Ever since Gabor Maté discussed epigenetics in his book In the Realm of Hungry Ghosts (2008), it has become a buzzword in the addiction treatment community, and any number of websites hawking rehab programs tell us that addiction is caused by epigenetically inherited trauma. Is there any truth to this claim?
Epigenetics is the study of changes in genes which do not involve changes in DNA. Every cell in the human body (except the sperm and eggs) contains a complete copy of the human genetic code. However, only certain genes are “turned on” in each type of cell. In a muscle cell, the genes that make a cell act like a muscle cell are turned on, whereas those which would make it act like a bone cell or a blood cell, for example, are turned off. Processes which turn genes on or off are called epigenetic processes.
Evidence suggests that some epigenetic changes can be passed on to offspring: This is known as epigenetic inheritance. Other epigenetic changes are not inherited.
Epigenetics and Trauma
Rodent models show us quite clearly that trauma can be passed from rodent mothers to offspring via changes which the trauma elicits in the mother’s behavior toward her offspring.
However, transmission of intergenerational trauma in humans is a more controversial proposition. For example, some researchers claim that overall rates of psychopathology are no greater in the offspring of Holocaust survivors than in other populations, despite a specific “predisposition to PTSD”—others find, for example, that not only PTSD, but mood and anxiety disorders and, “to a lesser extent,” substance use disorders are higher in this population following maternal (but not paternal) PTSD. Higher rates of substance use disorder in US Indigenous populations are often attributed to intergenerational trauma caused by racism and genocide. Still, the relative weights of the mechanisms of such transmission in humans cannot be definitively determined based on existing research.
Let’s look at some animal experiments that have aimed to shed light on this.
Although we know that—probably in people, but certainly in rodents—intergenerational trauma can be transmitted behaviorally, it has been hypothesized in recent years that epigenetic inheritance is also a factor. Let’s look at some animal experiments that have aimed to shed light on this.
Epigenetic inheritance of the effects of trauma has been studied in mice, using the maternal separation and unpredictable stress (MSUS) procedure to induce trauma. In the MSUS procedure, the mother mouse is separated from her offspring for three hours each day for two weeks, starting the day the offspring were born. The separation takes place at a randomly chosen, different time each day. In addition, the mother mouse is stressed each day by 20 minutes’ confinement in a Plexiglas tube or a five-minute forced swim in cold water during the period she is separated from her offspring. These procedures are intended to create traumatic stress in the mother and the offspring.
A 2011 paper from the Brain Research Institute in Zurich described an experiment where the female MSUS offspring, which we will call the first generation, were mated with untreated male mice to see if the effects of trauma would appear in their offspring, which we will call the second generation. A control group was also created by mating control female mice with untreated male mice.
To prevent any differences in maternal care between the groups from confounding the experiment—potentially passing on trauma through behavioral differences, not epigenetics—cross-fostering was used. Half the second-generation MSUS pups were reared by first-generation MSUS mothers, and half were reared by control mothers. The second-generation control pups were split in the same way.
There were significant differences between the behavior of second-generation MSUS mice and second-generation control mice.
The free exploratory test measures the time elapsed before mice enter unfamiliar areas in a new environment. The male second-generation MSUS mice took significantly less time than the male second-generation control mice before entering unfamiliar areas.
The elevated plus maze test uses a raised platform in the shape of a plus-sign. Two arms of the plus-sign are open and two are enclosed. The test measures the amount of time the mice spend on the open arms, the distance they travel from the center on the open arms, etc. Female second-generation MSUS mice traveled significantly further from the center on the open arms than female second-generation control mice.
Male second-generation MSUS mice also performed significantly more stretch-attends (a risk-assessment posture) on the open arms than male second-generation control mice. These behavioral differences can only be accounted for by epigenetic inheritance of trauma effects.
A 2018 paper by the Brain Research Institute described another MSUS experiment. In this experiment, RNA from the sperm of first-generation MSUS mice was injected into fertilized mouse eggs to create an experimental group, and RNA from the sperm of first-generation control mice was injected into fertilized mouse eggs to create a control group. There was a significant difference between the experimental and control groups in a forced swim test, with the experimental group spending significantly more time floating. This experiment demonstrated that some trauma effects are transmitted via epigenetic inheritance through sperm RNA.
In a 2011 study by David M. Dietz et al., male mice were traumatized using a chronic social defeat stress paradigm. In this paradigm, a male mouse is repeatedly placed in the home cage of a larger, dominant male mouse. I will refer to the mice subjected to chronic social defeat stress as “defeated mice.”
The defeated male mice were then mated with normal female mice and the offspring were tested using a social avoidance test (this measured time spent in an interaction zone with another mouse), a novel environment test (this measured locomotor activity in a novel environment), a forced swim test (this measured amount of time swimming vs. floating) etc. Their behaviors were compared to the behaviors of offspring of control fathers.
Offspring of defeated mice showed significantly more social avoidance and a significant decrease in the amount of time elapsed before becoming immobile in the forced swim test. Male offspring of defeated mice showed a significant increase in locomotor behavior in a novel environment.
It is important to emphasize that the applicability of these animal studies to humans is not demonstrated.
However, the researchers were concerned that mouse mothers who had mated with a defeated mouse might show different behaviors toward their offspring than mothers who had mated with a control mouse. Therefore, a second experiment was conducted using artificial insemination. In the second experiment, the only test which showed a significant difference between the offspring of defeated mice and the offspring of control mice was the forced swim test. This suggests that the epigenetic inheritance of chronic social defeat stress is rather limited.
Such research provides evidence, to different extents, of the epigenetic inheritance of trauma. But it is important to emphasize that the applicability of these animal studies to humans is not demonstrated. Clearly, no controlled experiments of this kind can be conducted with human subjects.
Epigenetics and Substance Use
A 2021 paper by Baratta et al. is an excellent review of animal studies of the epigenetic inheritance of substance-use patterns. Many of these outcomes were surprising, even the opposite of what one might have anticipated. All of the following studies took measures to avoid behavioral transmission and ensure that epigenetic inheritance was the only possible means of transmission.
Rompala et al. (2017) found that the male offspring of male mice that had been exposed to six weeks of chronic intermittent vapor ethanol showed significantly reduced ethanol consumption—and increased ethanol sensitivity—when compared to control offspring. There were no differences in the female offspring.
Campbell et al. (2018) reported a study in which alcohol-preferring rats were taught to self-administer alcohol, then the self-administering behavior was extinguished by punishment with electric shocks. Male offspring of these experimental rats were compared with male offspring of control rats in the same self-administration paradigm. Alcohol administration was extinguished significantly faster in the offspring of experimental rats than in the offspring of control rats.
Beeler et al. (2019) found that male offspring of male mice that had been allowed to drink ethanol every other day showed significantly reduced drinking in darkness compared to control offspring; other drinking behaviors were the same.
Hollander et al. (2019) reported a study where male Sprague Dawley rats (which don’t prefer alcohol) were force-fed alcohol and their offspring were tested for alcohol consumption. The offspring were given alcohol through an oral tube in a single session; the experimental offspring consumed significantly more alcohol than control offspring.
Collier et al. (2020) found significantly increased consumption of alcohol in offspring of zebrafish whose mothers had been exposed to alcohol prior to conception.
Vassoler et al. (2013) found significantly decreased cocaine self-administration in male offspring of male Sprague Dawley rats which had been taught to self-administer cocaine when compared to male offspring of controls.
Fant et al. (2019) found significantly increased cocaine self-administration in rats whose mothers had been exposed to cocaine prior to conception, compared to controls whose mothers had not been exposed to cocaine.
Vassoler et al. (2017) found that offspring of female Sprague Dawley rats which had been exposed to opioids as adolescents showed significantly decreased opioid self-administration compared to controls.
Goldberg et al. (2019) found that offspring of male mice which had been exposed to nicotine showed significantly decreased nicotine self-administration compared to controls.
As we have seen, some animal studies do suggest epigenetic inheritance of trauma. But when it comes to epigenetic inheritance of substance-use traits, the picture is mixed: Animal studies have apparently contradictory findings.
What’s more, there have been no studies directly examining the substance-use patterns of animals which have epigenetically inherited the effects of trauma.
To this, we can add the impossibility of conducting similar studies in human populations, and the severe difficulty of separating epigenetic and behavioral or societal factors in establishing the causes of real-world human transmission of intergenerational trauma.
Altogether, it is premature to conclude whether epigenetic trauma inheritance has any effect on people’s rates of substance use or substance use disorder.