This article is part of the 2018 NMJ Oncology Special Issue. Download the full issue.
Jinting L, Zhong R, Xiong W, Liu H, Eisenegger C, Zhou X. Melatonin increases reactive aggression in humans. Psychopharmacology. 2017;234:2971-2978.
Randomized, placebo-controlled, double-blind, between-participant design
To assess whether melatonin treatment impacts human aggression
Sixty-four healthy young men, mean age 21.3 years, participated in this study. They all typically went to sleep between 11:00 pm and 12:00 am and woke between 7:00 am and 8:00 am. For 2 hours prior to and during the study they abstained from food and drink (other than water), and for 24 hours prior (and during) abstained from caffeine, cigarettes, alcohol, and exercise. Exclusion criteria included shift work or transmeridian travel for the month prior to the study. All participants had full color vision. One person was excluded from the data analysis because he reported suspicion of the Taylor Aggression Paradigm (TAP).
Participants in the treatment group were given 5 mg melatonin at 1:40 pm, while those in the control group were given a placebo of 200 mg starch at the same time. Testing with the TAP and Stroop tasks were done at 3:10 pm.
During the TAP, participants “compete” with others via a computer interface. When a participant “wins” he can choose to give either a high or low punishment to the opponent. The results of the game are computer-controlled and pseudorandomized so that each participant has wins and losses against both a low-provoking and high-provoking opponent. High punishment was the highest tolerable noise (based on earlier individual threshold tests) and a financial loss of game money, while lowest punishment was the quietest audible noise and a smaller financial loss. Four sessions were played, each with 10 rounds against a low-provoking opponent and 10 against a high-provoker.
The Stanford Sleepiness Scale was administered before melatonin or placebo was ingested, and just before the test session. Testing included both the TAP and the Stroop Color Word Task, which was included to assess whether melatonin was affecting inhibitory ability.
The participants who received 5 mg of melatonin administered the high punishment more than those in the placebo group. They also gave more high punishment to the high-provoking opponent, indicating that fairness was preserved. The authors conclude that the study provides direct evidence that melatonin is involved in human social interactions.
Over the last several decades, melatonin has become one of the most highly used over-the- counter supplements, with 1.3% of US adults and 0.7% of children using it in 2012. This is more than twice the number of adults just since 2007.1 With the growing popularity of nutritional supplements in general, and melatonin in particular, any untoward effects may have significant societal impact. A well-established side effect of melatonin in animals is aggression.2 The current study under review evaluated a dose of midday melatonin and aggressive tendencies in young healthy men.
Because melatonin is most commonly used before bedtime, it would be useful for future research to evaluate aggression after evening supplementation.
Currently established side effects of short-term melatonin use are mild and include headache, nausea, dizziness, and sleepiness. Likewise, side effects from long-term use are considered mild and comparable to placebo. Due to lack of data, use of exogenous melatonin by pregnant or breastfeeding women, and long-term use by children and adolescents is not recommended.3
Most studies on the association of melatonin and aggression have been done in animals, many using an intruder challenge.4 In humans, aggression is classed in 2 subtypes.
Proactive/controlled aggression is premeditated for goal attainment and accompanied by low emotional arousal, while reactive/impulsive aggression is a highly emotional response to perceived provocation. There are 3 published reports in humans evaluating melatonin and aggression. In the first, a case study of brain injury–induced aggression, improvement was achieved by treatment with agomelatine (a melatonin receptor agonist).5 The second, a small study of 6 inpatients with dementia, found equivalent or increased aggression in patients treated with 2.5 mg melatonin combined with bright light therapy, as opposed to bright light therapy alone.6 The third was an observational report of 400 children with autism spectrum disorder. The study found that children with aggressive behavior disorder had a higher rate of sleep problems and melatonin use.7
Exogenous melatonin taken in the middle of the day is known to sharply increase sleepiness and decrease core body temperature.8 These effects are the same as those of the nocturnal melatonin pattern naturally occurring in dim light conditions. The natural nocturnal peak of melatonin occurs at the core body temperature nadir. At that time motivation is at its lowest, as is performance and mood.
Another model that induces sleepiness is sleep deprivation. Sleep deprivation can be partial or total, acute or chronic. Sleep deprivation studies allow us to look at the impact of sleepiness itself on aggression, as partial sleep deprivation is not associated with elevated melatonin levels. Sleep deprivation is associated with increased physical aggression in youth, and youth with the shortest sleep duration report the most aggression.9 There are other reports of increased irritability and anger with increased sleepiness. So, in this study is it the melatonin that directly increases aggression, or is it the associated increased sleepiness? The authors evaluated this question through the Stanford Sleepiness Scale given before intervention (melatonin or placebo ingestion) and 90 minutes after. The sleepiness was not found to be related to aggression; increased aggression was only associated with melatonin intervention. This is a significant distinction that moves our understanding forward.
We don’t know whether naturally elevated nocturnal melatonin levels are associated with aggression. But assuming they are, what would be the evolutionary advantage? Historically, people slept in dark conditions, and bedtime was preceded by a period of dim light in many parts of the world, and during the winter. This allows melatonin to increase significantly, starting before bedtime, thereby decreasing sleep latency and promoting sound sleep through the night. Many of us have probably experienced negative reactions to being awakened in the night, which may be due in part to the element of surprise, but at least some of the reaction may be due to higher melatonin levels at that time. Is there a protective mechanism to reacting with aggression when woken in the night? There may be, if faced with an intruder, although more often than not it is a loved one who needs attention for some reason, making any aggressive reaction most undesirable.
There is also seasonal variation in melatonin release, with a longer duration of secretion during the long nights of winter.10 Although human beings are not seasonal breeders like many of these animal models, winter historically has been a time of reduced resources. Therefore, increased melatonin with associated increased aggression could provide a competitive advantage when resources are limited.
In this study, the melatonin was taken in the middle of the day, at 1:40 pm. Participants then took the TAP at 3:10 pm, 1.5 hours after melatonin ingestion. In clinical practice, patients typically take melatonin preceding bedtime, and therefore are less likely to be interacting with others 90 minutes later. Based on these results, if patients did interact in the night, they’d be more likely to be involved in aggressive interactions. So, applying the results of this study clinically, if your patient anticipates being awakened in the night to interact with others, that would merit discussion and caution. Situations that come to mind are people who take care of loved ones, children, or elderly persons overnight, and employees who are on call and may be woken up in the night. Additionally, some people may use melatonin during the day as a sleep aid, including shift workers when they arrive home in the morning. Also, people with delayed sleep-wake phase disorder may use melatonin in the afternoon to phase advance. These people would be in normal modern lighting situations after ingestion (as opposed to the study participants, who were in dim light), so it’s unknown whether the light exposure would decrease any associated aggression.
Because melatonin is most commonly used before bedtime, it would be useful for future research to evaluate aggression after evening supplementation. Comparison studies of aggression provoked in the absence of supplementation, when participants are simply experiencing the naturally occurring melatonin release that occurs in dim light conditions, would also be useful. For now, it is unknown whether naturally occurring melatonin levels and increases due to supplementation produce the same effects on aggression.
Another notable feature of this study is that it included exclusively male participants. It’s been well established in the research literature that melatonin levels decline over the lifespan, and that there are gender differences. Young and midlife women tend to have higher melatonin levels than men, while older women have lower levels.11 There are other areas of physiology that show gender differences as well. Clarifying whether women also have increased reactive aggression with melatonin supplementation would be valuable.
This is the first of what may be an emerging body of evidence regarding a newly recognized adverse effect of melatonin. Given that so many Americans use melatonin supplements (and the number continues to grow), this study deserves attention. It is reasonable to warn patients who use melatonin of a possible aggressive reaction 90 minutes after ingestion, and advise them to take the supplement approximately 30 minutes before bedtime. Patients on melatonin should be encouraged to safeguard their sleep from interruptions (which is always a good idea anyway). For those patients who do eldercare or childcare in the night, or are otherwise on call, it may be more suitable to use a sleep aid that is known not to have the aggression side effect and will not impair the ability to perform nighttime tasks. This is a line of research to keep an eye on as the science matures.