So this is totally 100% my own anecdotal experience as a physician, and in no way constitutes medical advice, but I've noticed an interesting phenomenon lately in my patients that I honestly can't ignore anymore as its happened more than a few times and the effect seems fairly consistent.

I have a number of patients on Adderall. (Personally I've taken the drug now for 21 years).

Tolerance is a problem for some of them, which tends to result in gradual dose escalation to a point where I say "sorry, this is too much, I'm not going to prescribe more than this" and then they have to do a drug holiday to restore back to baseline. This is a fairly miserable process as anyone who has tried it knows.

Interestingly, some of these same tolerance patients also have treatment refractory depression. They have gone through many psychiatrists and every possible anti-depressant in the book. They just don't get better no matter what we try. In these cases, some of them I have put on intranasal ketamine spray (with most patients ranging between 30-60mg intranasal per day). Or psychiatry has put on spravato (another ketamine based therapy).

I've seen incredible results for anti-depressant benefit in many of these patients when nothing else worked before, but what surprised me was that almost all of them reported a sudden decrease in their adderall tolerance to a point where they had to massively cut down their dosing or they would be having significant problems feeling "overdosed". What was even more fascinating was that this effect persisted after the cessation of the ketamine therapy.

I did some digging into this, and apparently this is a known phenomenon with NMDA receptor antagonists.

Now, not every person is a good candidate for Ketamine therapy, and I only noticed this due to the coincidence they happened to ALSO be on Adderall. I'm not suggesting people use ketamine to reduce tolerance. Let me repeat that: "Don't go buy and do some street ketamine because you read some stuff on the internet".

However, there is a supplement that also functions as NMDA receptor antagonist like ketamine, which is magnesium (which is a fairly safe thing for most people at OTC dosing levels). In addition, the drug atomoxetine (strattera) which is an approved treatment for ADHD also has this effect.

In short, if you're experiencing problems with tolerance, talk to your prescribing doctor to see if a magnesium supplement or even possibly the addition of atomoxetine to your regimen would be a safe and effective option for you. All humans are different, so please do not start any sort of new medication without your doctor's approval. I cannot stress this enough. Do nothing on your own without talking to your own doctor first.

Again, this is not medical advice, this is just me as a person who happens to also be a doctor and has taken this drug for over two decades. I know it incredibly well through personal experience, through my education, and through experience with my patients. I am just stating my anecdotal findings. I was incredibly surprised to see this effect and after hitting the books to figure out why, I realized this could potentially be beneficial for people to know about and more research is needed. I do not suggest anyone change anything about their own medical care without first getting their own doctors approval.

Here is some research on the matter, which generally seems to be fairly old (20 years) and without recent publication on the topic. Because there is so little out there in terms of research, and people tend to follow my posts due to my history of trying to improve the care of transgender people, I figured if I posted this here, it may spur some people smarter than me to do some digging and perhaps a more modern, controlled, and quality study could be done on the topic:

​

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1527-3458.1999.tb00096.x

​

https://www.sciencedirect.com/science/article/abs/pii/000689939500322H

​

https://psycnet.apa.org/record/1990-03998-001

​

https://www.sciencedirect.com/science/article/abs/pii/009130579290463P