To date, there is no adjunctive pharmacological treatment for loneliness, but animal research sheds promising light on this issue

Cacioppo, Capitanio, & Cacioppo, 2014; Nelson & Pinna, 2011; Pinna, 2010); and iv) contextual fear conditioning and aggression can be regulated with ALLO (Nelson & Pinna, 2011)

For instance, research in which a social animal (e.g., prairie voles, titi monkeys) is chronically housed either with a preferred partner or alone has shown that isolation has deleterious neurological (see review by S. Cacioppo, Capitanio, & Cacioppo, 2014) and neuroendocrinological effects (see review by J. T. Cacioppo, Cacioppo, Capitanio, & Cole, 2015). Interestingly, animal research showed that the behavioral effects of social isolation could be improved with pharmacological help. For instance, pharmacological help includes administration of: 1) antidepressants of the selective serotonin reuptake inhibitors (SSRIs) class that have a broad range of effects including (but not restricted to) improving anxiety-like behavior and fear responses (fluoxetine; Pinna, 2010); 2) neurosteroids (such as allopregnanolone, ALLO) that activate the hypothalamic pituitary adrenocortical (HPA) axis, thereby facilitate the recovery of physiological homeostasis following stressful stimuli (e.g., Evans, Sun, McGregor, & Connor, 2012; cf. S. Cacioppo, Capitanio, & Cacioppo, 2014); or 3) oxytocin, a neuropeptide.

For patients who decline psychological interventions (such as CBT), SSRIs show consistent evidence of improvement

For instance, fluoxetine, an antidepressant of the selective serotonin reuptake inhibitors (SSRIs) class, has a broad range of effects including (but not restricted to) improving the behavioral effects of social isolation, anxiety-like behavior and fear responses (Pinna, 2010; ). Interestingly, this improvement does not occur through the inhibition of selective serotonin reuptake (as in depression), but rather through elevated cortico-limbic levels of allopregnanolone (ALLO) and BDNF mRNA expression (Pinna, 2010).

Research supporting the hypothesis of a crucial role of ALLO in social isolation demonstrates that: i) the exaggerated contextual fear response expressed by socially-isolated mice can be normalized with a single injection of ALLO (Pibiri, Nelson, Guidotti, Costa, & Pinna, 2008); ii) HPA dysfunction and impairment of hippocampal neurogenesis respectively can be normalized or prevented with the administration of exogenous ALLO either during or following a period of chronic stress; iii) the establishment of depressive/anxiety-like behaviors in rats can be precluded also with administration of exogenous ALLO (Evans et al., 2012; S. Although further investigations of the effects of ALLO on social isolation are needed in humans, ALLO may provide an adjunctive therapeutic target early in cognitive behavioral interventions to alleviate chronic loneliness.

A third potential adjunctive pharmacological treatment for loneliness is oxytocin, a hypothalamic neuropeptide known to have a high sensitivity to social affiliation (Carter et al., 2008; Goossens et al., in this issue; Grippo, 2009; Young et al., 2014). Recent work with prairie voles raises the possibility that oxytocin may help buffer the deleterious neural, behavioral, immune and autonomic effects of social isolation from a pair-bonded partner (Grippo et al., 2009). The prairie vole is a monogamous rodent whose social structure has similarities to that of humans. In prairie voles, long-term social isolation from a mate or partner produces several negative behavioral and physiological alterations, including depressive and anxiety-relevant behaviors, and autonomic and cardiac dysfunction (Grippo et al., 2007a–c, 2008, 2011, 2012; McNeal et al., 2014). The exogenous peripheral administration of oxytocin eliminates the adverse behavioral and autonomic changes associated with social isolation in the prairie vole (Grippo et al., 2009, 2012).

Oxytocin administration in humans has been shown to promote pro-social behaviors, affiliation, and trust (Kosfeld et al., 2005), cooperation with others (), social synchrony (Arueti et al., 2013), autonomic cardiac control (Norman, Cacioppo et al., 2011a), and to decrease the emotional arousal in response to threatening human stimuli (Norman, Cacioppo et al., 2011b), but negative and inconsistent social effects have also been observed (see Bethlehem et al., 2014, and Bali & Jaggi, 2014, for reviews). For instance, some research studies suggest that oxytocin may make neurologically healthy individuals evaluate participants as more trusting and more pro-social in relaxed social situations and more aggressive in tense social situations (for review see: Bartz, Zaki, Bolger, & Ochsner, 2011), whereas others indicate that oxytocin administration increases outgroup aggression (e.g., De Dreu et al., 2010; Taylor et al., 2006). The fact that oxytocin has some prosocial effects, at least for some individuals or situations, is intriguing but how precisely oxytocin might prove helpful in the treatment of chronic loneliness requires additional research.