to a companion through misuse of explosives. since then decades of research resulted in two large meta-analyses, which showed consistent immune dysregulation in healthy people who are experiencing stress. in the first meta-analysis by herbert and cohen in 1993, they examined 38 studies of stressful events and immune function in healthy adults. they included studies of acute laboratory stressors (e.g. a speech task), short-term naturalistic stressors (e.g. medical examinations), and long-term naturalistic stressors (e.g. divorce, bereavement, caregiving, unemployment). they found consistent stress-related increases in numbers of total white blood cells, as well as decreases in the numbers of helper t cells, suppressor t cells, and cytotoxic t cells, b cells, and natural killer cells (nk). they also reported stress-related decreases in nk and t cell function, and t cell proliferative responses to phytohaemagglutinin and concanavalin a . these effects were consistent for short-term and long-term naturalistic stressors, but not laboratory stressors. in the second meta-analysis by zorrilla et al. in 2001, they replicated herbert and cohen's meta-analysis. using the same study selection procedures, they analyzed 75 studies of stressors and human immunity. naturalistic stressors were associated with increases in number of circulating neutrophils, decreases in number and percentages of total t cells and helper t cells, and decreases in percentages of natural killer cell (nk) cells and cytotoxic t cell lymphocytes. they also replicated herbert and cohen's finding of stress-related decreases in nkcc and t cell mitogen proliferation to phytohaemagglutinin (pha) and concanavalin a (con a). a study done by the american psychological association did an experiment on rats, where they applied electrical shocks to a rat, and saw how interleukin-1 was released directly into the brain. interleukin-1 is the same cytokine released when a macrophage chews on a bacterium, which then travels up the vagus nerve, creating a state of heightened immune activity, and behavioral changes. more recently, there has been increasing interest in the links between interpersonal stressors and immune function. for example, marital conflict, loneliness, caring for a person with a chronic medical condition, and other forms on interpersonal stress dysregulate immune function. communication between the brain and immune system stimulation of brain sites alters immunity (stressed animals have altered immune systems). damage to brain hemispheres alters immunity (hemispheric lateralization effects). immune cells produce cytokines that act on the cns. immune cells respond to signals from the cns. communication between neuroendocrine and immune system glucocorticoids and catecholamines influence immune cells. hypothalamic pituitary adrenal axis releases the needed hormones to support the immune system. activity of the immune system is correlated with neurochemical/neuroendocrine activity of brain cells. connections between glucocorticoids and immune system anti-inflammatory hormones that enhance the organism's response to a stressor. prevent the overreaction of the body's own defense system. overactivation of glucocorticoid receptors can lead to health risks. regulators of the immune system. affect cell growth, proliferation and differentiation. cause immunosuppression which can lead to an extended amount of time fighting off infections. high basal levels of cortisol are associated with a higher risk of infection. suppress cell adhesion, antigen presentation, chemotaxis and cytotoxicity. increase apoptosis. corticotropin-releasing hormone (crh) release of corticotropin-releasing hormone (crh) from the hypothalamus is influenced by stress. crh is a major regulator of the hpa axis/stress axis. crh regulates secretion of adrenocorticotropic hormone (acth). crh is widely distributed in the brain and periphery crh also regulates the actions of the autonomic nervous system ans and immune system. furthermore, stressors that enhance the release of crh suppress the function of the immune system; conversely, stressors that depress crh release potentiate immunity. central mediated since peripheral administration of crh antagonist does not affect immunosuppression. hpa axis/stress axis responds consistently to stressors that are new, unpredictable and that have low-perceived control. as cortisol reaches an appropriate level in response to the stressor, it deregulates the activity of the hippocampus, hypothalamus, and pituitary gland which results in less production of cortisol. relationships between prefrontal cortex activation and cellular senescence psychological stress is regulated by the prefrontal cortex (pfc) the pfc modulates vagal activity prefrontally modulated and vagally mediated cholinergic input to the spleen reduces inflammatory responses pharmaceutical advances further information: neuropsychopharmacology glutamate agonists, cytokine inhibitors, vanilloid-receptor agonists, catecholamine modulators, ion-channel blockers, anticonvulsants, gaba agonists (including opioids and cannabinoids), cox inhibitors, acetylcholine modulators, melatonin analogs (such as ramelton), adenosine receptor antagonists and several miscellaneous drugs (including biologics like passiflora edulis) are being studied for their psychoneuroimmunological effects. for example, ssris, snris and tricyclic antidepressants acting on serotonin, norepinephrine, dopamine and cannabinoid receptors have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory cytokine processes, specifically on the regulation of ifn-gamma and il-10, as well as tnf-alpha and il-6 through a psychoneuroimmunological process. antidepressants have also been shown to suppress th1 upregulation. tricyclic and dual serotonergic-noradrenergic reuptake inhibition by snris (or ssri-nri combinations), have also shown analgesic properties additionally. according to recent evidences antidepressants also seem to exert beneficial effects in experimental autoimmune neuritis in rats by decreasing interferon-beta (ifn-beta) release or augmenting nk activity in depressed patients. these studies warrant investigation of antidepressants for use in both psychiatric and non-psychiatric illness and that a psychoneuroimmunological approach may be required for optimal pharmacotherapy in many diseases. future antidepressants may be made to specifically target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines. the endocannabinoid system appears to play a significant role in the mechanism of action of clinically effective and potential antidepressants and may serve as a target for drug design and discovery. the endocannabinoid-induced modulation of stress-related behaviors appears to be mediated, at least in part, through the regulation of the serotoninergic system, by which cannabinoid cb1 receptors modulate the excitability of dorsal raphe serotonin neurons. data suggest that the endocannabinoid system in cortical and subcortical structures is differentially altered in an animal model of depression and that the effects of chronic, unpredictable stress (cus) on cb1 receptor binding site density are attenuated by antidepressant treatment while those on endocannabinoid content are not. the increase in amygdalar cb1 receptor binding following imipramine treatment is consistent with prior studies which collectively demonstrate that several treatments which are beneficial to depression, such as electroconvulsive shock and tricyclic antidepressant treatment, increase cb1 receptor activity in subcortical limbic structures, such as the hippocampus, amygdala and hypothalamus. and preclinical studies have demonstrated the cb1 receptor is required for the behavioral effects of noradrenergic based antidepressants but is dispensable for the behavioral effect of serotonergic based antidepressants. extrapolating from the observations that positive emotional experiences boost the immune system, roberts speculates that intensely positive emotional experiences —sometimes brought about during mystical experiences occasioned by psychedelic medicines—may boost the immune system powerfully. research on salivary iga supports this hypothesis, but experimental testing has not been done.