipsychotics, antidepressants, and stimulants. In other words, the most common classes of medications given to this particular population to manage anxiety, mood disorders, hyperactivity, and other behaviors. So the research I'm going to cite here has to do with those medications. And it's worth noting that only around 1/3 of autistic people are prescribed these types of psychotropic medications or medications that act on a person's mental state. That's what psychotropic means. Unfortunately, adverse responses to medications in Autistics of all ages, and reactions to a variety of classes of medications, are under studied. 

Jacob Brown and his team, in an article titled pharmacogenomics of autism spectrum disorder, note that wide variations in response are commonly seen in autistic patients who are prescribed the above mentioned classes of medications. In other words, the psychotropic medications. Pharmacogenomics, the authors state, can help identify which individuals will respond well to certain psychotropic medications and which individuals might need to avoid certain psychotropic medications altogether. Pharmacogenomics can also help determine dosing and titration, which refers to dose adjustments over time. That said, I think they were talking about in the future, when pharmacogenomics gets to a more advanced place, when they know more about the genetics behind the various drug responses, and especially when it comes to adverse reactions or unexpected reactions. 

And Amaia Hervas and her team, in an article titled pharmacogenetic influences on the response to pharmacological treatment in autism spectrum disorders, note that autistic patients commonly experience treatment failure and side effects to medications. In their study, they were also looking at psychotropic medications. This research team found several associations between the genetic variants they were looking at and clinical outcomes in autistic patients. An SLC6A3 genetic variant, associated with dopamine transport, predicted drug responses to Ritalin, while HTR2A and HTR2C, genes involved in the serotonin pathway, variants there were associated with various adverse reactions such as excessive fatigue, mood alterations, and BMI disruptions following medication use. And, side note, I recall reading research papers detailing the known differences in dopamine and serotonin signaling in autistic people compared to non autistic people, at least at the population level. So that might be definitely something interesting there. 

An article by Dr. Theresa Regan notes that autistic patients with ADHD or ADHD symptoms who are treated with stimulant medications, like Ritalin, report more side effects such as insomnia, anxiety, stomach and gastrointestinal problems, excessive fatigue, and headaches compared to non autistic patients taking the same medication. So what's clear in all this, at least in my interpretation, is there's definite genetic factors at play in how autistic people metabolize medications. While genetics play a role in how anyone, autistic or not, metabolizes medication, it appears that autistic people may have more genetic variants underlying adverse or unexpected responses to medications. More research is needed to really look into this topic and lead to helpful and actionable results for the autism community. 

Before wrapping up, I wanted to say that in the last episode, I put out a call for diagnosis stories, specifically stories of late diagnosis in adulthood. And I've heard from a handful of people. I want to thank you all so far for getting in touch with me and have got a couple lined up so far. And a couple more I'm waiting to hear back. So excited about that. I offered a Zoom call that would be recorded and potentially played on a future episode, but I know that not everyone is comfortable hopping on a Zoom call with a stranger. So if you'd prefer, please email me your diagnosis story. Let me know what name you want to go by and I may read it in an upcoming episode. Stay tuned for some bloopers, which are just really quick little clips that I've pulled from the recording, basically me responding to sounds coming from my neighbors. Well, that's all I have for you today. Thank you so much for being here.

Until next time, bye.