How Drugs & Food Affect Drug Metabolism
"Taking ownership of your metabolic health starts with taking ownership of your information diet."
The proverb, “You are what you eat” is true on multiple levels. You are literally built from the atoms of what you consume. On top of this, the composition of your diet shapes how the body utilizes the complex soup of material flowing through it. From nutrients to hormones and psychoactive drugs, the way your body metabolizes things determines the patterns of physiological influence they will have. The way your metabolism operates shapes not just the molecular contents of your bloodstream, but the psychological contents of your experience.
Let’s connect some of the dots linking enzymes down in the liver and gut to neural networks up in the brain—the realm of “simple,” unconscious metabolism to the realm of psychology and mental health.
We will go over some basic biology and examples of drug-drug interactions that involve key metabolic enzymes, including how widely used prescription drugs affect the metabolism of other substances. When it starts to feel like we’re getting lost in the biological details, we’ll step back to consider the big picture, considering what you might do once armed with this knowledge.
(As usual, nothing here is medical advice.)
The Basics of Human Cytochrome Enzymes (CYPs)
An important superfamily of enzymes involved in the metabolism of many different substances are cytochromes P450 (“CYPs” or “CYP enzymes”). CYPs are found throughout the tree of life. Our focus will be on human CYPs, especially as they relate to the metabolism of psychoactive substances.
Cytochrome enzymes are found in most tissues of the body, typically in association with the membrane of organelles found within cells, such as mitochondria. These enzymes are important in the synthesis and metabolism of everything from sex hormones like estrogen and testosterone to cholesterol and vitamin D. Especially in the liver, they are critical for the metabolism of “xenobiotics,” substances foreign to the body. This can include artificial compounds created by humans—pharmaceuticals, pollutants, food additives—as well as natural products produced by other creatures (e.g. toxins).
CYPs account for around 75% of drug metabolism. If you ingest a prescription medication or other drug, there’s a pretty good chance a CYP will be responsible for metabolizing it. Humans have a number of different CYP enzymes, each of which will display some degree of genetic variation between individuals and populations. This is one reason why two different people can have distinct responses to the same drug.
In humans, over 50 different cytochrome enzymes are encoded in the genome, grouped into families (e.g. CYP1, CYP2, CYP3, etc.) based on sequence similarity. Only about eight of these enzymes are responsible for metabolizing the majority of drugs in clinical use. There are many, many drugs that influence how CYPs operate.
Let’s take a closer look at two CYP enzymes, CYP3A4 and CYP2D6, which are responsible for more pharmaceutical drug metabolism than other CYPs.
CYP3A4: Psychoactive Drugs & Sex Hormones
There are several related enzymes within the human CYP3A subfamily: CYP3A4, CYP3A5, and so on. They tend to be expressed highly in the liver and intestines, collectively facilitating the elimination of over one-third of the 200 most prescribed drugs in the US. This enzyme family metabolizes everything from chemotherapy agents (cancer treatment) to statins (managing blood lipid levels) and immunosuppressants (inflammatory conditions like arthritis).
CYP3A4 also breaks down a lot of different psychoactive compounds, such as psych meds, recreational drugs, and hormones. There’s way too many to list out completely, but here are some notable clusters of psychoactives:
Certain SSRIs and other antidepressants (e.g. Zoloft®, Celexa®)
Many antipsychotics (e.g. Haldol®, Abilify®)
Opioids & many analgesics (e.g. fentanyl, codeine, hydrocodone)
Benzodiazepines (e.g. Xanax®, Valium®)
Certain stimulants (e.g. caffeine, cocaine)
Sex hormones (e.g. estrogen, progesterone, testosterone)
Again, this is only a partial list. If CYP3A4 is inhibited, those things will stick around in the body longer. So what kind of drugs inhibit CYP3A4? Unlike the next cytochrome enzyme we’ll look at, CYP3A4 is not strongly inhibited by very many psych meds (with exceptions). Instead, medications that strongly inhibit it include various antivirals, antibiotics, and antifungals. Consuming one of these substances can inhibit CYP3A4’s ability to break down drugs such as those listed above, which will tend to enhance their effects or increase overdose risk.
If someone is consuming an antimicrobial or other drug that inhibits CYP3A4, they and their doctor need to be mindful of other drugs they may be taking which are broken down by this enzyme. In addition, they should expect the possibility of mood, behavioral or other side effects that may arise from inhibiting the breakdown of naturally occurring hormones. Sex hormones not only play a critical role in the development of the brain and body, but have a variety of effects on emotion and behavior.
The opposite of an enzyme inhibitor is an inducer. These enhance an enzyme’s ability to break things down, resulting in faster metabolism of the enzyme’s substrates. A class of drugs that often strongly induce CYP3A4 are anti-androgens. Androgens are steroid hormones associated with the development and maintenance of male-typical characteristics, such as testosterone. Anti-androgens work by blocking androgen receptors and/or interfering with hormone metabolism. Because CYP3A4 naturally metabolizes various sex hormones, anti-androgen drugs acting as CYP3A4 inducers can lower sex hormone levels by speeding up their metabolism.
Bottom line: some medications not only affect the metabolism of other drugs and xenobiotics, but the pattern of naturally occurring substances circulating throughout the body. In the case of hormones, this will have myriad physiological and psychological consequences. Sex hormones like testosterone and estrogen are powerful substances. They instigate many different physiological processes in the body, from purely physical things like muscle mass and bone density to emotion and cognition. (The word “hormone” is derived from a Greek term meaning, “setting in motion”).
CYP2D6: Psych Meds, Herbal Remedies & Neurotransmitters
Like CYP3A4, the CYP2D6 enzyme metabolizes many compounds. This includes everything from SSRIs to opioids, antipsychotics, stimulants, LSD, and more. Unlike CYP3A4, there seem to be more psych meds which strongly inhibit CYP2D6, such as the antidepressants fluoxetine (Prozac®), paroxetine (Paxil®), and bupropion (Wellbutrin®). A number of others act as weak-to-moderate inhibitors.
CYP metabolism is not just influenced by synthetic pharmaceuticals. Plenty of natural substances, including dietary nutrients and plant compounds (“phytochemicals”), can influence CYP enzymes. For example, the herb St. John’s Wort and the Cannabis-derived compound cannabidiol (CBD) are both CYP2D6 inhibitors. It has recently been shown that high doses of CBD (640 mg) given orally can increase blood levels of THC (20 mg) and its metabolites, likely through CYP inhibition. This results in greater subjective and physiological drug effects, such as cognitive impairment and heart rate.
Notably, some compounds are both substrates and strong inhibitors of CYP2D6, including the SSRIs fluoxetine (Prozac®) and paroxetine (Paxil®). In other words, they can inhibit their own metabolism in addition to that of many other psych meds. This is especially relevant to the increasing number of people concurrently taking multiple antidepressants and antipsychotics.
CYP2D6 is also involved in some of the metabolic pathways giving rise to endogenous neurotransmitters. For example, it influences dopamine biosynthesis. As a result, psych meds like Prozac®, which inhibit CYPD6, can exert an indirect effects on neurotransmitter systems (dopamine production) beyond those they act on directly (serotonin). The physiological and psychoactive effects of drugs can therefore extend beyond their primary mechanism of action, in ways that are complex and poorly understood.
Drug-Drug Interactions Between Psych Meds
For the sake of simplicity, we have so far considered just two of the major CYP enzymes and a handful of drugs they interact with. In reality, many drugs are metabolized by and influence multiple CYPs. For example, fluoxetine (Prozac®) and sertraline (Zoloft®) are both metabolized CYP3A4, CYP2D6, and other CYPs. Each of these popular SSRIs also inhibits the activity of several CYPs to some degree.
I’ve previously written about the growing trend of people chronically taking multiple psych meds. For example, if you’ve tried a few SSRIs to treat depression and they’re not working, your doctor might prescribe an adjunctive drug, something you take together with an SSRI. Brexpiprazole (Rexulti®), traditionally used as an antipsychotic, is such a drug. (I first heard about it from a TV ad at the airport).
Let’s say you’ve tried both Prozac® and Zoloft®. Neither was able to satisfactorily curb your depression, so the doctor suggests Rexulti® as an adjunct. Rexulti® is metabolized by both CYP3A4 and CYP2D6. If your doctor is on top of their drug-drug interaction game, they might suggest the combination of Zoloft® and Rexulti® rather than Prozac® and Rexulti®, as Prozac® strongly inhibits CYP2D6 whereas Zoloft® is a weak inhibitor.
Beyond the drug-drug interactions between Zoloft® and Rexulti® due to CYP inhibition, it is also expected that drugs like this will impact your metabolism more generally. One hint at this comes simply from considering their common side effects.
For an SSRI like Zoloft®, possible side effects include nausea and diarrhea. Gut issues are fairly common with SSRIs. This is to be expected, as most of the serotonin in your body comes from cells in the GI tract, not the brain. Any drug that systemically alters neurotransmitter levels, whether prescription or recreational, can influence gut physiology and the microbiome.
Even if you experience no obvious side effects from an SSRI, the inevitable change in the biochemical ecology of your gut is virtually guaranteed to affect your microbiome. As is becoming more appreciated, altering the microbiome can have various metabolic and behavioral consequences.
What about antipsychotics like Rexulti®? These drugs carry some risk of metabolic syndrome, a medical term referring to a cluster of metabolic symptoms including weight gain and obesity, high blood sugar, diabetes, and high blood pressure. An estimated one in three adults in the US have metabolic syndrome. Because SSRIs like Zoloft® inhibit the CYP enzymes responsible for metabolizing Rexulti®, the risk of its side effects is higher when taken with a CYP inhibitor.
While anyone taking multiple medications should be mindful of potential drug-drug-interactions, prescription pharmaceuticals are not the only consumables that influence metabolism.
Interactions Between Psych Meds & Food
If you’re taking medications metabolized by CYP3A4, your doctor will (hopefully) also alert you to the fact that certain dietary components should be monitored or avoided. From example, grapefruits and some other citruses contain natural CYP3A4 inhibitors like bergamottin.
Many phytochemicals and dietary components affects CYPs and other metabolic enzymes, acting as either inhibitors or inducers. We primarily think of the foods we eat as a source energy and nutrition. They are that and more—complex mixtures of macronutrients, micronutrients, drugs and other xenobiotics. Virtually everything you eat is going to contain a dizzying array of molecules, some of which alter metabolism itself. This just as true for all-natural whole foods as it is for anything else.
The high-level point is you are what you eat. Whether it’s synthetic drugs or organic kale, what you consume influences your metabolism. The biological consequences of this can extend far beyond the immediate medicinal or nutritive effects associated with what we ingest.
As you can tell, it’s easy to get lost in the physiological details. So what can you do about it? It’s not like you can learn every relevant fact of biochemistry, calculate the metabolically optimal dietary protocol, and just go about your life.
Owning Your Metabolism
A simplistic reaction to this information would be to conclude that you should avoid consuming any substance that alters the behavior of your metabolic enzymes. This would be completely unworkable, as an inordinate number of the compounds you ingest influence your metabolism, including components of any normal, healthy diet. For example, vitamin B3 can inhibit CYP2D6, but no sane person would conclude that vitamin B3 consumption should therefore be avoided.
Metabolism is supposed to react to what you put in your body. Our metabolic systems evolved the ability to dynamically reconfigure in response to continual environmental change, including diet composition. This is why fasting or adhering to different diets shifts your general metabolic state—the body changes how it processes things based on current demands.
Shouldn’t your doctor be responsible for alerting you to important drug-drug interactions or metabolic changes which may be induced by whatever they have prescribed to you? Sure, but no human being can memorize all of the potential drug-drug interactions. There are too many. Biology is complex and idiosyncratic. If a doctor prescribes you something, there’s a good chance they know some of the major interactions it has. But they might not.
Because your brain and body function as one integrated unit, your metabolic health is intertwined with your mental health. As the examples above illustrate, psychoactive drugs can have metabolic consequences. Likewise, the state of your metabolism can influence your body’s reaction to psychoactives and neurochemistry of your brain generally. It’s all connected, and the sum total of this biological complexity adds up to your life.
Ultimately, you are responsible for your own metabolic health. If you’re taking a drug, then take some time to look up any drug-drug interactions or metabolic effects it might have. You don’t need to be an expert in human physiology to research whether or not your Prozac® might affect your metabolism (it will) or influence how your body processes other medications (it can). Will you fully understand the details? Probably not. Will you have questions? I hope so. When you speak with your doctor, it should be a dialogue, not a monologue.
How do the drugs you take affect your metabolism? If you don’t know, perhaps it’s time to get curious. Taking ownership of your metabolic health starts with taking ownership of your information diet.
To learn more about the topics covered in this essay, try these episodes of the Mind & Matter podcast:
Dominic D'Agostino: Metabolism, Fat, Carbs, Protein, Ketogenic Diet, Nutrition, Blood Sugar & Personal Health Monitoring | #76
Maayan Levy: Ketogenic Diet, Cancer, Microbiome, Nutrition & the Immune System | #72
Amy Reichelt: Obesity, Diet, Eating Habits, Food Addiction, Psychedelics, Nutrition & the Brain | #55