ADD ADHD Medications – Amphetamines: 2D6 Drug Interaction Update

by Dr Charles Parker on December 21, 2008 · 36 comments

Image via WikipediaADD, ADHD Update: Prozac, Paxil and Antihistamine interact with amphetamines [AMP]

When they are used for treatment of depression and ADD simultaneously: Dexedrine, Adderall and Adderall XR, and Vyvanse
-by blocking the metabolic pathway of AMP, ‘CYP450 2D6′
-and have reported on this interaction vigorously for 2 years now [this is a picture of CYP450>>]
-they cause the AMP to accumulate over time
-the outcome is irritability, loss of focus, and frequently increased dosage to correct the inattention caused by the toxicity – making the patient doubly toxic, even more inappropriate

Those researchers, Cozza, Armstrong and Oesterheld, who constantly report on drug drug interactions [DDI], have confirmed what I have seen in the office since 1996 – regarding 2D6 interactions and my experience of regularly witnessing reactions to Prozac and Paxil with Adderall in hundreds of cases over many years.

Now we have a new kid on the block: Antihistamines

In comments on another CorePsychBlog post regarding ADD and Vyvanse titration Eddie brought to my attention another drug drug interaction you should know about:

Antihistamines and 2D6 Interact: Antihistamines block 2D6 as well. For complete transparency, you must know that I keep the Cozza, Armstrong and Oesterheld book right by my side all day every working day, but this is still a new one for me. I haven’t been watching for this interaction, but it looks like something we should all keep on our radar. Review this article on Antihistamines and 2D6, relevant for AMP, less so for methylphenidate. This table breaks down different generations of antihistamines – and in the body of the article indicates more about 2D6 interactions than is on this table.

This warning is not dire, – it’s not necessary to exclude the more efficacious AMP from your treatment program, just watch for a possible reaction. Most often these reactions aren’t dangerous, but create treatment adverse consequences that cause the team to stop the better [AMP] intervention.

This report from the article:

“The “classic” or sedating antihistamines, with diphenhydramine (Benadryl® and others) as the prototype, are greatly effective but rife with side effects, most notably sedation. In fact, they are often found in over-the-counter sleeping aids, allergy remedies, and numerous multicompound preparations for “colds and flu.” Finkle et al.3 indicated that 47% of people with allergies take over-the-counter medications that typically contain a first-generation antihistamine.”

This will be interesting to watch, and may be contributory to some of the “unpredictable” reactions with stimulants.

And, by the way, when you read it you will be reading also about the “narrowing of the Therapeutic Window” in their report – for many more articles on ‘The Therapeutic Window with ADD Treatment’ drill down to the bottom of this EzineArticles page.

Thanks Eddie, – thanks Cozza, Armstrong, and Oesterheld

ADD ADHD Medications Amphetamines: 2D6 Drug Interaction Update

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Colin

I know this is an old post. Regardless, thank you, Dr. Parker for this info. Not to pick on any specific antihistamine, but I think there might be more to the loratadine than can be effectively determined right now.

I noticed the “irritability, loss of focus” while on it and I did have my Adderall XR increased as a result. Thinking I was quickly becoming tolerant, I came across your post and decided to switch to cetirizine.

Since I did, I noticed my medication is working like it used to from middle school until about two years ago. Hopefully it’s not a placebo effect. Thanks once again.

http://www.corepsychblog.com drcharlesparker

Colin,
Cetirizine, as your doc likely knows, is clean across the board on all interactions.
Loratadine is a 2D6 substrate, comes up through, not a 2D6 blocker for the Adderall path.

Benadryl is the need-to-watch 2D6 blocker awash with possible stimulant interactions…

Said another way, all antihistamines, as you know, are not metabolized thru the same path, and while you likely weren’t having an overt reaction in a direct inhibitory way, you could have been experiencing a reaction due to competitive inhibition = two drugs trying to get up that same [likely narrow in your case] 2D6 pathway.

See this graph, it spells your situation our more completely: http://psy.psychiatryonline.org/cgi/content/full/44/5/430/T1

cp

http://www.corepsychblog.com drcharlesparker

AMP ADD-
This answer is at once simple and complex: get him off the AMP, and fix the Dopamine imbalance – an imbalance which could go either way – with increased or decreased dopamine – only found by testing, not by speculation.
cp
http://addictioncalifornia.com/amphetamine-addiction/ Amphetamine Addiction

Amphetamine Addiction can spoil the life of a man. my uncle is facing this addiction . i want to ask you ho he can leave this addiction
T

Quick question for you – do know of any issues with using mirtazapine with stimulants?

http://www.CorePsychBlog.com Dr Charles Parker

T,
None to my knowledge, works well for sleep, less well for depression, but can be quite effective for those who also have an appetite disturbance with stim meds.
cp

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Craig B

Hello Dr Parker.

My girlfriend suffers from severe ADHD, depression and anxiety. She has been taking 20mg methylin (Ritalin) three times a day for ADHD, 20mg x 2 fluoxetine (Prozac) twice a day for depression and her physician recently introduced 2mg clonazepam three times a day for anxiety. She seems worse than ever and I assumed it was an issue with drug interactions which led me here.

I’ve already done some research on the clonazepam and am pulling her off of it as it seems to describe most of the side effects she has had from drowsiness, motor function impact, irritability, memory loss, etc…. even depressing REM sleep. These effects seem to indicate that they may be amplified by the use of drugs such as Prozac and Ritalin. So we’ll see over the coming days how she does without the clonazepam.

But further, I’m worried that there may be an unfavorable interaction between the fluoxetine and methylin as well? It seems as though she could possibly take Aderral instead to address both ADHD and depression? Would this be a better route? What issues do you see with her combination.

Nutshell daily -
80mg fluoxetine
60mg methylin
6mg clonazepam

She also sometimes has to use an inhaler for asthma… currently I have her trying levalbuterol instead of albuterol due to the level of shakes she would get from using the inhaler.

Thanks so much for your input.

http://www.CorePsychBlog.com Dr Charles Parker

Craig,
My guess, not having asked more specific questions, is that she is indeed having interactions on several levels:
1. Methylphenidate does interact with MPH, as you so accurately point out, see the White Paper on Precise Solutions to the 10 Most Common Challenges for ADHD Medications – free. It blocks the Prozac, and toxicity results.
2. Prozac blocks it’s own metabolism causing a phenomenon many call Prozac Stupid – a prefrontal cortical cognitive slowing of working memory.
3. Prozac significantly blocks 3A4 the pathway for Klonipin, as also documented and linked in this post, leaving the patient over-sedated and clinically overdosed on Klonipin.

In a few words there are about 3 interactions here that could be causing all of her problems, and if she is on Prozac at all, the doc is very likely, having seen this many times, devoted to Prozac – but getting rid of that one will likely bring the entire scene into better balance. BTW, when someone comes in on 80mg of Prozac alone they are almost always toxic on Prozac simply by itself [= Prozac Stupid], setting aside all the other interactions noted here.
cp

http://coresiteblog.com eddie t

Hi Dr Parker
I have been on paxil 40 mg per day for 17 yrs,and just found out Iam ADHD.My doc put me on 50 mg of adderall per day and seemed to not only work for consentration but for depression as well.Just last fall she upped my paxil to 60mg per and went 3 weeks without sleep.She said I went manic?Do you think it was the combo of adderall and paxil over the course of 1year?I just started Lexapro last week and hope this works better than the paxil did.Thank you Eddie

http://www.CorePsychBlog.com Dr Charles Parker

Eddie,
No doubt in my mind – you may have looked manic from the outside, but your inside was toxic with too much Adderall when the Paxil clogged the drain. If you were bipolar you would have cycled somewhere along those 10 yrs with straight Paxil. Lexapro is clean on 2D6 – expect no interaction.
cp

Christine

I almost cried when I found this blog…I am so relieved. I took Prozac for panic disorder/depression for over 10 years. Worked great. I went back to school in my 30′s and could not concentrate on anything, put the pieces together, and my doc agreed that I had ADD. I then went on Wellbutrin 300mg and Lexapro 20mg—the Wellbutrin helped me concentrate and helped with my fatigue but made me super cranky, the lexapro was a beautiful addition for 5 years. After several highly traumatic/stressful events occured over the last three years my depression and brain fog was overwhelming.
The doctor added 30mg long acting Adderral to the Wellbutrin/Lexapro mix. The concentration was beautiful but I had wierd tingling/numbness in my extremities and I became very ANTI-SOCIAL. I did not want to leave the house, but I could do my homework and laundry without a problem.
I recently asked the doctor to switch the lexapro for prozac and decrease the wellbutrin to 150. I have been on the Prozac and Wellbutrin and Adderall combo for two months and feel horrible. I cant concentrate, I am totally anti-social, nervous, BUT no tingling in the extremities.
I would like to go back on the Lexapro and change to Dexadrine because I have read that Dex has less chance of the anti-social tendency than the Adderal.?? But what about the Wellbutrin?
On another note, I am having some hormonal issues ( 38 years old, on BC pills and having months wihout periods) but that started before the Prozac.
I take alot of anti-oxidants, Omegas, magnesium etc. My question is….Should I give the Lexapro another try with Dexadrine? And, can I also add the Wellbutrin? I need coverage for anxiety/depression/fatigue AND ADD.
Thank you,
Christine

http://www.CorePsychBlog.com Dr Charles Parker

Christine-
Many issues here, the easy one first: Hormone dysregulation will significantly contribute to any psych issues, and you likely suffer from estrogen dominance, and would do well to find a doc/compounding pharmacist combo to specifically correct those issues – psych meds don’t fix estrogen dominance. Listen to this audio program on estrogen dominance at CorePsychPodcast.

The Wellbutrin at the dose of 300 frequently will, over time, back up the Adderall as it is a ‘moderate’ inhibitor of 2D6 – I have contributed to this interaction myself, and can testify without question that it should be considered as a possible part of the interaction problem on your doorstep. Inappropriate for me to recommend exactly what to do – talk to your doc.

Finally, the big interaction, you got that one: Prozac, with Wellbutrin, with Adderall, that one is nothing less than an inevitable problem. Lexapro is often clean on 2D6, especially at the lower doses. Don’t reply here, but do talk to your MD about the likely bowel issues right away, and pay attention to correcting your transit time [likely too slow] asap.

Several work-up suggest in summary: the neurotransmitters precursor review [quite refractory responses with chronic presentation], specific testing for hormone dysregulation and medical review for immune dysfunction is likely necessary [bowel?] –

Do talk to your doc about any changes.
cp

Susy

So, now I’m all freaked out. I have been on Prozac on and off since 1987, mostly on. I have tried other drugs for depression, such as Paxil while I was pregnant, which I later found out was a huge no-no. Hated the Paxil and hated the withdrawals from Paxil…which was before it was figured out that there were withdrawals from Paxil. I’ve tried Zoloft and I may as well have been taking Tic-Tacs for all the good it did me. I was on Remeron for a while, it worked okay. But I am back to Prozac, 9 years now, 60 mg a day. I am prescribed Wellbutrin also, 200 mg per day, but I haven’t taken that in months. Wasn’t sure what I was supposed to get out of the Wellbutrin, but never felt any different on it. Doc doesn’t know I don’t take it. I finally, after researching and taking several quizes, that I and my doc believe I may be ADD. I am 45 years old, suffer from pretty significant depression, when not on Prozac, and have limited energy and NO concentration or focus. Doc started me 3 weeks ago on Adderall. I take the generic forms of all these meds. I am currently on 20 mg of Adderall daily, but after taking it for 3 weeks, I told Doc today that it just made me feel crappy. Can’t put my finger on it, just feel crappy. No sense of well-being whatsoever. Not depressed, just feel crappy. Energy is a little better and the Adderall doesn’t keep me up at night at all. Doc increased me to 30 mg Adderall daily and said to try that for another month and see if I improve. On the 20 mg I notice minimal improvement in concentration…very minimal. Just wondering what your opinion is of this regimen. From what I’ve read of your postings so far, I don’t think you would find this favorable. In a nutshell…60 mg daily Prozac, 30 mg daily Adderall, and am prescribed but not taking 200 mg daily Wellbutrin. Let me know what you think.

http://www.CorePsychBlog.com Dr Charles Parker

Susy,
No need to freak out! Many more options out there, and this one hasn’t fallen off the cliff yet – but likely will over time. The usual outcome of this combo: agitation, irritability, touchiness, – from an increased edge, to downright demanding and disrespectful, even raging. Sometimes the toxic presentation is increased depression. This usually happens over time, thus the puzzling nature of the presentation. I agree that your doc is thinking right for the short run with the increase in Adderall – but forewarned is forearmed for the long haul.

It is remarkably characteristic that other SSRIs actually aggravate ADHD and diminish focus and concentration if the stimulant is not appropriately on board simultaneously. Therefore all of those other guys, including Celexa, Lexapro, Effexor XR, Pristiq, etc, are all clean on 2D6 – and quite workable. – Many options with the right combo. Adderall is great, works well with all of these, and it doesn’t sound, from this short note, that Adderall is a problem, just the dosage.

On the Wellbutrin note: Always best to come clean and get that off the table with your doc. It is always more difficult to get it right when you don’t know what you’re actually doing on our end. If you have a feedback loop problem with your doc, address it, fix it, or move on. Healthy feedback loops are essential in this process – and if you distill all of what I am writing about on the process side, it’s all feedback loops. On the content side – it’s all brain and body evidence.

Get it straight with your doc, make the switches, and very likely the other SSRI will work effectively now that you have unearthed he ADHD.
cp

q

So are you saying that adderall and wellbutrin should not be taken together? Just curious – -thanks.

http://www.CorePsychBlog.com Dr Charles Parker

q,
Not a problem, just to be watched. Moderate inhibition of 2D6 by Wellbutrin, much more at higher doses, thereby creating possible accumulation of Adderall. Not dangerous, just a concern – seen many times, easily fixable, just drop dose of Wellbutrin.
cp

q

Thanks!

Higher doses of Wellbutrin, like in what range? I’m not too familiar with dosing of Wellbutrin. Have you found that combo with Adderall successful in your practice, or do you tend to use a different one?

http://www.CorePsychBlog.com Dr Charles Parker

q,
The higher doses of Wellbutrin that often show signs of 2D6 slowing with AMP stimulants: 450mg. I use Wellbutrin with Adderall but only with the full consciousness of this interaction with warnings to the patient. I prefer clean on 2D6 every time: Effexor, Celexa, Pristiq, Lexapro, Zoloft with children.
cp

q

Thanks – I just wanted to be sure. How high of a dose though? as I’m not familiar with dosing of Wellbutrin.

Also what’s the reason for combining adderall with wellbutrin? I do know wellbutrin is an antidepressant that has some properties that address some issues common with adhd…but what’s the real reason (normally) behind it? What have you seen in your practice? What do you prefer or suggest first in this regard?

Thanks!

http://www.CorePsychBlog.com Dr Charles Parker

q,
Wellbutrin blocks the reuptake of norepinephrine and dopamine… thus a mild positive effect with ADHD – but not as effective as stimulant meds.
cp

Jeff

This is a real eye opener. I have been suspicious of my prozac/adderall combo almost from the start. You mentioned celexa and lexapro as alternatives, if i remember correctly. Would you think favorably of using cymbalta with adderall? This is a med my doctor likes for me. Does zoloft play well with adderall? Mainly, though, im interested in cymbalta.

Do anti histaminic meds such as low dose seroquel (25mg) or desipramine interfere with adderall? I only take the sero for sleep, but instinct tells me it may interact. The desipramine was mentioned by pdoc for depression; but i’m aware it hits histamine receptors rather weakly. My pdoc believes it a potent antidepressant.

Thank you very much.

Jeff

http://www.CorePsychBlog.com Dr Charles Parker

Jeff,
Quick summary on all these questions: Prozac and Paxil are the main culprits. If you do as much work as I have you will see some of these others having problems, but not due to 2D6… Cymbalta does have a ‘moderate’ inhibition of 2D6, and I have seen some problems, just as with Wellbutrin with the same characteristic impediments. The rule for these latter two is simply the same old rule, go gently into that dark nite – not really a problem unless the doses get maxed out.

The rest have no direct problems with the interaction issues, except you must absolutely know that prozac and paxil also block elavil and desipramine – seen that for years on second opinions.
cp

randy

Thank you. I ended up not taking the vyvanse though. I had poison oak all over my legs thats why i had the prednisone. But i figured since i was just going to be lounging around the house for a few days until the poison oak got better then there really was no need, seeing as i had no homework and nothing really to do.
Tina

My 16-year-old daughter has been on Adderall since about age 10. Approximately one year ago she was suffering from severe depression. She now takes 20mg of Fluoxetine capsules (generic for prozak)(which has really helped with the depression) and she also takes 30 mg of D-Amphetamine Salt Combo tabs (generic for adderall). She constantly complains about clearing her throat in school (this has been going on for years), and students and teachers alike complain to her about it. I decided to take her off the Adderall for a couple of weeks, and low and behold she says she is not clearing her throat anymore and she is focusing at school. What gives?

http://www.CorePsychBlog.com Dr Charles Parker

Tina,
As indicated in this posting: very likely she experienced a mild degree of AMP accumulation with a slight cough tic based on the top of the window phenomenon… see my several articles at EzineArticles.com linked on the right column of this blog.

Taking her off the AMP solved the problem that was caused by the Prozac. If she needs a stimulant, AMP would work well with an antidepressant that doesn’t block it’s metabolism – such as Pristiq, Effexor, Lexapro, Celexa.

This correction has helped many with similar problems.
cp

Randy

I recently came down with poison oak Dr at walk in clinic prescribed me prednisone. Is it harmful if i take prednisone and vyvanse at the same time? I was reading up and i see that they both work through the liver, so would this be bad to mix? thanks

http://www.CorePsychBlog.com Dr Charles Parker

No problem Randy,
Just the side effects from prednisone in general, but no drug blockage or interruption of the Vyvanse at all.
Thx
cp

vicki

I have a son that takes 50mg of Amantadine in the morning and at night for slight ocd/anxiety/depression problem. He also takes 10 mg of prozac at night. He is 17, 6 feet and weighs 145. Once in a blue moon when he has a lot of shcool work I will give him one 10mg amphetamine salts, maybe 3 times last year. I gave him one 10mg of amphetamine today at 10am,(lots of tests and homework due tomorrow)but now it’s 10:45PM and he can’t fall asleep and he has all those tests tomorrow. Can I give him a teaspoon of Benedryl to help him sleep? Oy, am I medicating him too much? Very nervous.

http://www.CorePsychBlog.com Dr Charles Parker

Vicki,
As you can see from my regular negative postings on Prozac, I simply look at Prozac as one of the first contributory challenges with any kind of cognitive challenge. Prozac is known to *cause* cognitive challenges over time, and is a significant drug interaction product through 2D6 and 3A4.

My experience, without seeing your son, is that individuals as a group do better with *consistent* use of AMP salts, not occasional. Used once in awhile it’s difficult to say anything precisely as the peaks and valleys are so unpredictable. I don’t have my Drug Interaction Book with me at this moment [to report back on the Amantadine interactions], but I am certain that Prozac and Adderall do not mix, and that Prozac itself can lengthen the DOE on the Adderall – causing sleep problems.

Of course I have not examined him, but you asked both a specific and general question: I strongly advise against Prozac and even occasional Adderall. Switch in antidepressant would be indicated, but only through approval with your doc. Some docs don’t agree with this problem, but I have seen it not hundreds, but thousands of times, and each time I see improvement switching out the Prozac.

Hope he did well on the test, suggest a complete review before college.
cp

http://www.corepsychblog.com Dr. Charles Parker

Gary,
These interactions are so common it is dumbfounding – I have had two challenging consults in the last two days both of which have suffered with the drug reactions listed here for years, with multiple treatment attempts for bipolar illness and mood dysregulation based upon these simple facts – referenced in the medication/drug interaction books over at CorePsych Books.
cp
Gary Lamont

Very interesting. This would explain a lot of side effects my clients have been experiencing!

Narconon Vista Bay
http://profile.typekey.com/docparker/ Dr Charles Parker

Eddie,
Thanks again for your comments and question… Yasmin, without looking it up at this very moment, tracks up [is metabolized through] through CYP450 3A4 enzyme system, – not a problem with Vyvanse which itself is a substrate of 2D6, so no competitive inhibition.

On another negative note: Prozac and Paxil significantly block hormone metabolism [Yasmin and other BCs] through 3A4, and, while not making a woman overtly ‘toxic’ in the formal sense, can significantly add to the symptoms of estrogen dominance outlined in this interview at CorePsychPodcast:

http://docparker.typepad.com/corepsychpodcast/2007/08/estrogen-domina.html

Thanks,
cp
Eddie

Happy New Year!

Well dropping the Benadryl does seem to have made a difference. It took a couple of days to work itself out, but now things are better. Thanks for the info regarding 2D6 conflicts.

After seeing the family doc we have returned to the 40 mg of Vyvanse. The DOE at 30 mg was almost invisible. 40 mg itself seems low, but we will continue your advised “start low and go slow” approach before making any changes.

Now that we are paying close attention to drug-drug interactions. I have a new question: Birth control pills. The recent doc visit introduced this in regard to another health issue (beyond this blog.) However I want to ask another opinion here: any cautions/concerns regarding the use of *Yasmin* in conjunction with Vyvanse?

As always, thanks for providing your knowledge and experience!
Eddie
http://profile.typekey.com/docparker/ Dr Charles Parker

ADHD Warrior-
Last point first: MPH actually blocks 2D6, -that’s why so many get crazy on Prozac and Concerta. Prozac itself is a 2D6 substrate, so it blocks its own metabolism… causing self inflicted prefrontal cortical inhibition…an increase in ADD, out of the box toxicity over time [because it is lipophilically stored in the brain fat]. Add that built-in self accumulation to any MPH blocking of 2D6 and you can get a person that wants to jump out of a moving car.

Had a patient from Scotland, lovely 12-13 yo girl, and this interaction was the problem – and her SPECT scans clearly showed toxicity.

Lecturing around the country I have had docs ask about using Ritalin for the PM with Adderall for the day… this combo is another absolute problem and should be avoided.

Yes, no blockage/accumulation occurs on a rare single dose interaction, but ‘routine use’ is contraindicated – ‘always’ [Cozza et al completely agree with my oft repeated recommendation/observation, and the aforementioned Prozac/Adderall point - though misinformed others continue to suggest using these interactions routinely to increase the dose of the 2D6 substrate! Simply amazing!].

Regarding the genetic polymorphism on the alleles: yes. 5-7% of the Caucasian and ~ 3% African American have such a modified 2D6 that meds like AMP accumulate very easily and cause an atypical reaction – not the AMP fault, but the size of the 2D6 pipe genetically.

Thanks again for your excellent input and your deep ongoing review of these important med matters over at your site.

HNY,
Chuck
http://adhd-treatment-options.blogspot.com theadhdwarrior

Another great post! Given the relatively high comorbidity of ADHD and allergies, this observation is extremely relevant.

It’s amazing how versatile some of these P450 enzymes really are, but a royal pain when it comes to prescribing more than one medication for co-existing illnesses or disorders which share a similar metabolic pathway.

I wonder how much of a factor an individual’s genetic makeup plays in this too? If I’m not mistaken, the gene coding this 2D6 enzyme form has a number of different alleles which result in significant differences with regards to activity of this enzyme. For those unfortunate to have one of the less-active enzyme forms, these inhibitory effects by antihistamines could be especially pronounced.

While not a physician myself, I work at a school with a number of children with ADHD who are on stimulant meds. It’s amazing how many of them still receive 1st generation antihistamines for allergy symptoms, in spite of many of them taking amphetamines such as Adderall.

I had a quick question: does methylphenidate operate through this same 2D6 system as well, or is it metabolized via a different method?