Health - DXM and later-generation (non-drowsy) antihistamines

[Paracelsus]

William White's DXM FAQ warns twice about not taking DXM if a new-generation (non-drowsy) antihistamine was consumed in the last six weeks.

These new-generation antihistamines (acrivastine, lorataidne, terfenadine, etc.) are H1 antagonists just like the older first-generation antihistamines (diphenhydramine, chlorpheniramine, etc.), the difference being that the former don't get into the brain and therefore don't cause drowsiness and other anticholinergic effects. The first-generation antihistamines are still widely used, but the newer ones (second and third generation) are prescribed to persons with various allergies.

White does not give any explanations on why avoid mixing these new antihistamines with DXM, so I decided to dig into this topic.

Besides some parent education websites, I have found many documents & websites mentioning that mixing DXM with non-drowsy antihistamines is dangerous, but, again, in most cases I found no explanations (this makes me believe they all just repeated what White said).

I found a post on another forum saying that DXM interferes with the enzyme which metabolizes many non-drowsy antihistamines and that this combination can cause heart problems. I also found another warning about not mixing DXM with terfenadine and possibly other non-drowsy antihistamines because of heart irregularities.

All this and some previously gained knowledge make me believe that the danger doesn't consist in non-drowsy antihistamines in general, but in terfenadine.
This is a non-drowsy antihistamine which is metabolized into its active metabolite (fexofenadine) by CYP3A4. Terfenadine itself is cardiotoxic and has caused death when combined with grapefruit juice, a potent CYP3A4 inhibitor.
DXM is known to be a substrate of CYP3A4 (which is responsible for N-demethylation). In high doses, substrates of a particular enzyme can usually be considered inhibitors of that enzyme (the exception being cases in which a particular substrate stimulates the formation of more enzyme and acts as an inducer).

When this is applied to DXM and terfenadine, this means that: DXM inhibits CYP3A4 activity and therefore inhibits the conversion of terfenadine to fexofenadine. This results in higher levels of the cardiotoxic terfenadine. In combination with the sympathomimetic effects of DXM, this is likely to result in severe cardiovascular adverse effects and death. One recorded death has occured from this combination (Kintz P, Mangin P. Toxicological findings in a death involving dextromethorphan and terfenadine. Am J Forensic Med Pathol 1992 Dec;13(4):351-2).


From all this, I believe that only the combination of terfenadine and DXM is dangerous and therefore this doesn't have to be applied to other second- and third-generation antihistamines. And since terfenadine was replaced by fexofenadine (because it's cardiotoxic and dangerous with CYP3A4 inhibitors), I don't think anyone should worry about this.

Of course, I could be wrong. Maybe there are some antihistamines around that are dangerous with CYP3A4 inhibitors, even if I wasn't able to find any. The purpose of this thread was asking for opinions and information, because I am writing an article for the DXM section of DF and I don't want to have someone on my conscience because s/he was prescribed to loratadine or similar and died after taking DXM because I only mentioned terfenadine and no other non-drowsy antihistamines.

So, should the article contain a warning about terfenadine or about non-drowsy antihistamines in general? No matter what you choose to post, back your opinion up with arguments.

Reputation Comments on this post:

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[Graduisic]

SWIM has been a regular user of lorataidine for allergies, and over the 4+ years that SWIM has been around DXM, there have been no negative side effects. SWIM wondered about this as well, and attempted going some days without antihistamine and some days double-dosing. never noticed any negative side effects either way when SWIM would take up to 1200MG of DXM.

[Paracelsus]

It seems that astemizole can be added to the list of drugs not to combine with DXM.

I requested a couple of files on this topic (here).

Update (received and read the files):

From all new-generation antihistamines, only terfenadine and astemizole are reported to cause arrhytmias (possibly resulting in death), especially when combined with CYP3A inhibitors.

Since both of these drugs are withdrawn (at least in the US), I don't think this issue is relevant anymore. And I hope that the pharmaceutical industry will not put any more cardiotoxic antihistamines on the market.

[paranoid_android]

This certainly alleviates a concern of mine. SwiPA took loratadine with DXM and it didn't kill him, but he did experience a much more intense trip than he usually does, with only about 30% more DXM than usual. Now I can attribute the effects to a higher dose and cannabis synergy.