By: Dr. Geoffrey Modest
Interesting article in Sunday NY Times on human genetic variability and different responses to mind-altering drugs. In brief:
–the brain is full of receptors for the various psychoactive drugs, as well as endogenous stimulants for those receptors: the opiates (including the endogenous endorphins) stimulate the mu receptor, the cannabinoids (including the endogenous anandamide; its name by the way is taken from the Sanskrit word ananda, meaning “bliss”) stimulate the endocannabinoid system, the benzodiazepines (including the endogenous GABA, though not a benzo itself) bind close to the benzodiazepine binding site and affects benzodiazepine binding in the CNS, and nicotine which binds to brain acetylcholine receptors leading to stress reduction, pleasure and improved cognition.
–some people have lower levels of an enzyme called FAAH (fatty acid amide hydrolase, which deactivates the endocannabinoid anandamide) through a genetic variant, leading to increased levels of anandamide. These people, about 20% of the US population (21% of Americans from European background, 14% of Han Chinese, 45% of Nigerians), overall are less anxious, less likely to use marijuana, and get less of a blissful effect from marijuana. There was an article this week in Nature Communications (doi:10.1038/ncomms7395) which showed that the presence of the FAAH variant allele “enhances fronto-amygdala connectivity and fear extinction learning, and decreases anxiety-like behaviours.” Of some interest, they were able to implant this human genetic variant into mice and showed that in both humans and mice, there was enhanced fear-extinction and decreased levels of anxiety.
–these genetic differences may be reflected in drug use/self-medicating, eg patients without this mutation are more likely to use daily marijuana to decrease their anxiety symptoms, and are also more likely to suffer withdrawal from marijuana on stopping ingestion. In fact a study of 2100 healthy volunteers found that those with 2 copies of the mutant gene had lower rates of cannabis dependence (11% vs 26%)
–there are also many articles in the literature on mu opioid receptor variants (eg, see doi:10.1111/j.1471-4159.2007.04738.x) on the single nucleotide polymorphism A118G, which is variably common in the general population (from 1-2% in African-Americans to 50% in Japanese). This variant of the mu receptor affects endorphin binding and signaling of the receptor and clinically is associated with improved clinical outcomes in alcoholic patients treated with naltrexone. Other data show that mu-receptor polymorphisms are associated with higher requirements of morphine for pain relief (doi.org/10.1016/j.molmed.2004.12.006). –This may help explain the variability in opiate dosages needed in clinical practice and perhaps in developing addiction??
–the article does take pains to point out that the environment does play a key role here (ie, it is not just biological determinism), noting that primates at low risk genetic of addiction can easily become compulsive drug users in the setting of stress and access to cocaine. The primates lose their dopamine D2 receptors — I assume by down-regulation from excessive cocaine stimulation, but most of the primates are able to recover them on stopping the cocaine.
So, one implication of the genetic variations is that the concept of “just say no” is a tad more complex, given that there are apparently significant hard-wired differences in the drive to use drugs and maybe with the potential to addiction. Also these types of genetic differences could explain in part, for example, why when there is a significant trauma witness by many people, only some of them develop PTSD. It is also interesting that cannabinoid receptors are among the most numerous in the brain, which reinforces the evolutionary importance of the fear/anxiety (“fight or flight”) response and the ability to modulate it — eg, it is important to understand and protect oneself from dangerous situations, but also to be able to modulate that response (or else one just cowers in a dark corner shaking in fear of potential predators and starves to death…..). The point is that there are very developed intrinsic systems in the human body which regulate responses to external stimuli. Some of these involve the fear/anxiety and reward systems, as above. External psychoactive chemicals can overwhelm these intrinsic systems and have unfortunate adverse effects in this excessive, unregulated manner (affecting addiction, and the clinical sequelae of the many levels of functional and cognitive impairment).