by Dan Rusyniak
Let me just get this out of the way, I hate bupropion (Wellbutrin™ ) with the “white-hot intensity of a thousand suns” (Hulu). There is nothing “Well” about this drug. It was first synthesized by Burroughs-Wellcome (no, you are not Wellcome) in 1966, and was first approved by the FDA in 1989 as an antidepressant. It was pulled off the market, however, as it was found in post-marketing studies to have a significantly higher rate of seizures (~0.4%) than other second-generation antidepressants. Not willing to leave ill enough alone, they reformulated the drug as a sustained release version that lowered its seizure incidence rate to a more acceptable 0.1%.
So why do I hate this drug? But before I go there, a brief digression. It is important that everyone reading this understands that I am writing from an odd perch. My perspective is skewed, as if I borrowed someone else’s glasses. As a medical toxicologist, I only see the problems drugs cause. No one is calling up the poison center and telling the specialist “hey, guess what, I’m taking Xyban and I haven’t smoked in 7 months!” When you work at Midas all mufflers are broken. Ok, back to why I don’t like this drug. First, let’s look at its structure (it is a tox blog, of course there are structures). All structures were modified from Wikipedia. 
This is the structure of methamphetamine. It is a classic phenethylamine. That is to say it has a phenyl group (blue) and an ethylamine group (yellow). Throw in two more CH3’s and you get methamphetamine. Just ask Jessie Pinkman, yo.
Now, this is the structure of methcathinone (beta-methylamino-propiophenone or ephedrone). You may notice (if you did, you should do a tox fellowship) that it is nearly identical in structure to methamphetamine, with the exception of the double-bonded oxygen (beta-ketone in red). That ketone group makes this structure a cathinone. If you take away one CH3 group from this structure you get a naturally occurring stimulant found in the plant Catha edulis (khat). It is perhaps best known as that stuff the Somali pirates chewed in the movie Captain Philips.
Stay with me. . . only two more structures.
This is the structure of mephedrone. It is a “popular” bath salt. You know bath salts as the stuff that causes users to eat people’s faces (now you're awake). What do you notice. . . YES!!! It is a cathinone. All bath salts are synthetic cathinones.
What does any of this have to do with bupropion? Well let’s take a look at its structure.
So that drug that we use for smoking cessation and is written like candy to treat depression, is a sustained release bath salt. This is why persons who take bupropion can have urine drug screams that are positive for amphetamines (Casey 2011 PMID:21191682). It is also why, unsurprisingly, overdoses of it can cause tachycardia, agitation, hypertension, and seizures. All of these drugs work similarly by blocking the reuptake of dopamine and norepinephrine.
One of the main reasons I hate bupropion is because in overdose it is really, really bad. The two most concerning effects are seizures and cardiac toxicity.
So, while it might be technically incorrect to say bupropion causes seizures, it is probably more accurate to say bupropion metabolites (especially 6-hydroxybupropion) cause seizures; at least that is true if you are a Swiss albino mouse (Silverstone 2008 PMID:18922171). Seizures can occur even in persons taking bupropion at therapeutic doses, so it is no surprise that in overdose it is a common event. The risk is dose-dependent. In overdoses involving more than 3g of bupropion, the question is not if the patient will seize, but rather when they will they seize. Bupropion is now the most common cause of seizure in overdose (Thundiyil 2007 PMID:18072153). Seizures can be single, multiple, or can evolve into status. Patients can develop seizures as the only sign of toxicity. Most, however, will develop tachycardia and altered mental status before they seize. So, if you have a bupropion overdose and the patient is tachycardic and goofy, don’t sit around and wait for seizures – prevent them! All of these patients (IMHO) need either benzodiazepines (pick your favorite flavor – lorazepam, diazepam, or midazolam are all fine) or a prophylactic load of phenobarbital (10 mg/kg). I like the later because phenobarbital sticks around longer than buproprion. I like to think of phenobarb as the “Lantus of seizure prophylaxis”. It can cause sedation, so be aware. If the patient already has profound CNS depression, you may have to intubate them. Seizures are one of the causes of death in these overdoses, so stop them before they happen.
The kinetics of bupropion also stink. While the majority of seizures occur within 6 hours of ingestion, the sustained and extended release formulations can result in delayed onset of seizures – like 12, 15, and 24 hours delayed (Starr 2009 PMID:19857406). This is why, in overdose situations, the poison center recommends that patients be watched for 24 hours, even if they are asymptomatic (sorry, but I didn’t make the drug).
The second most concerning effect of bupropion overdose is cardiotoxicity. Like other antidepressants, bupropion can widen the QRS and prolong the QT, cause hypotension, and patients can develop arrhythmias, shock, and death. The effect on QRS was thought to be secondary to its effects at blocking fast sodium (Na+) channels in cardiac cells (Curry 2005 PMID:16183450). However, unlike TCA’s, the QRS widening effects of bupropion may not be responsive to boluses of sodium bicarb (Wills 2009 PMID:19114875). This led some investigators to study it in rat cardiac cells, where they showed that even at large doses bupropion does not block Na+ channels (Caillier 2012 PMID:21623902). Rather it seems to affect cardiac gap junctions. No, these are not a new type of multicultural blue jean. Gap junctions are kind of like the cardiac “Chunnel”. They connect adjacent cardiac cells. Not so the Queen can drink fine Bordeaux, but rather to allow for the movement of nutrients and electrical impulses between cells. They are critical to the heart contracting in a coordinated fashion (Rohr 2004 PMID:15094351). Blocking these gap junctions may decrease cardiac output and may be the underlying cause of refractory hypotension in severe cases (Shenoi 2011 PMID:21206256). The effects on QTc are, like many other antidepressants, from blocking cardiac potassium channels (Curry 2005 PMID:16183450).
So how do you treat bicarb-resistant refractory cardiac shock? You use everything you got. Like any life-threatening ingestion, you start with GI decontamination. Charcoal? Whole Bowel? As all tox is local, I suggest you talk you your friendly neighborhood toxicologist on their preference (yes, I am copping out of getting into the whole decon controversy). I for one give charcoal to these patients if they are not an aspiration risk. For hypotension, you can start with norepinephrine, but as noted above it may not help if the problem is your cardiac gap junctions are blocked. If the QRS is wide, it is reasonable to try some boluses of sodium bicarb but again, gap junctions. Because it is fat soluble, overdoses of bupropion have been treated with lipid emulsion therapy (Sirianni 2008 PMID:17766009). While, I think this is a reasonable thing to try in severe overdoses, the jury is still out on its benefit (Chhabra 2018 PMID:28644682). Another option that has been employed is ECMO (Shenoi 2011 PMID:21206256).
And if a sustained release drug that causes delayed onset of seizures and bicarb-resistant QRS prolongation isn’t enough to stoke your hatred, did I mention that it is also abused (PMID: 24778361)? You shouldn’t be surprised because, after all, it is a bath salt. And unlike those sold on the street, this one is labeled for human consumption.
Skull image by Mathew MacQuarrie
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Fantastic post, thanks. I concur with your hatred of bupropion. A few years ago I had a case involving status epilepticus, complete brain shutdown (isoelectric EEG with no brainstem reflexes), and repeated cardiac arrest. Bizarrely, the patient eventually did great. I think the total metabolic shutdown of his brain prevented anoxic injury, despite repeated cardiac arrest.
You’ve skirted around this issue, but I want to poke the tox bear. Bupropion is a tox nightmare, which is entirely capable of outrunning us (especially at a non-ECMO center). Therefore, I would propose the following: Suppose a patient presents with an overdose of bupropion XR, develops seizures, and gets intubated. The amount ingested is estimated to be large and potentially lethal. I would suggest that this patient should be treated immediately with whole bowel irrigation to mitigate further toxicity. Toxicologists of the world: discuss!
Thanks Josh. Hold that thought. T&H has plans to dive into the topic.
Enjoyed the post. Wondering if you intend to post or comment on glucagon vs high intensity insulin in BB overdose. At my hospital the pharmD will not be happy to deplete us of glucagon for a HD stable case. Last case I used it, the pt had significant emesis. Starting to wonder if insulin is in fact as reasonable an option. Also curious to your management of K2 OD. Keep up the good work.
Thanks for the comment. I am not sure if one of the Hounds is planning on addressing the topic. I will put it in the suggestion box. I personally am not a big fan of glucagon. I will, on occassion use it. I treat K2 ODs the same as all overdoses. Agitated – Benzo; Psychotic – Benzo +/- antipsychotic; Somnolent – supportive care; Bleeding – Vit K (sad that we have to add that ).
Really disappointing to see the use of the term “bath salts” and the pretending that significant modifications do not significantly change a molecule. Surely you know that even slight modifications can have a huge impact on effects?
The main body of the article was incredibly interesting to me as a synthetic chemist (1000 compounds leave the lab and from there it’s over to the clinical team, please don’t hate me) but the garbage about face eating zombies really made it feel more like a tabloid piece than the well researched article underneath
Thanks for your comment. You make a valid point that similarities in structre do not always equal similarities in function (e.g., flumazenil and diazepam). However, in overdose, bupropion causes clinical symptoms that are similar to those produced by an array of different synthetic cathinones sold for illicit use.
Well, but with most substituted cathinones, overdose may very well involve serious serotonin toxicity (esp. with something like mephedrone), and almost certainly involve psychosis. But more to the point, I can easily see how someone could accidentally overdose on methcathinone or mephedrone or MDPV (the “face eating” drug, which differs enormously from mephedrone in a variety of ways) etc…. But how do you accidentally overdose on bupropion (outside of prison)? At least, the context of such accidental overdoses is going to be radically different. Isn’t it noteworthy that every other substituted cathinone that would give cause for concern is reinforcing, but that bupropion is not? No one is using bupropion compulsively, escalating doses, etc. Would you say that bupropion is any worse than, say, amitriptyline when an overdose is intentionally consumed? It isn’t as safe as SSRIs, but the SSRIs don’t work very well for melancholic depression or other depressions where anxiety doesn’t dominate the clinical picture. (And, of course, a drug like paroxetine has the same .1% seizure rate — obviously the overdose profiles are rather different, but in typical use I think people tend to imagine the risk of seizures is higher for bupropion xl than for any… Read more »
[…] everyone to go The Tox & The Hound, and take a look at the amazing piece on bupropion (“Illbutrin”) by Dr. Dan Rusyniak. . . co-host of the podcast “The Dantastic Mr. Tox & Howard” with […]
Great article about a truly unique and dangerous drug. We recently published a case of dual bupropion and cocaine toxicity that we treated solely with metoprolol. The clinical thought was the lipophilicity of metoprolol might antagonize the CNS effects of both bupropion and cocaine. Metoprolol rapidly resolved the patient’s agitation, tachycardia, diaphoresis, and QT interval prolongation. After the metoprolol wore off, the hyperadrenergic symptoms reappeared, and the patient had seizures. Quantitative levels confirmed toxicity of both drugs. If you are interested the case is here:
https://www.ceemjournal.org/upload/pdf/ceem-17-247.pdf
Are there any safe dopamine agonists/ RI’s?
As the saying goes the dose makes the poison. My post was not commenting the safety of the drug used in prescribed doses. For many, it may be an effective and safe medication. It is just one I hate in overdose.
Haemofiltration any role in management of this toxicity? thanks for a great article.
I appreciate the comment. While I am not expert in extracorporal removal of toxins, it is is unlikely to be of benift based on it drug characteristics.
https://www.ncbi.nlm.nih.gov/pubmed/15292684
[…] discussion from the Tox and Hound about Wellbutrin…or maybe should be better known as Illbutrin. Think of this medication like a sustained release bath salt. […]
The ‘face eater’ from Miami was tested for cathinones and the results were negative. There is no evidence bath salts caused his behavior.
You are correct! Thanks for the comment.