Thursday, July 5, 2012

Just Say No Limit: Trayvon, Dextromethorphan, Marijuana, and MAOA

When I recently posted a photograph of Trayvon Martin, the African-American victim of a shooting during a confrontation with a neighborhood-watch volunteer, making an obscene gesture, many of my readers missed the inside joke. The national media packaged the earliest reports on this case to maximize sympathy for the 17-year-old Martin. We knew him by his cute, smiling visage from a few professional pictures taken when he was not older than thirteen. These appeared alongside a 2005 mug shot of the shooter. When a more recent photograph of Martin extending one middle finger at a camera came to light, a conspiracy theory emerged to defend his honor. Some insisted that the hand must have been photoshopped because another photograph exists utterly lacking said digit.


Alas, Martin’s YouTube page, which had not been accessed since before Martin’s death when I arrived at it, utilized the controversial photograph that I would post, containing, not one, but (count them!) two middle fingers! Similar photographs subsequently made the rounds, and it became clear that the new-media-savvy Mr. Martin had something of a trademark pose. Not only was Martin’s innocent image taking flak, but I felt my own moral sensibilities slipping away under the onslaught of a greater quantity of this vulgar sign than I had previously imagined.

At least Americans understood the senselessness of the shooting, given that Martin was merely taking a stroll to a corner convenience store to buy a package of Skittles and a can of iced tea. Well, the police report noted an “Arizona tea can,” but a photograph of the can clearly reveals it to be Arizona Watermelon Fruit Juice Cocktail. So what? Actually, this beverage and Skittles are ingredients of a recreational drug called “watermelon lean,” the knowledge of which I must credit to the blog The Conservative Treehouse. Martin actually acknowledged his use of lean on Facebook. The psychoactive ingredient of lean is the over-the-counter cough medicine, dextromethorphan, which happens to carry the street name, “Skittles.” At high doses, dextromethorphan acts as an addictive drug with the same dissociative symptoms as phencyclidine (PCP or “angel dust”). Case reports of psychotic symptoms, including paranoia and aggression, have followed dextromethorphan toxicity since the 1960s. Perhaps, then, it is small wonder that the young lady whom Martin’s family falsely described as his “girlfriend” shared that, in the cell phone conversation leading up to the shooting, Martin had told her that the shooter, George Zimmerman, was “looking crazy.” Even if the prosecution’s narrative is accurate, (cliché or not) another being out to get one cannot preclude one’s paranoia.


Much like Martin, dextromethorphan benefits from an innocent public image far removed from angel dust comparisons. However, the case reports have described “cough-syrup psychosis” as lasting several days even after disuse, and some factors, to which Martin was subject, can accentuate the effective dosage and half life of Skittles.

One such factor, arguably, is marijuana. Marijuana hashish is 2.5% cannabidiol, the second most common cannabinoid in marijuana after THC, which is the primary cause of marijuana’s psychological effects. Cannabidiol inhibits a liver enzyme called CYP2D6, which is the major enzyme of dextromethorphan metabolism. While a recent study called this inhibition “potent,” the blood levels of cannabidiol from smoking a single marijuana joint would be too low to significantly impact dextromethorphan metabolism. THC also inhibits CYP2D6 but with about three times less potency than cannabidiol. However, marijuana could interact with dextromethorphan by another pathway involving the enzyme produced by “the warrior gene.”

Because the liver enzyme CYP2D6 is inhibited or enhanced in its activity by a number of drugs, there are a number of potential drug interactions for dextromethorphan. However, only one class of drug received a specific drug interaction warning in a best-selling medical school pharmacology textbook, Katzung’s Basic and Clinical Pharmacology, as well as on UpToDate, a subscription-based Internet site heavily used by internal medicine physicians. This class of drug is called monoamine oxidase inhibitors (MAOIs), which were the first anti-depressants and are now much less commonly used since selective serotonin reuptake inhibitors (SSRIs) are available with far less severe side effects. Regular readers of my blog know that one of my obsessions is the study of the genetics of violence. The best understood gene that affects violent behavior is monoamine oxidase A (MAOA), which produces an enzyme of the same name. This enzyme is one of the two enzymes that MAOIs inhibit. The MAOA enzyme breaks down mostly the neurotransmitters serotonin and norepinephrine. Doctors believe that MAOIs work because having too few of such neurotransmitters in the synapses between neurons can result in depression. Many doctors and scientists also believe that having too many such neurotransmitters in synapses can result in antisocial personality disorder, conduct disorder, delinquency, and aggression. Of course, neurochemistry is more complicated than I am describing, but I think this is a fair summation of many decades of medical expertise on the treatment of depression. When dextromethorphan and MAOIs interact, serotonin levels can acutely rise and cause a potentially deadly reaction called serotonin syndrome. According to the Katzung text, the predictability of the interaction lacks sufficient data to qualify as “established.” Trayvon Martin was not taking MAOIs, but if he had reduced MAOA function for other reasons, it could have boosted his levels of serotonin and norepinephrine and given him a greater tendency towards aggression and delinquency.

THC inhibits the enzyme MAOA at roughly the same potency as it inhibits CYP2D6, according to a study of brain MAOA from pigs. That study also questioned whether common marijuana usage would have any meaningful effect on behavior or emotion with such a low level of potency, but it noted that brain levels of THC are higher than blood levels, and THC accumulates in neurons. Martin’s blood THC level was 1.5 ng/mL, far below the average peak concentration of 162 ng/mL caused by smoking a single marijuana cigarette. Peak concentration tends to occur about eight minutes after someone begins smoking, whereas Martin’s level matches a person who smoked one joint 3-6 hours prior. A professor of forensic science named Larry Kobilinsky claimed that the marijuana use could have been days earlier, but that conclusion does not match the results of a study from the National Institute on Drug Abuse, at least if the marijuana is limited to a single cigarette. Plus, Martin’s cousin, Stephen Martin, appears to have posted on Twitter that Trayvon Martin was “high” within twenty-four hours of the shooting.

Smoking tobacco seems to inhibit monoamine oxidase much more than smoking an occasional joint. Smokers typically have 20-30% lower MAOA enzyme activity and 30-40% lower activity of the other monoamine oxidase enzyme, MAOB, which accounts for about 30% of monoamine oxidase enzymes in the brain. Fowler et al determined that cigarette smoking lowers brain MAOA half as much as taking the MAOI tranylcypromine.

Martin might have been a smoker. He seemed to obtain cigarillos from three young men, according to some interpretations of the 7/11 surveillance videos, and a lighter was among his belongings at the scene of the shooting. Also, his lungs had mild anthracosis, which is a black discoloration that can result from smoking. Even if Martin only smoked marijuana, if he used cigarillos as marijuana blunts, then he was smoking the tobacco that constitutes the blunts with his marijuana, likely without filters.

Genetic differences can influence dextromethorphan response. Wide variation exists in the gene for CYP2D6, such that poor metabolizers experience blood concentration levels five times greater than extensive metabolizers. Martin’s African-American heritage does not affect his likelihood of having a version of the CYP2D6 gene that would cause him to slowly metabolize dextromethorphan, but this is not the case for the gene that determines MAOA levels.

Black people have 62% lower monoamine oxidase activity than white people, as measured by MAOB activity in the platelets of blood. Black men are about twice as likely as white people to have the “warrior gene,” which is basically just the 3-repeat allele of the MAOA gene promoter (rather than the 4-repeat allele, which most white people have). Five percent of African-American men (or about 10 times the prevalence of white men) have the understudied 2-repeat allele of MAOA, which appears to double the rate of aggression compared to men with the more common versions of the gene. However, the label of “warrior gene” for the less dangerous 3-repeat version is still highly appropriate. In fact, I would argue that the association of aggression with the interaction between the 3-repeat allele and childhood maltreatment is the strongest single-gene finding in all of behavioral genetics. I could list the breadth of corroborating lines of evidence: behavioral associations exist for the gene’s promoter, its enzyme product, the metabolites of the enzyme’s reaction, gene activity demonstrated in functional MRI, the degree of epigenetic methylation, epistatic interactions between the gene’s promoter and other genes, an interaction between this promoter and a second promoter of the MAOA gene, interactions between the MAOA gene promoter and sex hormones, and completely inactivating “knock-out” alleles in humans and animal models.

As the designs of the studies on this gene have improved, the robustness of their conclusions strengthened. Last year, I posed some pointed questions to one researcher about how more thorough consideration of confounding variables could produce more startling results, and a team of New Zealand researchers have recently published a study demonstrating exactly what I predicted. They sought to determine whether any of a list of possible risk factors could, in the presence of the 3-repeat allele but not the 4-repeat allele, increase the likelihood of violent behavior. Their study did not report all of the factors that failed this test, but five such measures did trigger the genetic predisposition: childhood maltreatment, the mother smoking during pregnancy, ten years of an interviewer’s assessment of poor material living standards, dropping out of school by age 18, and a low average of two IQ scores at ages 8 and 9 from the revised Wechsler Intelligence Scale for Children. In each case, the 4-repeat allele protected against adopting violent tendencies, and all five factors melded into a combined risk index that greatly accentuated the genetic differences at the highest index levels. I found it particularly interesting that, after ten years of studies replicating the original childhood-maltreatment-gene interaction, this study determined that the IQ-gene interaction influenced violence with a greater degree of certainty than the gene’s interaction with physical or sexual child abuse.

GWAS Jihadists

Opposition to the science of the MAOA gene has dwindled to an embattled coterie of shrieking moralists and charlatan scientists. When Harvard psychologist Steven Pinker published The Better Angels of Our Nature, Pulitzer Prize-winning columnist Nicholas Kristof bet that Pinker would join the ranks of Pulitzer winners. However, I used this little blog to point out that Pinker had passed on in the book a falsehood based on a copy-and-paste error, among other mistakes, to malign MAOA research. In the weeks prior to the Pulitzer committee’s decision, my Pinker post experienced a surge of readers. Ultimately, Pinker’s book would not win even an official nomination. None of this prevented yet another cheap “ethics” journal from publishing a screed by a “philosopher and biologist,” who repeated the error once more. Meanwhile, researchers who focus on genome-wide association studies (GWAS) have led a failed campaign to silence all candidate-gene research. According to Duncan and Keller, “the possibility that most or even all positive [candidate gene-by-environment interaction] findings in psychiatry discovered to date represent type I errors cannot be discounted [emphasis added].” In other words, every single association between a single gene allele in a certain environmental milieu affecting a behavior, including a decade of studies on the 3-repeat MAOA promoter, might be merely one of a series of falsely positive flukes. Well, if the studies are all wrong, then why publish them? According to Chabris et al:
At the time most of the results we have attempted to replicate were obtained, candidate gene studies of complex traits were commonplace in medical genetics research. Such studies are now rarely published in leading journals…. In our view, excitement over the value of behavioral and molecular genetic studies in the social sciences should be tempered—as it has been in the medical sciences—by an appreciation that for complex phenotypes, individual common genetic variants of the sort assayed by SNP [single-nucleotide polymorphism] microarrays are likely to have very small effects.
So, psychiatric and psychological journals should follow the lead of respectable medical journals and stop publishing studies on individual genes and instead wait for GWAS to fill the void. That might take a while because SNP microarrays only study common SNPs and a select number of copy-number variations and have no capacity to study a third form of genetic variation, called variable number tandem repeats (VNTR), which includes the MAOA promoter.

Psychiatry is an applied science. The gold standards for treating psychiatric illnesses include powerful drugs that target neurotransmitters. Doctors cannot afford to ignore gene variants that also interact with neurotransmitters, any more than they can ignore drug-drug interactions, therapeutic or recreational. Violent behavior is a diagnostic criterion of many mental illnesses. Indeed, I would advocate giving impulsive aggression a diagnostic label of its own (one that doctors and researchers would actually use, unlike “intermittent explosive disorder”).

In the Trayvon Martin shooting case, the defense might need to establish that Martin had a violent predisposition to strengthen a self-defense claim. Drug use and any indication of his cognitive abilities are relevant, and it would be useful to conduct genetic tests for the MAOA promoter and CYP2D6. If that is impermissible, then Martin’s African-American racial identity becomes more relevant with its associated allele frequencies. In some trials, MAOA gene tests have already served as exculpatory evidence in the mold of the insanity defense. The right to fight back against an individual who is warrior-gene positive makes just as much sense.

Amaladoss A, & O'Brien S (2011). Cough syrup psychosis. CJEM, 13 (1), 53-6 PMID: 21324299

Ivan Berlin, & Robert Anthenelli (2001). Monoamine oxidases and tobacco smoking The International Journal of Neuropsychopharmacology, 4 (01), 33-42 DOI: 10.1017/S1461145701002188

Christopher Chabris, Benjamin Hebert, Daniel Benjamin, Jonathan Beauchamp, David Cesarini, Matthijs van der Loos, Magnus Johannesson, Patrik Magnusson, Paul Lichtenstein, Craig Atwood, Jeremy Freese, Taissa Hauser, Robert Hauser, Nicholas Christakis, & David Laibson (2012). Most Reported Genetic Associations with General Intelligence are Probably False Positives Psychological Science

Duncan LE, & Keller MC (2011). A critical review of the first 10 years of candidate gene-by-environment interaction research in psychiatry. The American journal of psychiatry, 168 (10), 1041-9 PMID: 21890791

Fergusson DM, Boden JM, Horwood LJ, Miller A, & Kennedy MA (2012). Moderating role of the MAOA genotype in antisocial behaviour. The British journal of psychiatry : the journal of mental science, 200 (2), 116-23 PMID: 22297589

Fisar Z (2010). Inhibition of monoamine oxidase activity by cannabinoids. Naunyn-Schmiedeberg's archives of pharmacology, 381 (6), 563-72 PMID: 20401651

Fowler JS, Volkow ND, Wang GJ, Pappas N, Logan J, MacGregor R, Alexoff D, Shea C, Schlyer D, Wolf AP, Warner D, Zezulkova I, & Cilento R (1996). Inhibition of monoamine oxidase B in the brains of smokers. Nature, 379 (6567), 733-6 PMID: 8602220

Regina Groshong, Ross Baldessarini, Ann Gibson, Joseph Lipinski, Doris Axelrod, & Alfred Pope (1978). Activities of Types A and B MAO and Catechol-O-methyltransferase in Blood Cells and Skin Fibroblasts of Normal and Chronic Schizophrenic Subjects Archives of General Psychiatry, 35 (10), 1198-1205 DOI: 10.1001/archpsyc.1978.01770340048004

Huestis MA, Henningfield JE, & Cone EJ (1992). Blood cannabinoids. I. Absorption of THC and formation of 11-OH-THC and THCCOOH during and after smoking marijuana. Journal of analytical toxicology, 16 (5), 276-82 PMID: 1338215

Logan BK, Yeakel JK, Goldfogel G, Frost MP, Sandstrom G, & Wickham DJ (2012). Dextromethorphan Abuse Leading to Assault, Suicide, or Homicide. Journal of forensic sciences PMID: 22537430


Sistonen J, Sajantila A, Lao O, Corander J, Barbujani G, & Fuselli S (2007). CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure. Pharmacogenetics and genomics, 17 (2), 93-101 PMID: 17301689

Satoshi Yamaori, Yasuka Okamoto, Ikuo Yamamoto, & Kazuhito Watanabe (2011). Cannabidiol, a Major Phytocannabinoid, As a Potent Atypical Inhibitor for CYP2D6 Drug Metabolism & Disposition, 39 (11), 2049-2056 DOI: 10.1124/dmd.111.041384

Zawertailo LA, Kaplan HL, Busto UE, Tyndale RF, & Sellers EM (1998). Psychotropic effects of dextromethorphan are altered by the CYP2D6 polymorphism: a pilot study. Journal of clinical psychopharmacology, 18 (4), 332-7 PMID: 9690700