Psychoneuroimmunology (PNI) is the study of the interaction between psychological processes and the nervous and immune systems of the human body.^[1] PNI takes an interdisciplinary approach, incorporating psychology, neuroscience, immunology, physiology, pharmacology, molecular biology, psychiatry, behavioral medicine, infectious diseases, endocrinology, and rheumatology.

The main interests of PNI are the interactions between the nervous and immune systems and the relationships between mental processes and health. PNI studies, among other things, the physiological functioning of the neuroimmune system in health and disease; disorders of the neuroimmune system (autoimmune diseases; hypersensitivities; immune deficiency); and the physical, chemical and physiological characteristics of the components of the neuroimmune system in vitro, in situ, and in vivo.

PNI may also be referred to as psychoendoneuroimmunology (PENI).

[edit] History

Interest in the relationship between psychiatric syndromes or symptoms and immune function has been a consistent theme since the beginning of modern medicine.

Walter Cannon, a professor of physiology at Harvard University, looked at the need for mental and physical balance throughout the organism and coined the term, Homeostasis in his book The Wisdom of the Body,1932, from the Greek word homoios, meaning similar, and stasis, meaning position.

In his work with animals Cannon observed that any change of emotional state in the animal, such as anxiety, distress, or rage, was accompanied by total cessation of movements of the stomach. These studies into the relationship between the effects of emotions and perceptions on the autonomic nervous system, namely the sympathetic and parasympathetic responses that initiated the recognition of the freeze, fight or flight response. His findings were published from time to time in professional journals, then summed up in book form in The Mechanical Factors of Digestion, published in 1911. Dr. Cannon's seminal work, Bodily Changes in Pain, Hunger, Fear and Rage was published in 1915.

Picking up on Cannon's work was Hans Selye. Selye experimented with animals putting them under different physical and mental adverse conditions and noted that under these conditions the body consistently adapted to heal and recover. Several years of experimentation that formed the empiric foundation of Dr. Selye's concept of the General Adaptation Syndrome. This syndrome consists of an enlargement of the adrenal gland, atrophy of the thymus, spleen and other lymphoid tissue, and gastric ulcerations.

Selye describes three stages of adaptation, including an initial brief alarm reaction, followed by a prolonged period of resistance and a terminal stage of exhaustion and death. This foundational work led to a rich line of research on the biological functioning of glucocorticoids.^[2]

Mid 20th century studies of psychiatric patients reported immune alterations in psychotic patients, including numbers of lymphocytes ^[3][4] and poorer antibody response to pertussis vaccination, compared with nonpsychiatric control subjects.^[5] In 1964 George F. Solomon et all. coined the term "psychoimmunology" and published a landmark paper: "Emotions, immunity, and disease: a speculative theoretical integration."^[6]

[edit] Birth of psychoneuroimmunology

In 1975 Robert Ader and Nicholas Cohen at the University of Rochester advanced PNI with their demonstration of classic conditioning of immune function, and coined the term "psychoneuroimmunology".^[7][8] Adler was investigating how long conditioned responses (in the sense of Pavlov's conditioning of dogs to drool when they heard a bell ring) might last in laboratory rats. To condition the rats, he used a combination of saccharin-laced water (the conditioned stimulus) and the drug Cytoxan which unconditionally induces nausea and taste aversion and suppression of the immune system. Ader was surprised to discover that after conditioning, just feeding the rats saccharin-laced water was associated with the death of some animals and he proposed that they had been immunosuppressed after receiving the conditioned stimulus. Adler (a psychologist) and Cohen (an immunologist) directly tested this hypothesis by deliberately immunizing conditioned and unconditioned animals, exposing these and other control groups to the conditioned taste stimulus, and then measuring the amount of antibody produced. The highly reproducible results revealed that conditioned rats exposed to the conditioned stimulus were indeed immunosuppressed. In other words, a signal via the nervous system (taste) was affecting immune function. This was one of the first scientific experiments that demonstrated that the nervous system can affect the immune system.

In 1981 David Felten, then working at the Indiana University of Medicine, discovered a network of nerves leading to blood vessels as well as cells of the immune system. The researchers also found nerves in the thymus and spleen terminating near clusters of lymphocytes, macrophages and mast cells, all of which help control immune function. This discovery provided one of the first indications of how neuro-immune interaction occurs.

Adler, Cohen and Felten went on to edit the groundbreaking book Psychoneuroimmunology in 1981, which laid out the underlying premise that the brain and immune system represent a single, integrated system of defense. An updated fourth edition was released in 2006.

In 1985, research by neuropharmacologist Candace Pert revealed that neuropeptide-specific receptors are present on the cell walls of both the brain and the immune system.^[9][10] The discovery by Pert et al. that neuropeptides and neurotransmitters act directly upon the immune system shows their close association with emotions and suggests mechanisms through which emotions and immunology are deeply interdependent. Showing that the immune and endocrine systems are modulated not only by the brain but also by the central nervous system itself has had an enormous impact on how we understand emotions, as well as disease.

Contemporary advances in psychiatry, immunology, neurology and other integrated disciplines of medicine has fostered enormous growth for PNI. The mechanisms underlying behaviorally induced alterations of immune function, and immune alterations inducing behavioral changes, are likely to have clinical and therapeutic implications that will not be fully appreciated until more is known about the extent of these interrelationships in normal and pathophysiological states.

[edit] The Immune-Brain Loop

PNI research is looking for the exact mechanisms by which specific brainimmunity effects are achieved. Evidence for nervous system'immune system interactions exists at several biological levels.

The immune system and the brain talk to each other through signaling pathways. The brain and the immune system are the two major adaptive systems of the body. Two major pathways are involved in this cross-talk: the Hypothalamic-pituitary-adrenal axis (HPA axis) and the sympathetic nervous system (SNS). The activation of SNS during an immune response might be aimed to localize the inflammatory response.

The body's primary stress management system is the HPA axis. The HPA axis responds to physical and mental challenge to maintain homeostasis in part by controlling the body's cortisol level. Dysregulation of the HPA axis is implicated in numerous stress-related diseases. HPA axis activity and cytokines are intrinsically intertwined: inflammatory cytokines stimulate adrenocorticotropic hormone (ACTH) and cortisol secretion, while, in turn, glucocorticoids suppress the synthesis of proinflammatory cytokines.

Molecules called pro-inflammatory cytokines, which include interleukin-1 (IL-1), Interleukin-2 (IL-2), interleukin-6 (IL-6), Interleukin-12 (IL-12), Interferon-gamma (IFN-Gamma) and tumor necrosis factor alpha (TNF-alpha) can affect brain growth as well as neuronal function. Circulating immune cells such as macrophages, as well as glial cells (microglia and astrocytes) secrete these molecules. Cytokine regulation of hypothalamic function is an active area of research for the treatment of anxiety-related disorders. ^[11]

Cytokines mediate and control immune and inflammatory responses. Complex interactions exist between cytokines, inflammation and the adaptive responses in maintaining homeostasis. Like the stress response, the inflammatory reaction is crucial for survival. Systemic inflammatory reaction results in stimulation of four major programs^[12]:

• the acute-phase reaction
• Sickness behavior
• the pain program
• the stress response

These are mediated by the HPA axis and the SNS. Common human diseases such as allergy, autoimmunity, chronic infections and sepsis are characterized by a dysregulation of the pro-inflammatory versus anti-inflammatory and T helper (Th1) versus (Th2) cytokine balance.

Recent studies show pro-inflammatory cytokine processes take place during depression, mania and bipolar disease, in addition to autoimmune hypersensitivity and chronic infections.

Chronic secretion of stress hormones, glucocorticoids (GCs) and catecholamines (CAs), as a result of disease, may reduce the effect of neurotransmitters, including serotonin, norepinephrine and dopamine, or other receptors in the brain, thereby leading to the dysregulation of neurohormones. Under stimulation, norepinephrine is released from the sympathetic nerve terminals in organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released norepinephrine, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells.

Glucocorticoids also inhibit the further secretion of corticotropin-releasing hormone from the hypothalamus and ACTH from the pituitary (negative feedback). Under certain conditions stress hormones may facilitate inflammation through induction of signaling pathways and through activation of the Corticotropin-releasing hormone.

These abnormalities and the failure of the adaptive systems to resolve inflammation affect the well-being of the individual, including behavioral parameters, quality of life and sleep, as well as indices of metabolic and cardiovascular health, developing into a "systemic anti-inflammatory feedback" and/or "hyperactivity" of the local pro-inflammatory factors which may contribute to the pathogenesis of disease.

This systemic or neuro-inflammation and neuroimmune activation have been shown to play a role in the etiology of a variety of neurodegenerative disorders such as Parkinson's and Alzheimer's disease, multiple sclerosis, pain, and AIDS-associated dementia. However, cytokines and chemokines also modulate central nervous system (CNS) function in the absence of overt immunological, physiological, or psychological challenges.^[13]

[edit] Psychoneuroimmunological effects

There is now sufficient data to conclude that immune modulation by psychosocial stressors and/or interventions can lead to actual health changes. Although changes related to infectious disease and wound healing have provided the strongest evidence to date, the clinical importance of immunological disregulation is highlighted by increased risks across diverse conditions and diseases.

[edit] Link between stress and disease

Stressors can produce profound health consequences. In one epidemiological study, for example, all-cause mortality increased in the month following a severe stressor ' the death of a spouse.^[14] Theorists propose that stressful events trigger cognitive and affective responses which, in turn, induce sympathetic nervous system and endocrine changes, and these ultimately impair immune function ^{[15] [16]}. Potential health consequences are broad, but include rates of infection ^{[17] [18]} HIV progression ^{[19] [20]} and cancer incidence and progression.^{[21] [22] [23]}

Stress is thought to affect immune function through emotional and/or behavioral manifestations such as anxiety, fear, tension, anger and sadness and physiological changes such as heart rate, blood pressure, and sweating. Researchers have suggested that these changes are beneficial if they are of limited duration^[24], but when stress is chronic, the system is unable to maintain equilibrium or homeostasis.

Immune changes in response to very brief stressors have been a central theme in the last decade of PNI research, but older literature also provides early illustrations. In a study published in 1960, subjects were led to believe that they had accidentally caused serious injury to a companion through misuse of explosives.^[25]

Two meta-analyses of the literature show a consistent reduction of immune function in healthy people who are experiencing stress.

In the first meta-analysis by Herbert and Cohen in 1993,^[26] 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 [PHA] and concanavalin A [Con 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,^[27] 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).

[edit] Communication between the brain and immune system

• Stimulation of brain sites alters immunity (stressed animals have altered immune systems).
• Immune cells produce cytokines that act on the CNS.
• Immune cells respond to signals from the CNS.

[edit] Communication between neuroendocrine and immune system

• Glucocorticoids and catecholamines influence immune cells.^[28]
• Endorphins from pituitary & adrenal medulla act on immune system.
• Activity of the immune system is correlated with neurochemical/neuroendocrine activity of brain cells.

[edit] Connections between glucocorticoids and immune system

• Anti-inflammatory hormones that enhance the organisms response to a stressor.
• Prevent the overreaction of the body own defense system.
• Regulators of the immune system.
• Affect cell growth, proliferation & differentiation.
• Cause immunosuppression.
• Suppress cell adhesion, antigen presentation, chemotaxis & cytotoxicity.
• Increase apoptosis.

[edit] 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.

[edit] Pharmaceutical advances

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, SSRI's, SNRI's and tricyclic antidepressants acting on serotonin, norepinephrine and dopamine 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.^[29][30][31] Antidepressants have also been shown to suppress TH1 upregulation.^{[32][33][34][35][36]}

Tricyclic and dual serotonergic-noradrenergic reuptake inhibition by SNRIs (or SSRI-NRI combinations), have also shown analgesic properties additionally.^[37][38] 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.^[39]

These studies warrant investigation for antidepressants for use in both psychiatric and non-psychiatric illness and that a psychoneuroimmunological approach may be required for optimal pharmacotherapy in many diseases.^[40] 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.^[41]

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. ^[42]

[edit] See also

[edit] References

1. ^ Michael Irwin, Kavita Vedhara (2005). Human Psychoneuroimmunology. Oxford University Press. ISBN 978-0198568841. 
2. ^ Thomas C. Neylan, M.D. "Hans Selye and the Field of Stress Research" J Neuropsychiatry Clin Neurosci 10:230, May 1998
3. ^ Freeman H, Elmadjian F. The relationship between blood sugar and lymphocyte levels in normal and psychotic subjects. Psychosom Med 1947; 9: 226'33.
4. ^ Phillips L, Elmadjian F. A Rorschach tension score and the diurnal lymphocyte curve in psychotic subjects. Psychosom Med 1947; 9: 364'71
5. ^ Vaughan WTJ, Sullivan JC, Elmadjian F. Immunity and schizophrenia. Psychosom Med 1949; 11: 327'33.
6. ^ Solomon GF, Moos RH. Emotions, immunity, and disease: a speculative theoretical integration. Arch Gen Psychiatry 1964; 11: 657'74
7. ^ R Adler and N Cohen. Behaviorally conditioned immunosuppression. Psychosomatic Medicine, Vol 37, Issue 4 333-340
8. ^ Robert Ader- Robert Ader - Papers on Psychoneuroimmunology.
9. ^ Pert CB, Ruff MR, Weber RJ, Herkenham M. Neuropeptides and their receptors: a psychosomatic network. J Immunol. 1985 Aug;135(2 Suppl):820s-826s
10. ^ Ruff M, Schiffmann E, Terranova V, Pert CB.Neuropeptides are chemoattractants for human tumor cells and monocytes: a possible mechanism for metastasis. Clin Immunol Immunopathol. 1985 Dec;37(3):387-96
11. ^ Covelli V, Passeri ME, Leogrande D, Jirillo E, Amati L. Drug targets in stress-related disorders.Curr Med Chem. 2005;12(15):1801-9|PMID:16029148
12. ^ Elenkov IJ, Iezzoni DG, Daly A, Harris AG, Chrousos GP. "Cytokine dysregulation, inflammation and well-being". Neuroimmunomodulation. 2005;12(5):255-69
13. ^ Functional Links between the Immune System, Brain Function and Behavior
14. ^ Kaprio, J., Koskenvuo, M., and Rita, H. (1987). Mortality after bereavement: a prospective study of 95,647 widowed persons. American Journal of Public Health 77(3), 283-7.
15. ^ Chrousos, G. P. and Gold, P. W. (1992). The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 267(Mar 4), 1244-52.
16. ^ Glaser, R. and Kiecolt-Glaser, J. K. (1994). Handbook of Human Stress and Immunity. San Diego: Academic Press.
17. ^ Cohen, S., Tyrrell, D. A., and Smith, A. P. (1991). Psychological stress and susceptibility to the common cold. The New England Journal of Medicine 325(9), 606-12.
18. ^ Cohen, S. and Williamson, G. M. (1991). Stress and infectious disease in humans. Psychological Bulletin 109(1), 5-24.
19. ^ Leserman, J., Petitto, J. M., Golden, R. N., Gaynes, B. N., Gu, H., Perkins, D. O., Silva, S. G., Folds, J. D., and Evans, D. L. (2000). Impact of stressful life events, depression, social support, coping, and cortisol on progression to AIDS. The American Journal of Psychiatry 157(8), 1221-8.
20. ^ Leserman, J., Jackson, E. D., Petitto, J. M., Golden, R. N., Silva, S. G., Perkins, D. O., Cai, J., Folds, J. D., and Evans, D. L. (1999). Progression to AIDS: the effects of stress, depressive symptoms, and social support. Psychosomatic Medicine 61(3), 397-406.
21. ^ Kaprio, J., Koskenvuo, M., and Rita, H. (1987). Mortality after bereavement: a prospective study of 95,647 widowed persons. American Journal of Public Health 77(3), 283-7.
22. ^ Andersen, B. L., Kiecolt-Glaser, J. K., and Glaser, R. (1994). A biobehavioral model of cancer stress and disease course. American Psychologist 49(5), 389-404.
23. ^ Kiecolt-Glaser, J. K. and Glaser, R. (1999). Psychoneuroimmunology and cancer: fact or fiction? European Journal of Cancer 35, 1603-7.
24. ^ Chrousos, G. P. and Gold, P. W. (1992). The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 267(Mar 4), 1244-52.
25. ^ McDonald RD, Yagi K. A note on eosinopenia as an index of psychological stress. Psychosom Med 1960;2 22: 149'50.
26. ^ Herbert TB, Cohen S. Stress and immunity in humans: a meta-analytic review. Psychosom Med. 1993;55:364'379.
27. ^ Zorrilla, E. P., Luborsky, L., McKay, J. R., Rosenthal, R., Houldin, A., Tax, A., McCorkle, R., Seligman, D. A., & Schmidt, K. (2001). The relationship of depression and stressors to immunological assays: a meta-analytic review. Brain Behavior and Immunity, 15(3), 199-226.
28. ^ Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP. The pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med 1998; 128: 127'37.The Pathophysiologic Roles of Interleukin-6 in Human Disease Annals of Internal Medicine 15 January 1998 | Volume 128 Issue 2 | Pages 127-137
29. ^ Kubera M, Lin AH, Kenis G, Bosmans E, van Bockstaele D, Maes M. "Anti-Inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio." J Clin Psychopharmacol. 2001 Apr;21(2):199-206
30. ^ Maes M."The immunoregulatory effects of antidepressants". Hum Psychopharmacol. 2001 Jan;16(1):95-103
31. ^ Maes M, Kenis G, Kubera M, De Baets M, Steinbusch H, Bosmans E."The negative immunoregulatory effects of fluoxetine in relation to the cAMP-dependent PKA pathway". Int Immunopharmacol. 2005 Mar;5(3):609-18.
32. ^ Diamond M, Kelly JP, Connor TJ. "Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade". Eur Neuropsychopharmacol. 2006 Oct;16(7):481-90.
33. ^ Kubera M, Lin AH, Kenis G, Bosmans E, van Bockstaele D, Maes M. "Anti-Inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio." J Clin Psychopharmacol. 2001 Apr;21(2):199-206
34. ^ Maes M."The immunoregulatory effects of antidepressants". Hum Psychopharmacol. 2001 Jan;16(1):95-103
35. ^ Maes M, Kenis G, Kubera M, De Baets M, Steinbusch H, Bosmans E."The negative immunoregulatory effects of fluoxetine in relation to the cAMP-dependent PKA pathway". Int Immunopharmacol. 2005 Mar;5(3):609-18.
36. ^ Brustolim D, Ribeiro-dos-Santos R, Kast RE, Altschuler EL, Soares MB. "A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice." Int Immunopharmacol. 2006 Jun;6(6):903-7
37. ^ Moulin DE, Clark AJ, Gilron I, Ware MA, Watson CP, Sessle BJ, Coderre T, Morley-Forster PK, Stinson J, Boulanger A, Peng P, Finley GA, Taenzer P, Squire P, Dion D, Cholkan A, Gilani A, Gordon A, Henry J, Jovey R, Lynch M, Mailis-Gagnon A, Panju A, Rollman GB, Velly A; Canadian Pain Society.Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society. Pain Res Manag. 2007 Spring;12(1):13-21
38. ^ Jones CK, Eastwood BJ, Need AB, Shannon HE. Analgesic effects of serotonergic, noradrenergic or dual reuptake inhibitors in the carrageenan test in rats: evidence for synergism between serotonergic and noradrenergic reuptake inhibition.Neuropharmacology. 2006 Dec;51(7-8):1172-80.
39. ^ Covelli V, Passeri ME, Leogrande D, Jirillo E, Amati L. Drug targets in stress-related disorders. Curr Med Chem. 2005;12(15):1801-9
40. ^ Kulmatycki KM, Jamali F. "Drug disease interactions: role of inflammatory mediators in depression and variability in antidepressant drug response". J Pharm Pharm Sci. 2006;9(3):292-306.
41. ^ O'Brien SM, Scott LV, Dinan TG. "Cytokines: abnormalities in major depression and implications for pharmacological treatment". Hum Psychopharmacol. 2004 Aug;19(6):397-403.
42. ^ Roberts, Thomas B. (2006). "Do Entheogen-induced Mystical Experiences Boost the Immune System?: Psychedelics, Peak Experiences, and Wellness." Chapter 6 in Psychedelic Horizons. Westport, CT: Praeger/Greenwood.

[edit] Recommended Reading

• Berczi and Szentivanyi (2003) NeuroImmune Biology, Elsevier, ISBN 0-444-50851-1 (Written for the highly technical reader)
• Goodkin, Karl, and Adriaan P. Visser, (eds), Psychoneuroimmunology: Stress, Mental Disorders , and Health, American Psychiatric Press, 2000, ISBN 0-88048-171-4, technical.
• Ransohoff, Richard, et al. (eds), Universes in Delicate Balance: Chemokines and the Nervous System, Elsevier, 2002, ISBN 0-444-51002-8
• Robert Adler, David L. Felten, Nicholas Cohen , Psychoneuroimmunology, 4th edition, 2 volumes, Academic Press, (2006), ISBN 0-12-088576-X
• Roberts, Thomas B. (2006). "Do Entheogen-induced Mystical Experiences Boost the Immune System?: Psychedelics, Peak Experiences, and Wellness." Chapter 6 in Psychedelic Horizons. Westport, CT: Praeger/Greenwood.

[edit] External links

• Psychoneuroimmunology Research Society
• Home page of Robert Adler - University of Rochester
• UCLA-NPI Cousins Center for Psychoneuroimmunology
• Biochemical Aspects of Anxiety