Social play is the first non-mother directed social behavior in young animals. It is characterized by exaggerated and distinct behavioral patterns related to social, sexual, and aggressive behavior (Vanderschuren et al., 2016). It is part of normal social behavior and is considered an indicator of emotional wellbeing, general health, and welfare of animals (Ahloy-Dallaire et al., 2018). This behavior is essential for social, cognitive, emotional, and motor abilities development, having a role in the environment and social context adaptation (Vanderschuren et al., 1997; Vanderschuren et al., 2016). Social play behavior is a highly pleasurable rewarding activity, especially in young individuals (Trezza et al., 2010) across species. This behavior starts around weaning and continues until early adolescence (Vanderschuren et al., 2016), where the type of response in the play depends on age and sex (Pellis and Pellis, 1987; Pellis and Pellis, 1990).

In rodents, social play is also known as ‘rough and tumble play or play fighting’ and it is characterized by highly physical and vigorous movement patterns between peers. In the context of juvenile rats, social play behavior can be divided into two basic components such as pouncing (interaction in which an animal nose rubs the partner’s nape “asking for play”) and pinning (interaction in which an animal stands over the ventral surface of another animal “wanting to play”), along with grooming, chasing, and boxing (Homberg et al., 2007; Argue and McCarthy, 2015a; Argue and McCarthy, 2015b). Furthermore, in rodents this type of behavior is accompanied by physical, facial, and vocal (ultrasonic vocalization) signals with ludic intention (Vanderschuren et al., 2016).

Thus, social play generates emotional excitement and bonding having a neurobiological function in development. Some studies have shown how animals with play deprivation generate higher levels of anxiety (Lukkes et al., 2009; Vanderschuren et al., 2016) and hence higher sensitivity to drugs (Whitaker et al., 2013; Lesscher et al., 2015; Heilig et al., 2016). Play is sensitive to several factors including motivational state, isolation periods and housing conditions. For example, in young Sprague Dawley rats, different housing conditions produce high or low levels of playing, and isolation usually diminishes general social interactions in young and adult rats regardless of sex (Varlinskaya and Spear, 2008).

Psychostimulants can profoundly alter social play behavior due to their effects on brain mechanisms involved in reward (Trezza et al., 2014; Knell, 2022). For instance, AMPH, MPH, and cocaine suppress social play. It has been shown that AMPH and MPH have a suppressive effect on social play through the stimulation of α2 adrenoceptors but not through DA receptors (Achterberg et al., 2014). The inhibitory effects of MPH on social play are mediated by a distributed network of prefrontal and limbic subcortical regions involved in cognitive control and emotional processes. Thus, microinjections of MPH in the infralimbic cortex, anterior cingulate cortex, basolateral amygdala and habenula produce a decrease in social play behavior (Achterberg et al., 2015). The motivation for social play is mediated by DA receptors stimulation and the suppression in the expression of play is mediated by stimulation of adrenergic α2 receptors, suggesting that the decrease in social play behavior promoted by MPH is regulated by a network that could work in parallel (Achterberg et al., 2016). Besides, it has been shown that chronic treatment with MOD in pre-adolescent rats, changes dopaminergic neurotransmission in the NAc decreasing DA release induced by a depolarizing stimulus, and suggesting a decrease in the ability of rats to perceive the rewarding effects of social play (Cid-Jofre et al., 2021).

In addition, cocaine, MPH and AMPH have demonstrated to impair social play behavior when are administrated acutely (Vanderschuren et al., 2008; Manduca et al., 2016), but not after chronic MPH (Bolanos et al., 2003). These data suggest that the extent of psychostimulant exposure is crucial for determining behavioral and molecular outputs in the brain reward circuit such as receptor expression, second messenger signaling, transporter function, and trafficking, among others (Anderson and Pierce, 2005).

Aggressive behavior is a form of social communication, used to exert control over the social environment. It is characterized by a series of specific sequenced patterns that vary across the species in terms of frequency and duration. These are usually aimed at intruders considered rivals and are meant to suppress their reproductive success (Bartholow, 2018).

Aggressive behavior can be offensive or defensive. The offensive behavior is typically displayed by the resident and is characterized by introductory and threatening demonstrations towards the intruder intended to damage him, sometimes including an attack or behaviors such as aggressive groom, charge, and chase, among others (Koolhaas et al., 2013). The intruder usually displays in response a defensive behavior, characterized by the lack of initiative, evade, flee, jump, and others, which can result in non-intentional damage (Olivier and Young, 2002; Koolhaas et al., 2013).

It is important to note that aggression and violence are not the same. Aggressive behaviors are social responses considered normal and adaptive in animals and humans. On the other hand, violence is a harmful form of offensive aggression, given that it is a form of behavior regardless of the context that may include attacks towards vulnerable body spots such as paws, belly, and throat. In contrast, the aggression is usually directed to the back and the neck, both considered non-vulnerable targets for the attack (Koolhaas et al., 2013). It has been shown in mice a phenomenon known as “addiction to aggression.” Aggression is highly sought due to its gratifying effects, despite negative consequences in the short and long term, registering high rates of relapse, which reminds some features observed in drug addiction (Golden et al., 2019).

Several studies have focused on the impact of psychostimulants on aggressive behavior. Currently, mounting evidence shows that the use of drugs like AMPH, MAMPH, and ecstasy influences aggressive behavior, whereas the effect of MOD on this type of behavior has been less studied (Dawe et al., 2009; Machalova et al., 2012). Machalova and colleagues (Machalova et al., 2012) showed in an animal model of social conflict interaction (agonistic behavior model), that MOD inhibits attacks in aggressive mice and increases aggression in shy mice. On the other hand, acutely administrated MAMPH in aggressive mice produces a dose-dependent inhibition of aggressive behavior and an increase in timid behavior at high doses (Machalova et al., 2012). Finally, when they administered MDMA, both types of mice (aggressive and shy) showed an increase in the frequency of timid displays and a decrease in aggressive behavior was observed only in aggressive mice (Machalova et al., 2012). Similar results have been shown in BALB/cJ mice, an animal model of ADHD and conduct disorder, where the administration of 3 mg/kg intraperitoneal MPH produces a decrease in aggressive behavior while 10 mg/kg increases aggression, showing a dose-dependent effect (Jager et al., 2019). The first studies done with AMPH showed similar results (Miczek, 1974; Miczek and Tidey, 1989). Currently, the National Institute on Drug Abuse (NIDA, USA) directly relates the chronic use of MAMPH with violent behavior (NIDA, 2023). However, an increase in aggression levels due to the therapeutic use of AMPH has not been reported (O’Malley et al., 2022).

Regarding cocaine effects on aggression, controversial results have been reported. For instance, exposure to a single high dose of cocaine in adult rats produces a decrease in defensive behaviors in the resident-intruder paradigm (Alves et al., 2014), whereas when a social interaction test was used, the results were opposite (Rademacher et al., 2002). In isolated adult mice that receive cocaine in a single-binge administration, an increase in their defense behavior was observed (Estelles et al., 2004).

As indicated by the evidence, psychostimulants effects on aggressive behavior are diverse. This variability could be related to different paradigms, drug dose, age, type of administration (acute or chronic), and the specific neurobiological effects of each drug.

Maternal care is a complex behavior that directly influences the survival chances of the offspring (Fischer and O’Connell, 2018). This behavior includes building a nest and crouching over pups to keep them warm, nursing pups to provide nutrition, grooming them, protecting them from intruders, and retrieving pups back to the nest when they become displaced. The neurobiology of maternal care has been frequently studied in rodents, since females display very well characterized maternal behaviors towards their offspring that are easily distinguished and measured (Stolzenberg and Mayer, 2019).

Maternal care is sensitive to several environmental factors such as drugs of abuse, experience, housing conditions, isolation, and pharmacological manipulations. For instance, Perry and colleagues studied the effects of 3 days of MAMPH administration at three different doses on parental behavior in prairie voles. They found that the lowest dose (0.2 mg/kg) was enough to reduce the contact with the pups (Perry et al., 2019). When MAMPH injections (5 mg/kg) were used prenatally in pregnant rats, during the first or second half of the gestation period, several physiological and sensorimotor effects were observed in the offspring, although there were no differences in maternal behavior (Malinová-Ševčíková et al., 2014). On the other hand, repeated MPH (5 mg/kg) exposure during the lactation period impairs both maternal and adult offspring behavior. Regarding maternal behavior, the latency of retrieving pups was increased accompanied by a lower number of dams retrieving their pups (Ponchio et al., 2015).

In an interesting study with a fostering approach, the maternal behavior in juvenile offspring that were reared by dams exposed to intermittent cocaine was poor (Johns et al., 2007). Besides, chronic cocaine administration twice daily to pregnant rats for the entire gestational period elicited those dams to spend significantly less time next to the pups on postpartum day 1, and at postpartum day five, pups engaged in less ultrasonic vocalizations (Lippard et al., 2015). In contrast, another study showed that 10 days of cocaine administration to females prior to mating was enough to increase subsequent maternal behavior (Nephew and Febo, 2010). In particular, these mothers retrieved pups more quickly, spent more time taking care of the pups, and were more aggressive towards a male intruder on day 2 of lactation compared to control animals. However, no effects were observed on days 9 and 16 of lactation (Nephew and Febo, 2010).

In summary, maternal behavior is a set of complex behaviors towards pups with their survival as a major goal. As with other social behaviors, caring for pups is a rewarding experience that can be positively or negatively affected by psychostimulants.

Pair bonding is the social behavior associated with the ability to form intense and selective social attachments (pair bonds) usually, but not exclusively, related to sexual attraction and the partner preference for mating. The brain areas associated with this behavior are PFC, NAc and VP among others.

The rodent prairie vole (Microtus ochrogaster) is an animal widely used to study pair bonding and the effects of drugs of abuse on the neurobiological mechanisms behind this behavior. This species is highly social and monogamous (although now it is known that there are two species, one monogamous and the other promiscuous) and forms long-term and exclusive pair bonds with a partner after mating (McGraw and Young, 2010). In this case, preference for the partner over a stranger conspecific is considered a pair bond index and is usually measured as time or percentage of total time of close physical contact between the animals.

In adult prairie voles, it has been reported inhibition of partner preference after AMPH exposure in both sexes (Liu et al., 2010; Young et al., 2014). Notably, the effects of AMPH were observed exclusively on partner preference since other related behaviors such as mating frequency or locomotor activity were not affected. Studies performed in monogamous species have suggested that neuropeptides such as OXT and AVP facilitate pair bond (Rigney et al., 2022). For instance, it has been reported that OXT administration into the mPFC restores both partner preference and NAc DA levels, impaired by AMPH administration (Young et al., 2014). On the other hand, in agreement with the protective effects of social bonding on drug abuse, Liu and colleagues (Liu et al., 2011) have demonstrated that pair bonding prevents AMPH-induced CPP, through a D1R-mediated mechanism. Moreover, as shown in female prairie voles, AMPH exposure increases DA levels in the NAc but not in mPFC or VTA, increases D1R mRNA in the NAc and decreases D2R mRNA in VTA. These data indicate that the effects of AMPH upon pair bonding in female prairie voles exhibit nuclei and receptor specificity (Young et al., 2011).

In the same way, a study using a continuous 2 bottle choice procedure (one bottle with tap water and other bottle with MAMPH), showed that MAMPH had an inhibitory effect in partner preference, an effect that is accompanied by a decrease of OXT levels in the paraventricular nucleus of the hypothalamus (Hostetler et al., 2016).

Globally, these works highlight the profound effects of psychostimulants in pair bonding. Since, OXT modulates the DA system and the reward process, drugs acting on OXT receptors appear promising as treatments for conditions in which these behaviors are altered.

Table 1 summarizes the results of the studies evaluating the effects of different psychostimulants upon diverse social behaviors in animal models.

One of the most studied drugs in relation with social behavior is MDMA. In 2012, MDMA was estimated to be the 3rd recreational drug among adults (between 18 and 25 years old) and in the same year, nearly 869,000 consumed it for the first time in the USA (Substance Abuse and Mental Health Services Administration, 2014). In addition, MDMA is under examination as a potential counterpart for psychotherapy (Feduccia et al., 2023; Kangaslampi and Zijlmans, 2023). In various reports it has been described that MDMA has a prosocial effect. For instance, Wardle and de Wit (Wardle and de Wit, 2014) analyzed the effects of MDMA using a three-session within-subjects design over 36 healthy volunteers of both sexes. In females only, MDMA (1.5 mg/kg) both increased smiling (zygomatic muscle activity) and reduced frown (corrugator muscle activity) in response to happy facial expressions, indicating more positive reactions to positive facial expressions. Therefore, MDMA altered emotional perception processing and response. It also impacts behavior and perception in an actual social scenario with a partner (Wardle and de Wit, 2014).

In a non-social and controlled laboratory setup, the administration of MDMA (from 0.5 to 2.0 mg/kg) increased (relative to placebo) self-report ratings of a broad range of socially relevant mood states. In this line, there is some evidence suggesting that MDMA prosocial effect depends on the social setting used in research. When MDMA (1.0 mg/kg single administration) was analyzed in volunteers, the increased feelings of confidence only appeared in subjects that were accompanied by other participants (exposed to MDMA too) (Kirkpatrick and de Wit, 2015). Interestingly, MDMA (0.75 mg/kg) increased the rating of loneliness (Bedi et al., 2010) in individuals who received the drug alone in isolated laboratory setups. In a study of free speech, MDMA increased the use of social and sexual words, as well as words referring to death, (Baggott et al., 2015), suggesting that consequences on speech reflect underlying alterations in social mood states. Thus, these findings suggest that MDMA generates prosocial feelings and different mental states in humans in controlled laboratory conditions that depend on social settings.

Studying several domains of social cognition in cocaine, MAMPH, and non-medical MPH users, interesting results have been described. For instance, a negative impact in the total performance for emotion cognition was observed only in MAMPH users. For emotional empathy, cocaine and MAMPH score lower than controls. Regarding cocaine users they show decreased social and moral decision-making, and lower social reward compared to controls [reviewed in (Quednow, 2017). As we mentioned previously, social network size is influenced by psychostimulant abuse. In both cases, cocaine and MPH users exhibit smaller social networks (Quednow, 2017).

More recently, social decision-making was analyzed in males with MAMPH use disorder. Applying a modified dictator monetary game where two scenarios were present (disadvantageous and advantageous), the pro-sociality behavior was measured. If the subject chose no money or less money for themselves against the hypothetical strangers, the choice was selected as pro-social. In the disadvantageous context, males with MAMPH use disorder made fewer pro-social choices compared to controls, however, in the advantageous context authors reported no differences in pro-social choices between groups (Li et al., 2022). Although the pro-social decisions could be different if the interaction were face to face, this study suggests that in disadvantageous scenarios MAMPH male users have less consideration of other’s benefits as compared to healthy controls.

On the other hand, there is evidence that ADHD patients have some problems with emotion recognition and social skills. MPH is the first-line medication for this disorder and several works have studied the effect of the drug on different aspects of social performance. Alkalay and Dan (Alkalay and Dan, 2022), after reviewing 15 studies on the impact of MPH on social performance in children between 6 and 14 years old with ADHD, concluded that MPH seems to improve the social deficit after weeks of treatment, increasing the capacity to recognize emotions and decreasing conflictive behaviors. However, as mentioned, these authors recognize that still controversial results exist and further studies are required to confirm conclusions.

On the other hand, the administration of lisdexamphetamine (LDX) to parents diagnosed with ADHD improved parenting behaviors. The pharmacological intervention reduced ADHD symptoms -negative talk during free play and quiet time components. Also, parents treated with LDX made over four times more praising statements, reduced their number of verbalizations during the homework task, and reduced the percentage of demands during tasks (Waxmonsky et al., 2014).

High aggression is a problematic social behavior that can be explained, among other causes, by a deficit of social cognition skills that could be impaired by the use of drugs. Impulsivity, a characteristic related to drug abuse, has also been associated with aggressive behaviors. In addition, although not well studied, the use of psychostimulants seems to be a cause of aggression. A study performed in medical students assessed the relationship between the use of psychostimulants for non-medical reasons and aggressive-hostility behavior. The study was carried out using a 73-question anonymous survey that included the Zuckerman–Kuhlman Personality Questionnaire in which aggressive behavior is described as a “tendency to express verbal aggression and show rudeness” among other qualities such as “thoughtlessness, vengefulness, spitefulness, quick temper and impatient behavior.” Results showed that the use of psychostimulants is related to aggressive behavior at least in this student sample (Bucher et al., 2013).

Among psychostimulants, several studies have shown that the use of amphetamine-related drugs, in particular MAMPH, increases aggressive behaviors or trait aggression (Sekine et al., 2006; Plüddemann et al., 2010; Payer et al., 2012; Lederer et al., 2016). A study assessed the magnitude of deficit in social cognition skills and its relation with aggression in MAMPH dependent individuals, compared with MAMPH users with psychosis and a control group. The criteria used were the facial morphing “emotion recognition task” with emotions such as anger, fear, happiness, and sadness, the “reading the mind in the eyes task” and the aggression questionnaire. The MAMPH dependent groups showed impairment in social cognition skills and higher levels of aggression, although there were no associations between them (Uhlmann et al., 2018).

Although it is well known that the use of MAMPH increases aggression, little is known about the underlying biological mechanisms. It has been shown that MAMPH withdrawal increases aggressive levels and decreases the expression of serotonin transporters in several brain regions like the midbrain, striatum and cortex (Sekine et al., 2006). Other studies have shown that MAMPH dependent individuals exhibiting higher aggression levels also showed higher activity in PFC and occipital cortex (Payer et al., 2012) and a decrease of frontal white matter (Lederer et al., 2016). Altogether these results suggest that MAMPH abuse increases aggression due to, at least in part, the alteration in frontal cortex functions.

The use of alcohol is related to aggression, and on many occasions people combine the use of alcohol with other drugs. It has been shown that in amphetamine-type stimulant users, the combination with alcohol increases aggression and hostility only in MAMPH users but not in those who combine alcohol with MDMA (EllenLeslie et al., 2017). Another risk factor that could increase aggressive behavior in MAMPH users is post-traumatic stress disorder (Wahlstrom et al., 2015). These results highlight the importance of different risk factors that could increase the levels of aggression in psychostimulant users.

Regarding cocaine, less is known about the relationship between this drug and aggression. In a 2002 study, Moeller and colleagues (Moeller et al., 2002) investigated the effects of cocaine on impulsivity. In brief, impulsivity was measured in both cocaine dependent subjects and controls using an impulsiveness scale and a monetary delayed behavioral task using a computer. The results showed a higher impulsivity in cocaine dependent volunteers compared to control individuals and this outcome was not related to a history of aggressive behavior (Moeller et al., 2002). Importantly, the impulsiveness scale applied did not distinguish between social and non-social related impulsive behavior. In another study, detoxified cocaine-dependent patients had higher levels of physical aggression and hostility, and also, higher levels of dysfunctional impulsivity than healthy control subjects (Roozen et al., 2011). On the other hand, in the context of ADHD treatment, it has been shown that the treatment with MPH was effective on aggressive behavior when ADHD is comorbid with oppositional defiant disorder and aggression (Masi et al., 2017). However, this study has several limitations (non-randomized, non-blinded and few patients), and therefore more studies are needed to elucidate the effect of psychostimulants on aggressive behaviors, when used as a therapeutic treatment.

Table 2 summarizes the results of the studies evaluating the effects of different psychostimulants upon diverse social behaviors in humans.