Drug Metabolism, Substance Interactions, and Genetics— Understanding Possible Implications for Psychiatric Drug Tapering

Most of us know that, when taken together, certain drugs have potentially dangerous chemical interactions with other drugs. However, this is only one way in which dangerous interactions can occur. Another way – and one that is less well known but may well be more common – involves dangerous impacts on the body’s natural metabolic processing of drugs. There are several pieces of this puzzle that are important to understand.

First, there are various naturally-occurring enzymes that are known to be extremely important for helping metabolize and gradually eliminate many types of drugs from the human body. And certain, specific enzymes – the most significant of which is the family of enzymes called Cytochrome P-450 (CYP) – are known to be particularly important for metabolizing many psychiatric drugs. Such drugs are called “substrates” of CYP and other enzymes.

Second, it is also known that all of us are genetically predisposed towards having different levels of these metabolizing enzymes in our bodies naturally. Though mass genetic testing has never occurred, it is generally believed from smaller studies that significant percentages of the population can be categorized as either especially rapid or especially slow or “poor” metabolizers of certain types of drugs – or anywhere in between.

Third, at the same time, many prescription and recreational drugs and even certain foods and supplements are known to either increase or decrease the effectiveness of some of these same metabolic enzymes. These substances are typically labeled as either "inducers" or “inhibitors” of enzymes such as CYP– that is, these substances can either significantly increase the efficiency and rapidity with which certain drugs are metabolized and eliminated from the body, or they can significantly decrease the efficiency and rapidity with which certain drugs are metabolized and eliminated from the body. Many antidepressant drugs are inhibitors, for example, while cigarette smoke is an inducer. Some drugs do both – that is, they inhibit one enzyme and induce another.

The impacts of all of this can be very significant. Though these issues are rarely discussed by average physicians with patients and have gotten relatively little visibility in the lay withdrawal community and even less in the media—likely in part because of the complexities involved in understanding this very dense biochemical and pharmacological topic area—some people who’ve had particularly difficult withdrawal experiences believe that these issues may have played a role. And the science suggests that they may be right. Poor metabolizers are far more likely to experience more—and more serious—adverse effects from drugs that they have difficulty metabolizing. It’s not uncommon that “normal” drug doses can in effect be ten times stronger or ten times weaker depending on whether a person is a poor or rapid metabolizer or is ingesting some other substance that interacts with the metabolizing of that drug. For example, the common warnings from doctors to not eat grapefruit when taking particular drugs is rooted in these issues: Grapefruits contain ingredients that can influence the metabolizing of drugs in different ways, to the point that in some cases eating even a single grapefruit can significantly interfere with drug effectiveness and/or increase drug toxicity.

Many people have tapered off psychiatric drugs without having a good understanding of what sorts of interactions their bodies may be experiencing and how those interactions could change during the course of a taper; nevertheless, others have found it valuable to take the time to become better informed about these issues. Here are some actions that laypeople often take to become more informed about their own drugs, ideally in ongoing consultation with a well-informed health practitioner and pharmacist:
 

• Read through all of the TWP articles listed in Step 12: Interactions, Reactions and Sensitivities.
   
• Check for any possible prescription or recreational drug-drug interactions by looking for interaction warnings in the FDA-approved drug label (see Step 10 for more information).
   
• Search in different types of online, automated “drug interaction checkers” – though these vary in completeness and reliability.
   
• Check the FDA’s ‘Table of Pharmacogenomic Biomarkers in Drug Labeling’. It provides a list of drugs that have pharmacogenomic information in their drug labels. 
   
• Check sample lists of some common substrates, inducers and inhibitors such as the FDA’s or Indiana University School of Medicine’s – though these also vary in completeness and reliability.  
   
• Consider getting genetically tested specifically to determine whether one metabolizes any types of drugs particularly slowly or particularly rapidly. Note that the tests alone are sometimes difficult to understand without a knowledgeable person to help interpret their implications.

• The following readings may be helpful:
   
  • Gardiner, Sharon J., and Evan J. Begg. “Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice.” Pharmacological Reviews 58, no. 3 (September 1, 2006): 521–90. doi:10.1124/pr.58.3.6.
     
  • Eikelenboom-Schieveld, Selma, MD. “CYP Testing to Help Prevent Dangerous Adverse Drug Reactions.” (Mad in America, January 24, 2017.)
     
  • Lynch, Tom, PharmD. “The Effect of Cytochrome P450 Metabolism on Drug Response, Interactions, and Adverse Effects - American Family Physician.” Accessed April 27, 2017. 
     

The image of a CYP1A2 protein is courtesy of Emw and Creative Commons/Image has been modified by adding a background.