The Genetics of Alcohol Withdrawal
By Kenneth Anderson, MA
Two people of the same weight, height, and sex can drink the same amount of alcohol over the same period of time, and when they stop, one will have few if any symptoms of alcohol withdrawal, while the other will go through severe alcohol withdrawal. Why is this? Although environmental factors (e.g., kindling) may have some influence, the primary reason for this difference appears to be genetics.
One of Several Studies on Genetics of Alcohol Withdrawal
A 2005 study conducted at a detoxification unit in Germany by Martin Driessen et al. gives us an idea of what percentage of people will develop alcohol withdrawal. There were 217 patients in this study, and they had drunk an average of 15.6 US standard drinks per day during the 30 days prior to the study. The researchers divided withdrawal symptoms into two categories: physical symptoms and psychiatric symptoms. The six physical symptoms were pulse rate, diastolic blood pressure, body temperature, breathing rate, sweating, and tremor. The five psychiatric symptoms were agitation, anxiety, tactile disturbances, disorientation, and hallucinations.
Physical symptoms were scored on a range from 0 to 17 using the Alcohol Withdrawal Scale; psychiatric symptoms were also scored on a range from 0 to 17 using the same scale. For patients who had not reported having withdrawal seizures during previous detoxifications, medication for withdrawal was given only if the score for physical symptoms was seven or greater, or the score for psychiatric symptoms was seven or greater. All patients who had reported prior withdrawal seizures were medicated. In all, 20.7% of patients (45 patients) received no medication for withdrawal while 79.3% (172 patients) received withdrawal medications.
In 24.0% of all patients, withdrawal symptoms lasted less than 24 hours (one day). In 33.2%, withdrawal symptoms lasted less than 48 hours (two days). In 13.8%, withdrawal symptoms lasted less than 72 hours (three days). In 10.6%, withdrawal symptoms lasted less than 96 hours (four days). In 7.8%, withdrawal symptoms lasted less than 120 hours (five days). In only 10.8% of patients, withdrawal symptoms lasted 5 days or more (up to 10 days).
The researchers divided the patients into five clusters based on the severity of their withdrawal symptoms:
Cluster one consisted of 40 patients (18.4% of the total sample). This group had drunk an average of 15.5 US standard drinks per day during the 30 days prior to the study. The patients in cluster one did not develop any clinically relevant withdrawal symptoms. For physical withdrawal symptoms, the average peak score for cluster one was 2.60. For psychiatric withdrawal symptoms, the average peak score was 0.65. Withdrawal lasted an average of 1.3 days for the patients in cluster one. However, one of the 40 patients (2.5%) in cluster one had a seizure.
Cluster two consisted of 41 patients (18.9% of the total sample). This group had drunk an average of 13.6 US standard drinks per day during the 30 days prior to the study. The patients in cluster two showed only physical withdrawal symptoms; they showed no clinically relevant psychiatric withdrawal symptoms. For physical withdrawal symptoms, the average peak score for cluster two was 6.46. For psychiatric withdrawal symptoms, the average peak score was 0.76. Withdrawal lasted an average of 3.0 days for the patients in cluster two. Two patients (4.9%) in cluster two had seizures. Cluster two patients showed physical withdrawal symptoms such as increased heart rates (87.8%), increased systolic blood pressure (95.1%), increased temperature (63.4%), sweating (90.2%), and/or tremor (97.6%).
Cluster three consisted of 88 patients (40.6% of the total sample). This group had drunk an average of 16.0 US standard drinks per day during the 30 days prior to the study. The patients in cluster three showed both physical and psychiatric withdrawal symptoms. For physical withdrawal symptoms, the average peak score for cluster three was 5.62. For psychiatric withdrawal symptoms, the average peak score was 2.25. Physical withdrawal symptoms were similar to cluster two. All patients in cluster three had anxiety. None of the patients in cluster three were disoriented and none had hallucinations. Withdrawal lasted an average of 2.8 days for the patients in cluster three. Four patients (4.5%) in cluster three had seizures.
Cluster four consisted of 24 patients (11.1% of the total sample). This group had drunk an average of 18.9 US standard drinks per day during the 30 days prior to the study. The patients in cluster four showed both physical and psychiatric withdrawal symptoms. For physical withdrawal symptoms, the average peak score for cluster four was 7.21. For psychiatric withdrawal symptoms, the average peak score was 3.42. Physical withdrawal symptoms were similar to cluster two. All patients in cluster four were disoriented, and 75.0% had anxiety. None of the patients in cluster four had hallucinations. Withdrawal lasted an average of 5.0 days for the patients in cluster four. Three patients (12.5%) in cluster four had seizures.
Cluster five consisted of 24 patients (11.1% of the total sample). This group had drunk an average of 14.7 US standard drinks per day during the 30 days prior to the study. The patients in cluster five showed both physical and psychiatric withdrawal symptoms. For physical withdrawal symptoms, the average peak score for cluster five was 6.71. For psychiatric withdrawal symptoms, the average peak score was 7.13. Physical withdrawal symptoms were similar to cluster two. All patients in cluster five had hallucinations, 70.8% had anxiety, and 83.3% were disoriented. Withdrawal lasted an average of 3.9 days for the patients in cluster five. Five patients (20.8%) in cluster five had seizures.
There was no significant difference in the average amount of alcohol consumed by patients in the five clusters in the 30 days prior to checking in to the hospital for detoxification, nor was there a significant difference in the number of years that they had been drinking dependently.
One striking fact apparent in the above data is that alcohol withdrawal seizures appear to be quite independent of other alcohol withdrawal symptoms such as anxiety, disorientation, or hallucinations. Fifteen of the 217 patients (6.9%) had alcohol withdrawal seizures; had most of the patients not been medicated, this number would likely have been much higher. This suggests that there are genetic factors which determine susceptibility to alcohol withdrawal seizures.
Alcohol Withdrawal in Mice Supports Theory of Genetic Link
Rodent studies bear this conclusion out. It is well known that B6 mice are very resistant to alcohol withdrawal seizures, whereas D2 mice are very susceptible to alcohol withdrawal seizures.
Alcohol withdrawal seizures are caused by too little activity in the GABA system and too much activity in the glutamate system of the brain. Simply put, GABA (gamma aminobutyric acid) is a neurotransmitter which causes relaxation, and glutamate is a neurotransmitter which causes excitement. Drinking alcohol increases the activity of the GABA system, causing people to feel more relaxed, while decreasing the activity of the glutamate system, reducing excitation. However, the brain tries to fight the effect of alcohol by decreasing the activity of the GABA system (downregulation) and increasing the activity of the glutamate system (upregulation). This results in a tug of war between alcohol and the brain. When a person who has been drinking large amounts of alcohol for a long time suddenly stops, it is like one person in the tug of war has suddenly let go of the rope, and the other person goes flying off in the opposite direction. The results are anxiety, increased heart rate, increased blood pressure, tremors, and sometimes seizures.
2020 Study by Kozell on Withdrawal-Related Seizures in Mice
A 2020 study by Laura B. Kozell et al. investigated the genetic differences between mice which were resistant to alcohol withdrawal seizures and mice which were prone to alcohol withdrawal seizures. The seizure-resistant mice showed greater expression of certain genes encoding GABA receptors (the Gabrb3 and Gphn genes), certain genes encoding glutamate receptors (the Grid1, Grin2b, Grin2c, and Grm3 genes), and certain genes encoding cell adhesion (the Mpdz gene, the Dlg2 gene, and 23 protocadherin genes). Cell adhesion is essential for the transmission of a signal from one neuron to another across the synapse.
The seizure-prone mice showed greater expression of genes encoding the function of the mitochondria, sometimes called “the powerhouse of the cell” (the Nedd8, Guk1, Elof1, Ndufa8, and Atp6v1f genes; these are all hub genes).
As we saw from the Martin Driessen et al. study discussed above, alcohol withdrawal hallucinations and disorientation occur quite independently of alcohol withdrawal seizures, although hallucinations, delirium, and disorientation frequently occur together with each other.
Genetics, Alcohol Withdrawal, and Hallucinations
Withdrawal hallucinations can occur when alcohol withdrawal is moderate or severe. Hallucinations can be visual (seeing things), auditory (hearing things), or tactile (feeling bugs under the skin). Alcohol withdrawal hallucinations are generally believed to be due to too little serotonin and too much dopamine. While it is easy to study seizures in animals like mice since the seizures can be directly observed, it is not possible to ask a mouse whether it is having hallucinations, which greatly limits the possibility of doing animal experiments to investigate this topic. However, given the distribution of hallucinations which we saw in the Martin Driessen et al. study it is reasonable to assume that susceptibility to alcohol withdrawal hallucinations is genetic.
When hallucinations occur during moderate alcohol withdrawal, the patient is generally aware that the hallucinations are not real. However, during severe withdrawal, the hallucinations are believed to be real and are often accompanied by delirium, delusions, and high fever: this combination of symptoms is referred to as delirium tremens (DTs), and when untreated, is estimated to be fatal in up to 37% of cases. There is evidence that two genes involving the dopamine system (the Drd3 gene and the Slc6a3 gene) may be involved in alcohol withdrawal hallucinations.
Variations of the SorCS2 Gene is a Possible Cause
Finally, a 2018 study by Andrew H. Smith et al. implicated the SorCS2 gene as playing an important role in alcohol withdrawal in humans. The subjects of this study were 1,478 European Americans and 1,231 African Americans, all of whom had experienced alcohol withdrawal. Subjects were given a survey to determine the severity of the withdrawal they had experienced, and their DNA was analyzed. Then a statistical analysis was conducted to see if there were any statistically significant correlations between alcohol withdrawal severity and genetic makeup.
In the European American sample, the researchers found two variants of the SorCS2 gene. One variant was found in individuals who were resistant to alcohol withdrawal, and the other variant was found in individuals who were prone to alcohol withdrawal. I will refer to these as the withdrawal-resistant variant and the withdrawal-prone variant. One job of the SorCS2 gene is to build proteins which deal with stress hormones in the hippocampus. Although the hippocampus is best known as the part of the brain which stores long-term memories, another function of the hippocampus is to react to stress.
In the withdrawal-resistant variant, the SorCS2 gene correctly created proteins to deal with the stress hormones in the hippocampus. However, in the withdrawal-prone variant, the SorCS2 gene failed to correctly create proteins to deal with this stress. It is believed that this hippocampal stress contributes to the severity of alcohol withdrawal.
Although the SorCS2 gene was found to affect the severity of alcohol withdrawal in the European American subjects, this gene was not found to have any effect in the African American subjects, nor were any other genes identified which correlated with withdrawal severity in African Americans. Interestingly, a 2009 study by Gar Ming Chan et al. showed that African Americans were at less risk for severe alcohol withdrawal than European Americans.
Summary of Evidence for Genetic Link to Severity of Alcohol Withdrawal
In summary, the evidence suggests that the odds of going through severe alcohol withdrawal are strongly influenced by genetic factors. Variations in genes which encode GABA and glutamate receptors determine the likelihood of having alcohol withdrawal seizures and anxiety, whereas the likelihood of having hallucinations and delirium is probably controlled by genes which encode dopamine and serotonin receptors.