Hair growth is affected by a number of physiological and psychological factors. Stress modulates the hypothalamic-pituitary-adrenal (HPA) axis responses to create both acute and chronic changes in neuroendocrine and inflammatory patterns. These changes indirectly affect hair growth via elimination of immune privilege at the hair follicle level. As a result, mood imbalances may show clinical changes in hair health that may be modified by therapies aimed at balancing mood. This review looks at the stress-induced immune-mediated changes at the hair follicle that induce hair loss, and surveys both conventional and natural therapeutic strategies that can help address these factors.
The immune system is a critical part of the human body that protects against disease and injury. It is a defense system comprising entire organs and a vascular system, as well as individual cells and proteins. Some anatomical areas are naturally less subject to immune responses than other areas, including the central nervous system, eyes, testes, and hair follicles.1 The protection given to these specific areas is known as immune privilege. Considered in previous research to be a passive occurrence, immune privilege is now thought to be both active and passive with the goal of peripheral tolerance of certain tissues. The chronic pathophysiology associated with stress is known to adversely affect the immune system, both systemically and locally, and lead to loss of immune privilege. Collapse of immune privilege has a deleterious effect on hair follicles, causing an inflammatory cascade and eventual damage of the hair follicle. This effect has been implicated in hair follicle pathologies, including alopecia areata.2
The Immune System
The immune system encompasses 2 distinct categories of response, termed innate and adaptive immunity. Innate immunity designates the immune system’s initial antigen-nonspecific defense that reacts within hours after exposure to invading organisms. Adaptive or acquired immunity is a deliberate, antigen-specific defense that reacts to and removes explicit antigens. Adaptive immunity develops over time and occurs throughout one’s life, whereas innate immunity is present from birth.
Innate immunity includes the physical barrier of the skin, chemicals in the blood, and immune system cells. It is a nonspecific defense that quickly takes effect in response to the chemical properties of an antigen.3 Immediate innate immunity is the action of preformed, soluble enzymes, peptides, and complement system proteins secreted by epithelial cells and found in blood and extracellular tissue fluids. It also includes mechanical mechanisms of antigen removal.
The innate immune response is nonspecific, recognizing molecules shared by related microorganisms but not found in the body. It recruits defense cells resulting from pathogen-associated molecular patterns (PAMPs) binding to pattern-recognition receptors (PRRs).4 These include phagocytic leukocytes (neutrophils, eosinophils, and monocytes), tissue phagocytic cells (macrophages), mediators of inflammation (macrophages and mast cells), leukocytes (basophils and eosinophils), and natural killer cells.
Adaptive immunity is an antigen-specific immune response and is more complex than the innate response. It is also slower, taking several days to react with and remove a specific antigen. Adaptive immunity allows the immune system to “remember” antigens and react more efficiently against them in the future.5 During the adaptive-immunity process, antigens are transported to lymph nodes, the spleen, and related tissues, where they are recognized by naïve B lymphocytes and T lymphocytes, which become activated, proliferate, and differentiate into effector cells.
An antigen is recognized as foreign when the epitope of that antigen binds to complementary epitope-specific receptor molecules on B lymphocytes and T lymphocytes.5 T cells express T-cell receptors that recognize antigen bound to human leukocyte antigen molecules. As relatively few B cells and T cells are allocated to recognize any 1 epitope, once a foreign antigen has been identified, they must then take time to proliferate to produce enough cells to mount an effective immune response. While the adaptive response is building over several days, the body must temporarily depend on the innate immune system. Once an adequate level of response has been achieved, cytotoxic T lymphocytes take responsibility for destroying invading microorganisms, while CD4+ lymphocytes, or helper T cells, mediate the immune response.
Some parts of the body can tolerate the introduction of antigens without eliciting an immune response. This principle is referred to as immune privilege and is believed to represent an evolutionary adaptation to protect vital structures from inflammatory injury directed against pathogens.6 Foreign antigens entering these tissues generally do not trigger immune responses. Immunologically privileged areas include the eyes, placenta and fetus, testicles, central nervous system, and hair follicles.7 This important feature prevents damaging inflammation that could, for example, impair vision or fertility.
Mounting evidence suggests that stress can impose a significantly detrimental effect on immune privilege, which can damage the hair follicle and contribute to hair loss.
One mechanism for immune privilege is the transmembrane death receptor (Fas), which induces cellular apoptosis upon binding with a Fas ligand (FasL). Fas is widely expressed on nonlymphoid cells and is induced on T cells after activation, while FasL is expressed on very few cell types found in immune-privileged sites. Interaction of Fas on an activated T cell with FasL induces the activated T cell to undergo apoptosis before it can differentiate into an effector cell that can attack tissue or secrete damaging inflammatory cytokines. Immunosuppressive cytokines, immune deviation, and the actions of regulatory T cells also contribute to immune privilege.8
Any intrinsic or extrinsic stimulus that evokes a biological response is known as stress. Common definitions are “physical, mental, or emotional strain or tension” and “a condition or feeling experienced when a person perceives that demands exceed the personal and social resources the individual is able to mobilize.”8 According to the general adaptation and stress syndrome model, “anything that endangers life causes stress unless it is met by adequate adaptive responses.”8 The compensatory reaction to stress is known as a stress response. Based on the type and circumstances, stress can alter homeostasis and illness.9 Stress is directly implicated in heart disease, stroke, musculoskeletal disorders/injuries, and mood disorder and indirectly in cancer, chronic liver disease, and chronic bronchitis/emphysema.10
Stressors disrupt homeostasis, activating both the HPA axis and the sympathetic nervous system (SNS). Together, these systems provide neural and endocrine adaptations to stress.9
When activated, the stress response of the SNS is the release of catecholamines. This provides rapid, beneficial physiological adaptation resulting in short-lasting responses, such as alertness and vigilance, the so-called “fight or flight” response.11 The theory of “fight or flight,” first proposed in 1915, describes physiological changes causing immediate intensification or total interruption of homeostasis in order to better mobilize energy through increased glycogenolysis and gluconeogenesis, lipolysis, thermogenesis, and expanded oxygen consumption.11 Although this physiological phenomenon is fundamental to survival, an exaggerated or prolonged response is strongly associated with several brain disorders including depression, anxiety, and post-traumatic stress disorder.
Reflecting the behavioral stress response commonly demonstrated by many females as an alternative to “fight or flight” is the theory of the “tend and befriend” stress response, which promotes prosocial behavior and cooperation.12 The stress response “tend and befriend” is reported to occur without differences in physiological responses to “fight or flight,” such as impacts on cortisol response. These 2 responses are theorized to exist on a spectrum, with the antagonism of “fight or flight” being higher expressed in the male population, and the prosocial response of “tend and befriend” being preferentially expressed in females.
Allostasis, defined as “achieving stability through change,”13 describes the active responses of the body to maintain stability of homeostasis despite stressors. This is achieved through mediators, such as cortisol, produced by the HPA axis, autonomic nervous system (ANS), and general immune system. When stressors become repeated, or when systems of allostasis remain active longer than appropriate or necessary, these wanton mediators can cause unfavorable impacts on both the brain and body, such as increases in accumulation of abdominal fat or atrophy of nerve cells. This allostasis-related impact is referred to as allostatic load.
Activating the HPA axis initiates a cascade of events that begins with the release of corticotropin-releasing hormone (CRH) from the hypothalamus, which causes the release of circulating adrenocorticotropic hormone (ACTH). Acting on the adrenal cortex, ACTH influences the release of glucocorticoids such as cortisol into blood, which provides negative feedback to terminate the release of CRH. Dysregulation of the HPA axis can have serious health consequences. Individuals experiencing chronic stress have anxiety, depression, diminished response to disease, and increased age-related disorders.14
Chronic stress leads to supraphysiological levels of cortisol, which alters regulation of the inflammatory and immune response by decreasing tissue cortisol sensitivity15 whereby the system can exhibit glucocorticoid resistance. As the body responds to injury, inflammation becomes a stress response. While acute inflammation and stress are beneficial to normal systemic functioning, chronic stress and its associated inappropriate inflammatory response can lead to tissue breakdown and impaired immune function.
Scrutinizing the influence of profuse cortisol relating to chronic stressors and their impact on systemic dysregulation, hair cortisol may be a useful biomarker of chronic stress, as it reflects total cortisol secreted into hair over several weeks and is associated with both the incidence of cardiovascular disease and risk factors including high blood pressure, diabetes, and adiposity.16
Stress, Immune System, & Hair Loss
Normal hair growth
The 3 stages of normal hair growth are the anagen, catagen, and telogen phases. During the anagen phase, hair grows at a rate of approximately 1 cm per month and can last from 2 to 7 years. At any given time, approximately 90% of hair is in the anagen phase. The catagen phase lasts about 2 weeks, during which time the hair follicle shrinks and detaches from the skin.16 During the telogen or resting phase, the follicle remains dormant for 3 months. About 10% of hair is in the telogen phase.17 The epidermal cells lining the follicle channel continue to grow around the base of the hair, anchoring it in place. Eventually, the follicle begins to grow again. The base of the hair shaft will break free from the root and the hair will be shed. Within 2 weeks, a new hair shaft will emerge, ending the telogen phase.
Immune privilege and hair follicles
Growing evidence indicates stress is associated with the collapse of immune privilege of the hair follicle, leading to follicle destruction.18 One contributing factor is upregulation of major histocompatibility complex (MHC) classes I and II expression. The proinflammatory IFN-γ (interferon-gamma) triggers immune privilege collapse and ensuing immune-mediated epithelial hair follicle stem cell damage by enhancing expression of MHC I and II, which makes these cells more visible to T cells.17 Increased expression of MHC I may enhance autoimmune attack by CD8+ T cells.19 Other factors are MHC-I chain-related A gene (MICA), a stress-induced ligand that activates recognition receptors on natural killer and CD8+ T cells; decreased macrophage migration inhibitory factor (MIF) expression in the proximal follicular epithelium; and mast cell degranulation leading to collapse of anagen hair follicle immune privilege.
The anagen hair bulb and epithelial stem cell in the outer root sheath of hair follicles are areas of relative immune privilege.20 The loss of immune privilege integrity in these areas incites vulnerability to dysfunction and injury of the hair follicle. This is most notable in alopecia areata, an autoimmune disease leading to hair loss. Alopecia areata is identified as a pattern of nonscarring hair loss21 with variable clinical presentation, initially beginning as patches of focal hair loss with the potential to progress to diffuse hair loss of both the scalp and body,22,23 commonly accompanied by negative psychological implications such as depression.24 In alopecia areata, 1 of the proposed underlying mechanisms is a loss of immune privilege of hair follicles.25,20 Hair follicles are then attacked by natural killer cells.26 The cytokine IFN-γ plays an important role in the collapse of hair follicle immune privilege, CD8+ T-cell-driven inflammation at the hair follicle bulb, and premature catagen development.27 Other drivers of disease include natural killer subsets, which also produce large amounts of IFN-γ.28
Histologically, alopecia areata is not significantly affected by patient age, race, or gender29 but is dependent on the duration of the episode and can be divided into acute or active, subacute, and chronic stages.30 In the acute phase, bulbar lymphocytes surround terminal hairs in early episodes and miniaturized hairs following repeated episodes.26 This stage is often characterized by peribulbar inflammatory infiltrate composed of activated T lymphocytes, mixed with few histiocytes, plasma cells, and eosinophils. This pushes the follicle into catagen or telogen, with reversal of the anagen-to-telogen ratio.27 In the subacute stage, there is an increase in the number of catagen followed by telogen hairs, which often exceed 50% of the total follicles.31 In the chronic phase, decreased terminal and increased miniaturized hairs occur with variable inflammation.32
Clinical Relationship Between Hair Health and Stress
As psychoneuroimmunology research emerges, it is becoming clear that there is a relationship between healthy hair growth and a healthy mental state. As previously mentioned, short- and long-term stress adaptations create a bidirectional path between immune changes and neuroendocrine function. These changes lead to inflammation that contributes to mood imbalances. This inflammation will also make the mood-labile patient more susceptible to changes in hair growth.
This relationship between stress and changes in skin and hair has been documented for at least 7 decades.33 One report from 1953 looked at 55 alopecic cases, where 63% showed severe symptoms of stress and some type of mental health disorder, with only 14% of these patients without any psychiatric concerns. Since then, numerous reports have correlated the relationships between mental health issues and alopecia. One 1991 cohort of 31 individuals established that high rates of anxiety (39%) and depression (39%) occur in patients with alopecia areata.34 More recently, a cross-sectional study looking at 529 medical students revealed that those students who considered themselves “highly stressed” were much more likely to suffer both skin and hair issues, with hair loss being the most common in 67.2% of those highly stressed. Also commonly found was the need to pull on their own hair, as well as numerous skin disturbances such as flaky skin, rashes, and pimples.35 Another recent study of 18 healthy final-exam-taking female medical students also showed a modulated immune response favoring type 1 helper T cells (TH1) with concomitant decrease in hair pigmentation (an early indicator of hair damage and growth termination) and lowered anagen hair-follicle signaling that was transient in nature.36 While these changes were considered reversible in these healthy individuals, it is possible that long-term chronic stress may create allostatic changes that are more durable.
Treatment Modulation of Stress to Manage Alopecia
Given the relationships among hair growth, stress and mental health, and immunity, it is reasonable to consider therapeutics that address psychiatric concerns as possible supports for hair regrowth. These may address imbalances in HPA axis function and balance neurotransmitters to address dysfunction in HPA and SNS activity and/or calm the inflammatory response as a means to improve hair growth.
When the system is in parasympathetic mode and is relaxed, there are adequate levels of both the neurotransmitters serotonin and gamma-aminobutyric acid (GABA). Balanced levels of these 2 neurotransmitters are factors in a healthy inflammatory cascade. Serotonin is known to modulate function for both the innate as well as adaptive immune systems. Serotonin can upregulate monocytes and lymphocytes and influences the secretion of cytokines. Additionally, in the presence of serotonin, smooth muscle cells produce interleukin. Interleukin 6 (IL-6) is a proinflammatory molecule.37 GABA is the premier inhibitory neurotransmitter in the central nervous system. It is a potent regulator of cytokine secretion known to suppress inflammatory cascade.38
Mood-enhancing conventional medications
While corticosteroids and immunotherapies are first- and second-line conventional options for alopecia, serotonin-modulation medications may take a different tack toward the goal of hair regrowth by modulating HPA and SNS status. Mouse models of alopecia given tianeptine, a serotonin reuptake enhancer (which lowers serotonin levels) and an opioid agonist, have shown improvement in hair growth and thickness, as well as improved hair cycle function.39 In this case, lowering serotonin may help decrease inflammation response. Conversely, though, in a study of 12 alopecic cats with psychogenic alopecia, after physiologic causes of hair loss were ruled out, these were treated with 3 different psychiatric medications. Out of the 5 cats treated with clomipramine, a tricyclic antidepressant known to increase serotonin, 3 demonstrated hair growth. Two of the 3 treated with amitriptyline (which allows for more available serotonin and norepinephrine) showed benefits, while only 1 of 4 treated with buspirone (an agonist of serotonin) had regrowth.40
A small, 6-month, double-blinded study of 13 patients found that 5 of 7 patients treated with imipramine (which acts to increase acetylcholine, dopamine, norepinephrine, and serotonin) demonstrated significant regrowth versus none in the placebo group.41 In another double-blinded, randomized trial on alopecic patients with anxiety or depressive disorder, the serotonin reuptake inhibitor paroxetine (which employs the opposite mechanism of tianeptine discussed above) was given to 8 patients, while 5 patients were given a placebo for 3 months. Both groups enjoyed similar reductions in symptoms. Two patients in the paroxetine group had complete hair regrowth, while 4 exhibited partial benefits, with only 1 placebo patient having a near regrowth of hair. Interestingly, all patients recounted a stressful life event in the 6 months preceding the onset of alopecia.42 In these cases, we are seeing improved response to either increasing or decreasing serotonin levels. It is our opinion that there may be a therapeutic balance for optimal hair growth, likely mediated via both the kynurenine pathway and sympathetic nervous system, that may be responsible for whether raising or lowering serotonin might be best for a given individual. And this is already seen regarding the ability of these medications to help or exacerbate depression in various individuals. While the effect of serotonin modulation may be unclear, it seems benzodiazepines (which raise GABA) do not contribute to baldness.43 Additionally, studies have shown improvement in alopecia using benzodiazepine medications.44 More than likely, it may not be solely the direct response by neurotransmitters on immune function that is affecting the hair loss, but instead the indirect effect of serotonin and GABA modulation is calming the sympathetic nervous system, mitigating the stressful life that contributed to the hair loss.
Sleep disturbances are highly prevalent affective disorders.45 Lack of sleep will contribute to overactive inflammatory responses, likely due to sympathetic activation.46 According to a recent retrospective cohort study looking at 25,800 patients with sleep disorders, sleep disorders are considered independent risk factors for alopecia.47
Exercise improves mood48 and balances cortisol49 while lowering inflammation.50 One cross-sectional study of 83 patients with alopecia areata found almost 82% of the subjects did not meet baseline physical activity guidelines. Of these, those with more than 50% scalp hair loss were much more likely to suffer from severe depression, moderate anxiety, or mild stress.51
Hypnotherapy uses deep relaxation and concentrated attention and can improve anxiety-related disorders.52 One study of 21 treatment-resistant alopecia patients using hypnotherapy reported significant improvements in anxiety and depression. Twelve enjoyed significant improvements in hair growth. Four of these had complete loss of scalp hair.53 Known to reduce immunologic dysregulation, hypnotherapy is also well known to balance the sympathetic and parasympathetic systems and raise GABA.54
Healthful diets can modulate inflammatory responses that contribute to hair growth challenges. One diet that stands out for both lowering anxiety and supporting hair growth is the Mediterranean diet. This diet is inversely correlated with the promotion of affective orders and psychological distress.55 A meta-analysis of 24 studies revealed that both the Mediterranean diet and other diets encouraged hair growth in androgenetic alopecia. In the Mediterranean diet, it is likely that the intake of phytonutrients such as polyphenols has both anti-inflammatory and antioxidant effects that can inhibit reactive oxygen species production which in turn inhibits transforming growth factor beta 1 (TGFβ1) secretion, allowing robust growth of hair. Also, in this meta-analysis, it was suggested that a high mercury intake from fish may trigger both alopecia areata and telogen effluvium.56
Electroacupuncture uses stainless steel needles stimulated with electric current at specific acupuncture points. ST36 is a point well-known in traditional Chinese medicine to calm inflammation.57 Electroacupuncture on ST36 and other points showed benefits in mood in a small trial of depressed patients given acupuncture 5 times a week, with effects similar to the antidepressant fluoxetine.58 Working with C3H/HeJ mice, investigators applied electroacupuncture to the ST36 point to reveal a significant decrease in mast cell degranulation around hair follicles and improvement in alopecia areata.59 Mast cell activity likely participates in alopecia by collapsing anagen hair-follicle immune privilege.
Essential fatty acids
Essential fats provide pleiotropic activity, including anti-inflammatory activity, nerve growth factor production, glucose metabolism, and sedation of the anterior cingulate and prefrontal cortices.60,61 Essential fatty acids have been shown in murine studies to calm the HPA axis62 and upregulate anagen activating pathways.63 One randomized, comparative study assessed 120 women given 460 mg fish oil and 460 mg blackcurrant seed oil (a source of gamma-linolenic acid), along with 5 mg vitamin E, 30 mg vitamin C, and 1 mg lycopene, daily for 6 months or no product. In the treated subjects, telogen percentage was decreased, and both hair coverage and density improved.64
Deficiency in zinc, a mineral cofactor, contributes to emotional instability and depression.65 Zinc is also recognized to attenuate hair follicle regression as well as encourage hair follicle recovery.66 One evaluation looked at 312 patients with different kinds of alopecia, including telogen effluvium, male- and female-patterned hair loss, and alopecia areata. In this review, all alopecic groups had statistically significant lower levels of zinc versus controls.
While clinical trials looking at zinc for hair growth are scant, some small studies do suggest supplementation provides a therapeutic benefit.61,62 Zinc is also necessary in the development of a key player in the adaptive immune system: leukocytes.67
Lavandula angustfolia (lavender) and essential oils
Lavender is well-known for its anti-anxiety effects, with double-blinded studies clearly supporting the use of this botanical over placebo68 as well as producing equivalent effects as lorazepam in clinical studies for anxiety.69 Lavender is known to contain linalool, a monoterpene that can be easily inhaled to increase blood levels and create a relaxation effect.70 Animal studies are starting to suggest lavender may also positively affect hair growth. C57BL/6 mice models given topical lavender oil revealed a robust hair-growth–promoting effect, as the oil was shown to promote the anagen phase and delay the transition to the catagen phase. The authors showcased that this effect was induced by mast cell activity modulation.71
A 7-month, double-blinded, randomized, controlled trial of 86 subjects diagnosed with alopecia evaluated the calming and hair-growing effect of essential oils. Volunteers were either given a scalp massage with thyme, rosemary, lavender, and cedarwood in a mixture of jojoba and grapeseed carrier oils, or they received the same scalp massage with only carrier oils. Nineteen of 43 patients in the active group showed clear improvements, compared to only 6 of 41 patients in the control group.72
Withania somnifera (Ashwagandha)
Ashwagandha, or as it is most commonly referenced, Withania somnifera, is a well-known stress adaptogen, traditionally used in the Ayurvedic and Eastern systems of medicine. It is touted for its ability to support balanced mood via modulating cortisol levels to reduce anxiety and stress response.73 Additionally, it has been clinically shown to improve immune response via its active withanolides constituents.74,75 A number of withanolides have demonstrated significant immunomodulatory effects, depending on the compound. Extracts isolated from Withania coagulans have demonstrated immunosuppressive effects similar to prednisolone, by inhibiting T cell proliferation and Th1 cytokine production, acting to reduce inflammation.76 This may theoretically reduce the immune impact on the hair follicle to help preserve immune privilege. A case report of a 57-year-old female with adrenal hyperplasia who self-treated with Withania somnifera showed documented improvements in cortisol parameters as well as a clear reduction in hair loss.77
Rhodiola rosea (Rhodiola)
Rhodiola, or Rhodiola rosea, has been traditionally used to fight stress, fatigue, and depression. It is another well-known stress adaptogen, key in supporting healthy levels of cortisol production. The stress-protective effects of Rhodiola lie in mediation of stress-response products reducing serum levels of corticotropin-releasing hormone (CRH) and cortisol and downregulating the expression of gene C-FOS, a key genetic component of inflammatory response and release of pro-inflammatory cytokines. Additionally, the bioactive salidroside, a glucoside compound extracted from rhodiola, exerts an anti-inflammatory effect by directly inhibiting the production of proinflammatory cytokines tumor necrosis factor alpha (TNF–α), interleukin 1 beta (IL-1β), and IL-6.78 While there are no known studies of rhodiola that show benefits in alopecia, it may be worth considering in a stress-modulating treatment.
The immune system is integral to maintaining proper systemic function, ensuring appropriate protection from physiological harm and maintaining homeostasis. Stress has been shown to elicit both systemic and local pathological implications on the body, including those leading to dysfunctions of the immune system. Mounting evidence suggests that stress can impose a significantly detrimental effect on immune privilege, which can damage the hair follicle and contribute to hair loss. Collapse of immune privilege is propagated by multiple factors secondary to the stimulus of chronic stressors, including dysregulation of the HPA axis and immune response, leading to the induction of inflammatory cascades and injury to formerly protected systems such as the hair follicle. Certain medications may help assuage the stress-induced immune effects leading to alopecia. Notably, there are also specific natural therapeutics such as sleep support, exercise, Mediterranean style diet, hypnotherapy, electroacupuncture, and supplements (essential fats, zinc, lavender, ashwagandha, and rhodiola) that may be of value to address the underlying factors of stress by calming HPA activation, as well as balance inflammatory cascades to improve anagenic activity, to restore immune privilege, and ultimately improve hair growth.