Amphetamines: CYP 450 2D6 Drug Interaction Update

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December 11, 2008
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December 22, 2008
Cytochrome P450

Cyp450 – From Wikipedia

Prozac, Paxil and Antihistamine Interact With Amphetamines [AMP] Through CYP 450-2D6

    • When those two antidepressants are used for treatment of Depression and ADHD simultaneously with : Dexedrine, Adderall and Adderall XR, and Vyvanse
    • They block the metabolic pathway of AMP, CYP450 2D6
    • This important interaction remains overlooked but often markedly significant [this is a picture of CYP450>>]
    • The Prozac and Paxil cause the AMP Stimulants 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.
    • For example: I have one patient who was treated for psychosis with 6 psych hospitalizations over 10 years, and corrected when taken off the combo of Prozac and Adderall. “Corrected?” = No longer any hint of psychosis, on ADHD meds and a different antidepressant.

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 CYP 450 2D6 interactions and my experience of regularly witnessing reactions to Prozac and Paxil with Adderall in hundreds of cases over many years.

The Drug Interaction Book:

Drug Interaction Principles For Medical Practice – Wynn, Oesterheld, Cozza, and Armstrong – 2008

Polymorphisms of CYP450 2D6 make that interaction more unpredictable – and deniable.


YouTube Video Details


Now we have a new kid on the 2D6 interaction block: Antihistamines

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

Antihistamines and CYP 450 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.


More Details On CYP 450 Liver Enzymes

From: Nursing Link

The CYP450 enzyme system is a key pathway for drug metabolism. Many lipophilic drugs must undergo biotransformation to more hydrophilic compounds to be excreted from the body. Drug biotransformation reactions consist of Phase I (e.g., oxidation, reduction) or Phase 2 (e.g., conjugation) reactions that occur primarily in the liver. The most common Phase I reaction is oxidation, which involves the insertion of an oxygen atom into the compound to form a polar hydroxyl group. Of the enzymes involved in Phase I reactions, the CYP450 group is the most important.

Cytochromes P-450 are a superfamily of hemoproteins which can be divided into families, subfamilies and/or single enzymes.3 The cytochrome P-450 enzymes act as a major catalyst for drug oxidation. To unify nomenclature, a given gene family is defined as having >40% amino acid sequence homology and a subfamily as having >55% identical sequence homology Using this nomenclature, the cytochrome P450 enzymes are designated by the letters CYP (representing cytochrome P450), followed by an Arabic numeral denoting the family, a letter representing the subfamily (when 2 or more exist) and another Arabic numeral designating the individual gene within the subfamily (e.g., CYP2D6).

Each enzyme is termed an isoform (or isoenzyme) since it is derived from a different gene.5 An important subset of the cytochrome P450 family is the CYP3A4 isoenzyme, which accounts for nearly 60% of the total CYP450 in the liver and approximately 70% in the intestine.6 CYP3A4, which catalyzes the biotransformation of many drugs, is significantly expressed extrahepatically. Extensive metabolism by CYP34A in the gastrointestinal tract contributes to the poor oral bioavailability of many drugs.

Many substrates, inhibitors and inducers of CYP3A4 have been identified. By definition, a substrate is a drug that is metabolized by an enzyme system. An inhibitor decreases the activity of the enzyme and may decrease the metabolism of substrates, generally leading to an increased drug effect. Inducers, however, may increase the metabolism of substrates and generally lead to a decreased drug effect.


Thanks Eddie, – thanks Wynn, Cozza, Armstrong, and Oesterheld.

Dr Charles Parker
Author: New ADHD Medication Rules – Brain Science & Common Sense
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  1. Lynn says:

    **I am wondering if you know if there are any issues with St. John’s Wort, SAMe, L-Tryptophan or 5-HTP and Vyvanse or generic Adderall IR?

    I have never taken a prescription anti-depressant, but have been taking SAMe 400mg twice a day, about an hour before breakfast and then an hour before lunch. I have been taking 450mg of St. John’s Wort twice a day with breakfast and with dinner. I used to take 5-HTP 50mg before bed to help with depression and sleep. I quit that and went back to L-Tryptophan 500mg to help with sleep. My doctor suggested these supplements to avoid having to take anti-depressants. I have watched all of your videos on DOE, titration, gut issues, etc. and bought and read your book, “New Rules.” I had an IgG test done and ‘mostly’ avoid my higher foods. Occasionally, I will have dairy (Greek yogurt or goat or sheep cheese mostly) but do take digestive enzymes with protease specifically for casein and gluten to help me digest it. Same thing with wheat, although that didn’t test that bad actually, but I know from personal experience I just do better without it.

    **Do you know if these enzymes are an acceptable way to eat my not-good IgG foods occasionally or am I just fooling myself?

    I am on Vyvanse 40mg, but do find myself needing to add my generic Adderall IR WITH (not after) my Vyvanse many days to get the same amount of focus and attention to get things done (and it actually seems to work better for me – this combo than when I tried Vyvanse alone or generic Adderall alone. Real, brand-name Adderall XR was pretty good, but I can’t afford the cost since insurance says I should get the generic and won’t pay as much as they do for the Vyvanse which does not have a generic yet.) I was on Vyvanse 30mg and titrated slowly – actually down to 20mg first and then up to the 40mg. It seemed ok at first, but now, not as good. I do find myself hyper-focusing more some days and it’s harder to really push myself to do my household cleaning and paperwork tasks. I’m 49 and was just diagnosed with ADD for the first time back at the end of April this year.

    I’m in menopause, but am doing the Wiley Protocol (WP) for bioidentical hormone replacement therapy. My hormones seem to be pretty well balanced now I think. WP is a cyclical system of hormones, replicating the Estradiol and Progesterone ups and downs just like healthy women’s cycle their hormones in their 20’s. I get a withdrawal bleed each month to protect my uterus just as younger women get their monthly period. I have read some of Dr. Pat Quinn’s work regarding some women needing more stimulant med during their Luteal Phase (more P4 than E2). I have discussed it with my doctor and he suggested the same. I have experimented some and it does seem to help. Still, then, there are days like today when I am just not feeling much of anything in terms of stimulant med help. With my hyper focusing, I’m not sure if I’m toxic with too much med or if I might need more – I’m mostly inattentive and am very good at hyper focusing 🙂

    I looked at the “you script” from the meds interactions website you had linked somewhere along the way and found the St John’s Wort under, “Common CYP2C19 Inducers (increase the ability of CYP2C19 to metabolize drugs)
    primidone (Mysoline®)
    St John’s Wort”

    **Does that CYP2C19 pathway have anything to do with Vyvanse or Adderall? Any other thoughts or advice regarding the other anti-depression supplements and how best to adjust stimulant dosages for women’s monthly hormone cycle changes for optimum DOE?

    Thanks ever so much in advance, may need to call for an appointment, but hopeful you can shed some light here and may possibly help others in my similar situation.
    Best, Lynn

    • Lynn,
      Your comments and questions drive home the important point that I’ve found increasingly true since opening the Amen DC office in 2003 – the public is becoming so well informed about biomedical issues with internet info availability. Without knowing you it’s like we’re already distant colleagues – wherever you are. Excellent job taking care of yourself!

      Short answers:
      **Saint-John’s wort, a common herbal remedy induces CYP3A4, but also inhibits CYP1A1, CYP1B1, and CYP2D6.[19][20] – relevant for 2D6 and worthy of consideration as contributory to your narrow therapeutic window, and your search for the right dose.
      **SAMe & CYP450: These results suggest that SAM interacts with cytochrome P450s, especially CYP2E1, and inhibits the catalytic activity of CYP2E1 in a reversible and non competitive manner. However, SAM is a considerably weaker inhibitor than other typical CYP2E1 inhibitors – not a problem
      **No prob w Tryptophan or 5HTP
      **My own experience, listening to my colleagues who talk and teach and treat IgG even more frequently than I do: stay on the diet, don’t waver.
      **CYP2C19 not a prob at all w stimulant meds.
      **St John’s Wort is referential, linked above, to 2D6 and Adderall, Vyvanse accumulation likely.
      **My take: enzymes don’t work as effectively in some folks and encourage denial, thereby increasing reactions.

      For you, because you’re doing so much correctly, I would look at 2 things:
      1.Candida possibilities: Take they Yeast Test on the back of this page: – Specific treatments available.
      2. Possible other contributory factors to review – see Dr Walsh at the bottom of this page: – Bill is a maven on the methylation process and a variety of other measurable imbalances not yet up to standard radar.

      Hope this helps,
      Fair winds and following seas,

  2. C says:

    Vyvanse isn’t effective for me nearly as long as it should be (maybe 8hrs max with 60mg). I’ve also noticed that Cetirizine (Zyrtec) and Fexofenadine (Allegra) are closer to 12 hour meds (instead of 24 hrs). Could the shorter half life of all of these be related to a polymorphism with the 2D6 enzyme? (other info: I haven’t taken a bunch of other meds but the effectiveness of ibuprofen and lamotrigine/Lamictal (past…before ADHD made so much more sense) seemed ‘normal’. Prior to taking Vyvanse, I was on 72mg of Concerta, which also wasn’t effective as long as it should have been. I’ve also had no therapeutic response to Benadryl and had bad side effects after taking bupropion for a couple of days a few years ago.) There seems to be some conflicting research and it’s been difficult to figure it out. It sounds like you might have some insight about it though! Thanks!

    • C,
      More than likely it isn’t polymorphism, but metabolic challenge. More in a moment.

      When you need higher dosage of stimulant, specifically AMP, to find successful outcome the polymorphism challenge is one of a larger pipeline at 2D6, with a faster burn rate. That incidence in population with ultrarapid metabolism is in the range of 7% as I recall, and produces a very difficult clinical situation in which the person does require larger doses to achieve Predictable Solutions. See this article on 2D6 in Wikipedia that outlines these rates of metabolism and polymorphism [Remember AMP and MPH interact differently with 2D6 – MPH blocks, AMP is substrate]:
      – poor metabolizer – little or no CYP2D6 function
      – intermediate metabolizers – metabolize drugs at a rate somewhere between the poor and extensive metabolizers
      – extensive metabolizer – normal CYP2D6 function
      – ultrarapid metabolizer – multiple copies of the CYP2D6 gene are expressed, and therefore greater-than-normal CYP2D6 function

      Zyrtec and Allegra are not 2D6 substrates, therefore no interaction. More on interactions of these two at This Link.

      It’s a guess on the metabolism, but worth taking a look. Liver metabolic rates change with allergies that arise from immunity issues. The most frequently witnessed allergies that change psych drugs in my practice? – Food sensitivities measured by IgG – see these tests:

      See these videos for much more explanation:
      ADHD Meds Problems – Mind and Gut:
      ADHD Meds & Allergies – Milk and Wheat:
      ADHD Meds & Allergies – Street Immunity:

      Thanks for asking – hope this helps!

  3. Ryan says:

    Very interesting! Thanks for all the articles, videos, and book. I was recently diagnosed with ADHD but have always had sleep/insomnia issues for most of my life (for sure by age 14). This involves difficulty falling asleep about half the time, and frequent night wakings most every night (I’m up every 90-120 minutes on average). Due to daytime fatigue, I did have a sleep study done a few years ago without any issues.

    Because of this, the past 5-10 years have been littered with sleep medication. First this was Ambien (and then Ambien CR) which works fine but makes me irritable if taken more than a few days in a row. I did Lunesta for probably two years straight. After trying to get off that (for no real reason other than not wanting to need a hypnotic every night) I found my way to 0.5 Xanax nightly. After getting off that, I ended up at 25mg of diphenhydramine/Benadryl for the last couple years (or 50mg at most 1-2x per month).

    I had some really bad sleep after first starting 30mg of Vyvanse (benadryl would make me super tired but still couldn’t sleep), but those issues have resolved now. My current regimen is 30mg Vyvanse at 6am, another 20mg around 12-1pm, and then 25mg of Benadryl around 9pm to sleep by 10p which works great without any grogginess the next day (the short Vyvanse DOE is another problem I’d guess! I did try your transit time test the other day and it was normal at 22 hours).

    Could the nightly Benadryl cause an AMP buildup long term? Are any of the other sleep meds I mentioned earlier preferred? Any other ideas or suggestions?

    For the last month I’ve done everything I can for good sleep hygiene (no TV/comp for an hour or more, a very predictable/relaxing night time ritual). I’ve tried Melatonin (with no effect). I’ve also tried 0.1mg Clonidine (with no effect). I also have an email in to Desiree to hopefully talk with you more in detail someday soon 🙂

    Thanks again for all the info!

    • Ryan,
      Look forward to talking. Short answer: I am quite sure your sleep challenges are metabolically related, specifically adrenal in origin. Why would I guess that on this paucity of info? Because the way you’re not metabolizing anything in a predictable way. You likely have some rusty pipes, likely some inflammation, likely changes in rate of passage with liver, likely a food immunity issue – all guesses, but without data that’s all that’s possible. The good news: you aren’t the first person I’ve seen with this presentation. For you the best next step is data collection. Download this in preparation for a Brief Call when Desiree comes back on Monday to schedule:

  4. […] AMP and MPH both have different pathways. AMP is a substrate of 2D6, while MPH blocks 2D6. AMPs are very significantly effected by some antidepressants – so one must pay careful attention. […]

  5. […] Medication Problems: 121. Asthma Medication 122. Allergies Medication 123. Headache Medication 124. Seizure Disorder Medication 125. Other […]

  6. D_in_SF says:

    Interesting. So in a healthy liver, changes in the rate of metabolism are a function of…??

    Are those change potentially indicative of a hepatic health concern, which wouldn’t get picked up by standard LFTs?
    Thank you

    • D,
      …A function of several things, – not the least of which is the relative load on the metabolic system of the liver due to detox and process downstream from inefficient bowel activity and detox there. They may or may not be associated w an hepatic health concern. Liver issues may occur over years of inadequate, compromised, excessive metabolic challenges in that specific pathway.

  7. D_in_SF says:

    I ran across this and was interested in a bit of what you wrote
    I’m on Focalin XR (20mg) as well as bupropion (300mg).
    I take both, typically, at 6am, as I’m in the office by 630am. The focalin works great at the dosage; however, it has given up by 1-130pm; which typically leaves another 4-5 hours in the office.
    I’m going to mention this to my Dr at the next appointment. However, given your focus on these issues of metabolic impact of multiple meds, I thought I’d ask if there was any metabolic reason, which might be down to the mix of the two meds

    • D,
      Not a problem w these two meds for a drug interaction perspective.

      Tow other variables to consider:
      1. GI and Liver issues with metabolic rate.
      2. Dosage of Focalin: 8 Hr is just about the max of DOE on XR well titrated. Certainly would be useful to have a short acting 10 IR for the PM. That would make excellent sense.

      • D_in_SF says:

        Dr Parker
        Thank you. Have recently had an LFT as part of my annual, and all is well with the liver

        • D,
          LFT only tells you if your liver is damaged – it tells very little about metabolic time, genetic changes in CYP 450 systems, or “burn rates” of meds coming thru.

          I just saw a person last night in the office who had been well maintained for many months on Vyvanse 20mg and began to show signs of toxicity. Upon careful review she has Transit Time of 48 hr. – Didn’t check, but quite likely here LFT was WNL within normal limits.

  8. Alice says:

    Hello. I have recently been diagnosed with ADHD at age 45. I started taking Adderall about a month ago and when I first started I had been really lax on taking my Prozac. So the first week the Adderall seemed to help. But then I got to thinking I better take my anti-depressant (60mg a day). At the time I didn’t think the two had anything to do with each other, but did notice that my Adderall wasn’t working as well. I did a lot of research online about it, and saw how you were supposed to take it on an empty stomach, eat normally while on it, even if you don’t want to, but eat good. I also found a few forums that said sometimes you have to take a break because you get a tolerance to it and you have to go off it a few days to get back to the level of energy and focus you had before.

    I tried everything. But still it wasn’t giving me the energy or focus or motivation I’d gotten the first week, something I must say I have missed for years. So my doctor increased it to 40mg twice a day. And I took 3 days off to see if that helped. Still nothing.

    Then I saw your article and it clicked. Maybe because I had starting taking my Prozac again it was messing with it. I had gone in again to see my doctor since it wasn’t working well, and she said before she changes the type, to try to change the anti-depressant. So she put me on Effexor XR. I read in your YouTube video comments about how it takes 5 days to get the Prozac out so the Adderall starts working again. Though I had also read somewhere that the half life of Prozac was 45 days.

    After 6 days I felt a slight change, though not the ‘normal’ I’d felt before, but now I’m back (a week later) to the blah, like all I did was eat sugar pills.

    I read above how you don’t like skipping days. I honestly am not sure what to do now. I see her in 3 days and I was thinking of having her put me on Ritalin but I was wondering… Are Prozac and Ritalin bad? I’m asking in case I’m one of the few who it takes longer then 5 days to completely get it out of my system since I was on such a high dose.

    And if you don’t take days off, and the Adderall isn’t working like when you first started, is it because it’s not the right medication? Or maybe the wrong dose? I honestly don’t know what to do. I know that for the last week I’ve taken my meds and still don’t feel the desire to get off my bed. Which only makes the depression worse and the house dirtier. LOL

    Thank you for any help you might be able to give me. I want to be able to know what to ask my doctor on Friday since this is all so new to me and I don’t seem to understand why it worked for the first 3 days, and now it’s not working as well. Anyone I’ve asked on the forums so far think it’s tolerance and that I have to wait 3-6 days of taking nothing, to get it so my body will accept it again. I just want it to work again, as I want to feel normal. It’s taken years for them to figure this out and now that they have, I don’t want it to stop working. Especially now that I have hope that this can be fixed since before the depression was so bad because I couldn’t even clean the house properly without MAKING myself do certain things on garbage night. And even then it was hard to get the motivation. Now I know it’s not my fault and there is help, as the Adderall did seem to work for a few days, but has given me a hard time since.

    • Alice,
      Many key possibilities here:
      1. 2D6 is but one if on Prozac and either MPH or AMP – just too many interactions. Just forget Prozac, way too many probs if you have ADHD.
      2. You could be on too much Adderall.
      3. Effexor might not be the right antidepressant.
      4. You may have metabolic issues that supervene – if you’re medically challenged psych meds always work unpredictably.
      5. Take a look at the Mind Gut Video playlist for more info:
      6. Your hormones could be off.
      7. You may suffer w adrenal slowing, adrenal fatigue and be trying the stimulants to fix that challenge… and they won’t work on the adrenal, only the adrenal symptoms.

      Hope this helps.

  9. Carol says:

    I am currently taking 40mg Cymbalta at night for depression and anxiety and 40mg Vyvanse in the morning for ADD. I have been on the Cymbalta for several years with no issues. I started Vyvanse in the last 4 months beginning at 20mg increasing to 30mg and then 40mg. I have gained approximately 10-15 pounds since starting the Vyvanse. Most of the side effects I locate on web searches about Vyvanse indicate weight loss, not weight gain. I crave more sweets when taking the Vyvanse too. Is the weight gain a side effect of these two drugs being taken together?

    I have taken many different anti-depressants and feel that the Cymbalta is working great. I also like the productivity I gain when taking the Vyvanse. Before the Vyvanse, I would wonder at the end of the work day what I did because I could see minimal results. The Vyvanse has improved my work quantity and quality.

    I don’t like the idea of giving up either of these medications. Are there alternatives that would work with less side effects?

    Is the Vyvanse supposed to be taken daily? My son took ADHD medication as a child (Ritalin). I was told to give it to him only on school days. I have tried taking Vyvanse only on work days and off on weekends (my choice, not doctor instructions). When I do not take the Vyvanse on weekend days, I am exhausted all weekend, sleeping a lot and no energy. Is this a normal reaction to not taking the Vyvanse?

    • Carol,
      The suggestion that one should take stimulants only during the week is a pet peeve of mine, and my colleagues who do as much ADHD work as I do. Naturally there are some exceptions to that rule of taking it every day, but far more often meds work best if taken daily. Pediatricians are notorious for that recommendation as many live in the dark ages when stimulants were only for school and the psychological issues weren’t adequately considered. With a focus on brain function, yours is an excellent example of the limitations of that practice.

      Yours is a quite atypical situation and might be encouraged by the fact that Cymbalta moderately blocks 2D6 the AMP pathway, creating a mild AMP interaction/back-up/accumulation leading to disinhibition w food. – Not typically a finding, but noteworthy and seen in practice.

      A suggestion to keep both ‘almost’ on board would be to try changing the Cymbalta for Effexor, Venlafaxine, Pristiq [all the same drug in different forms] as those 3 SNRIs [Cymbalta is an SNRI] are clean completely on 2D6, and often even more efficacious in my experience than Cymbalta. If you continue w that problem consider coming down slightly on the Vyvanse, back to 30mg w your doc and chase it w an IR AMP in the pm to obviate that possible reaction.

      Do take a look at this ADHD Med Dosing Playlist of Videos to get that DOE thing right: .

  10. Kathleen says:

    I just found this page and I was curious about this interaction between prozac an vyvanse.

    I’m on low doses of both (Prozac 10mg and Vyvanse 20mg) and I can’t seem to get on without either of them. I was on prozac alone for a long time for depression but in college my ADD became harder to manage so I stopped taking the prozac (I heard about possible interactions via the internet) and started taking the 20mg of vyvanse. Unfortunately my depression symptoms came back and now I’m trying to take both. I noticed the vyvanse doesn’t seem to be as effective as it was before. Is this a bad combo of drugs at these dosages? My physician seemed to be under the impression that since I was taking such low doses it wouldn’t be a problem but I’m still skeptical. Also is there another ADD medicine that doesn’t interact with prozac?

    • Kathleen,
      Some docs do take the position that it isn’t a problem, but over time, having made that mistake repeatedly until I figured it out in 96 with Adderall [also a 2D6 substrate], I can say with certainly you will be chasing dosage until you move forward. Suggest Effexor, Venlafaxine, Celexa, Lexapro, Zoloft, all are clean on 2D6 and it appears that you are using small dosages effectively. See this Prozac Interaction Video for more on the topic over at YouTube and then look at the dosing strategy video playlist on that drcharlesparker YouTube channel.

  11. Beth says:

    I have been on Sertraline 150mg and Clonazapam .5mg x2 daily for 3 years for anxiety and OCD. My doc suspected ADHD, referred me to a psych for confirmation and put me methylphenidate while waiting for the psych evaluation and I wasn’t happy with the results… anxiety, made hyperactivity symptoms worse, irritability and migraines… suffice to say, not the best. I went for an ADHD psych evaluation and the psychiatrist diagnosed me with ADHD combination-type and suggested Adderall XR 20 mg.

    The first day was amazing. I felt normal and could function with ease. I felt I had found the answer and finally my life would be manageable. I can’t explain what a relief this was…. until a few days later when I noticed the medication stopped working after a few hours and I began to feel like a zombie. Confusion, could not focus on anything, exhaustion, spaced right out and I felt sick… toxic even. I started doing research on possible interactions and now I have been switched to Biphentin for the time being, I mentioned the possible interaction and have begun tapering off sertraline slowly.

    Question: Is it possible that the sertraline is causing an interaction with the adderall by causing it to build up in my system and thus becoming ineffective?

    I felt “normal” for that one day and if it’s even remotely possible that I can get Adderall XR to work for me consistently by removing the sertraline from the mix then I am willing to try it (with my doc’s approval of course).

    Please shed some insight on this. Thank you.

    • Dr Charles Parker says:

      Zoloft is not a 2D6 inhibitor… it blocks a couple of other important pathways counter productively, but is not a stimulant challenger. My best guess on this very tiny amount of info is that your doc didn’t start low enough, and the second day caught up with you.

      MY recommendation with your doc:
      1. First watch this vid on Med Sensitivity –
      2. Then this one on Titration:

      I think you were, as I say in the second vid: “Overdosed right off the bat..” Not disparaging your doc, however, as this titration problem happens all the time. I just never start any adult on 20mg of Adderall XR out of the box, because I don’t want to have any possibility of creating the problem you had. I’ve done it far too many times myself, so have self corrected.

      Then do consider metabolism as noted in several of the other videos, including the playlist on Immunity Gut and Brain… could be a prob, – worth considering.

  12. aaron says:

    I have been on Wellbutrin 150 XL for about 10 years as a treatment for fatigue. In the beginning we tried to get the dose up to 300 mg daily, however I was not able to sleep.

    Two years ago I started on Dexedrine of which I take 30 – 40 mg daily.

    I noticed over the last year that I was having more problems sleeping. I tried going off the Wellbutrin and sure enough I sleep very well when off the Wellbutrin. However the first side effects I get is that my muscles, primarily from the waist down feel like I really need to stretch. I wish I could describe this feeling better but it is like you have been in a car for 12 hours and you have to stop because the need to stretch is almost numbing. No matter how much I stretch I do not get the relief you would expect.

    For the last year I have been taking 1/2 a tablet of 150 XL hoping that taking half the medication as well as shortening the half life by cutting the XL tablet would let me sleep better. However I keep having a feeling like the Wellbutrin is building up.

    After searching for information on how these drugs are metabolized I found information about Cytochrome P450 2D6 (CYP2D6). After looking into CYP2D6 maybe there is something to my idea of wellbetrin building up.

    Although I have not been able to tolerate alcohol as much since being on wellbutrin this has become very noticeable over the last few months. This Sat Oct 13th I had one drink and the results would have made it appear as though I had many. My ability to think and complete tasks was reduced far beyond what is normal.

    If I could take a a higher amount of welbutrin I would have lots of energy the same day, yet I would be up all night if I took 300 mg.

    The Dexedrine appears to work better without the wellbutrin, yet the tired, tight muscles are very hard to deal with to the point that it become a cause of fatigue.

    Any thoughts on this would be gratefully appreciated. I have a great Doctor but they are all on time constraints so I try to have things layed out when I go there so that we have a productive visit.

    Also at times when off the welbutrin and having muscle problems I have taken tramadol in the evening and I sleep better. Anti Inflammatories like ibuprofen and toradol don’t touch the muscle problem.

    Thanking you in advance.


    • Aaron,
      Very likely that you have two issues:
      1. a low grade metabolic problem that is slowing the metabolism period, thus the both the narrow therapeutic window [search here for more details] and the roving therapeutic window as well.
      2. Wellbutrin can back up Dex over time.

      Chronic low grade issues like this do encourage a more careful laboratory assessment rather than simply guessing and trial and error. I would start with IgG and consider trace element, tissue mineral analysis, if your problems persist.

  13. Peter Meret says:

    Are there any anti-depressants that would work synergistically with Adderal rather than
    blocking Adderal’s effects? Would Trazodone be a suitable choice?

    • Peter,
      All of them work without drug interactions except the two I mention most frequently: Prozac and Paxil. Moderate inhibition occurs with Cymbalta and Wellbutrin as documented in Cozza and Armstrong et al, and only requires specific attention, from my personal experience, when the dosage goes too high on either of these in an effort to turn that depression around – more rare that common.

      The reaction on the interaction is simple: too much = agitated, angry, can’t sleep, paranoid, can’t eat, loosing weight, judgement out the window.

      Trazodone is never a problem.

  14. Colin says:

    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. 

    • 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:


  15. 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.

  16. 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

  17. T says:

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

    • 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.

  18. Craig B says:

    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.

    • 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.

  19. eddie t says:

    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

    • 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.

  20. Christine says:

    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-
      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.

      • Susy says:

        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.

        • 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.

      • q says:

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

        • 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.

          • q says:


            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?

          • 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.

          • q says:

            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?


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

  21. Jeff says:

    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,
      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.

  22. randy says:

    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.

  23. Tina says:

    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?

    • 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 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.

  24. Randy says:

    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

  25. vicki says:

    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.

    • 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.

  26. 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.

  27. Gary Lamont says:

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

    Narconon Vista Bay

  28. 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:


  29. Eddie says:

    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!

  30. 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.


  31. 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?

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