Cortisol, the Stress Response, and Metabolic Markers of Stress

Research has long depicted the importance of the hypothalamic-pituitary-adrenal (HPA) axis  in mediating the stress response and maintaining physiologic homeostasis. Chronic stress propagates a systemic cascade of ultimately dysfunctional metabolic events initially intended to be adaptive. HPA dysfunction appears to be a major initiating and contributing factor to this process, eventually giving rise to disruption of the normal, daily cortisol release pattern.

Maladaptive cortisol release patterns can be characterized by excessively high or low cortisol levels, corresponding to overly exaggerated or underdeveloped responses to stress. While hypocortisol has been often characterized as “adrenal fatigue,” this term does not fully account for the complex, multi-step process that results in low cortisol states. Additionally, dismissing hypocortisol as “adrenal fatigue” undermines the body of literature that characterizes hypocortisolism as an adaptive response to stress.

This series reviews the components of the stress response, mechanisms of alterations in cortisol production, and common botanical therapies utilized in mitigating the stress response and protecting the health of the individual.

Physiological Adaptation to Stress

Physiological stress is a threat to homeostasis that occurs in the central nervous system (CNS) and surrounding tissues and organs.₁ It triggers an intricate series of metabolic responses collectively called the “adaptive stress response” that is intrinsically designed to help the body reestablish equilibrium to counteract a perceived “stressor,” whether extrinsic or
intrinsic._1-4

Multiple stress factors may promote dysregulation of the adaptive stress response:

• Duration
• Intensity
• Frequency

These and other lifestyle behaviors can result in a myriad of health problems, thus affecting an individual’s ongoing resiliency or “successful adaption to change.”_1-6 In particular, the brain’s ability to resist the effects of stress plays a central role in determining the integrity of the stress response itself. This integrity level includes whether the stress response remains intact or develops abnormal patterns of reaction over time._1,2,5

Allostasis: Balance in the Stress Response

“Allostasis” is the ability to achieve stability through change. Within the stress response, allostasis relies on a system of healthy interactions across a variety of system components:

• Neuroendocrine, cellular, and molecular components
• Hypothalamic-pituitary-adrenal (HPA) axis
• Autonomic nervous system (ANS)
• CNS and periphery
• Cardiopulmonary system
• Endocrine system
• Immune system
• Gastrointestinal (GI) tract._1-4

When these systems remain resilient and produce a positively coordinated reaction to stress, resiliency and metabolic reserve is maintained and the health of the individual protected.

Allostatic Load: Overwhelming the Stress Response

Chronic activation of the stress system contributes to the “allostatic load,” a term which reflects the total strain on the stress response.₁ Contributors to allostatic load include:

• Major life events
• Trauma
• Abuse
• Work
• Home
• Community
• Lifestyle behaviors (sleep, diet, nutrition, exercise, toxins, and substance abuse)_1-8

If allostatic load overwhelms the body’s ability to compensate, thus degrading allostasis, a number of emotional and physiological manifestations can arise._1-9

These manifestations can be organized into primary, secondary, and tertiary markers (outcomes) of allostatic load. Primary mediators that have a direct response from stress and predictive validity in the context of longitudinal behavioral assessments include:

• Cortisol
• Adrenaline
• Sympathetic and parasympathetic activity
• Pro- and anti-inflammatory cytokines
• Metabolic hormones
• Neurotransmitters and neuromodulators₁₀

Secondary markers are indirect measures of immune system efficacy, a result of the aggregate impact of primary markers, including:

• Waist-to-hip ratio
• Blood pressure
• High-density lipoprotein (HDL) cholesterol
• Cholesterol/HDL ratio
• Glycosylated hemoglobin
• Inflammatory markers (IL-6, C-reactive protein, and fibrinogen)
• Telomere length
• Telomerase activity_1-10

Individuals who experience early life adversity are likely to experience higher levels of oxidative and inflammatory stress (primary markers) resulting in telomere shortening (secondary outcome) or obesity (secondary outcome). These individuals are also at increased risk for depression, diabetes, cardiovascular disease (CVD), and substance abuse._1-10

Tertiary markers result from the extreme values of secondary outcomes due to increased allostatic load. Tertiary mediators include:

• CVD
• Decreased physical activity
• Severe cognitive decline
• Alzheimer’s disease
• Vascular dementia
• Cancer₁₀

The Stress Response Begins in the Brain

The stress response begins in the HPA axis, a collective made up of the paraventricular nucleus (PVN) of the hypothalamus (the anterior lobe of the pituitary gland) and the adrenal gland._1-9 Neurons in the medial parvocellular subdivision of the PVN synthesize and secrete vasopressin (AVP) and corticotropin-releasing factor (CRF), the principal regulator of the HPA axis and the autonomic nervous system (learning, memory, feeding, reproduction).₉

CRF is released in response to stress and binds to the CRF type 1 receptor (CRFR1) on pituitary corticotropes, which activates the cyclic adenosine monophosphate (cAMP) pathway and release of adrenocorticotropic hormone (ACTH) into systemic circulation._1,3,4,9 Circulating ACTH binds to the melanocortin type 2 receptors (MC2-R) in the adreno-cortical zona fasciculata, causing steroidogenesis and glucocorticoid, mineralocorticoid (MR), and androgenic steroid synthesis and secretion._1,3,4,9

Stress-receptive neurons in the brain stem relay sensory information from cranial nerves to the PVN. This sensory information excites large areas of thoracic and abdominal viscera.₉ Projections from the prefrontal cortex and amygdala limbic structures regulate the behavioral responses to stress by releasing catecholamines.₉ The anterior cingulate and prelimbic cortex increase ACTH and glucocorticoid responses to stress._1,2,9

Medial (MeA) nuclei of the amygdala are activated following exposure to “emotional” stressors while central (CeA) nuclei are activated by “physiological” stressors and regulate the HPA axis through intermediary brain stem neurons._1,9,10 The amygdala is a target for circulating glucocorticoids, and CeA and MeA express both GR and mineralocorticoid receptors (MR). In contrast to the effects on hippocampal and cortical neurons, glucocorticoids increase expression of CRF in the CeA and potentiate autonomic responses to chronic stress._1-10

Activation of brain stem noradrenergic neurons and sympathetic and renomedullary circuits further contribute to the body’s response to stressful stimuli including emotion, vigilance, memory, and resiliency._1,3,9,10 Stressful stimuli alter neuronal electrophysiological activity and induce release of norepinephrine and ACTH, anxiogenic-like activity, and immune suppresion._1-10

Metabolic Response to Stress

The metabolic response to acute stress outside of the CNS includes:

• Rapid and strong elevation of plasma concentrations of glucose, insulin, glycerol, and ketone bodies
• Stimulation of adipose tissue lipase by circulating catecholamines
• Activation of the autonomic nervous system via glucagon secretion
• Decrease in triacylglycerol levels_1,4,9

Several neuropeptide systems in the brain are substantially affected by stress, including:

• Norepinephrine
• Epinephrine
• Serotonin
• Dopamine
• Glutamate
• Taurine
• GABA
• Glycine
• Phenylethylamine (PEA)
• Histamine_1-10

Ongoing disruption of neurotransmission can potentially lead to neuropsychiatric symptoms and acceleration of neurotransmitter depletion. The mesoprefrontal pathway is particularly at-risk, thus impacting reward-mediating neurotransmitters and possibly leading to addictive behaviors._1,9,10

Activation of cerebral cholinergic transmission impacts arousal, motivation, and cognition._1,4,9,10 Extracellular levels of glutamate (the major excitatory amino acid transmitter) increase in numerous regions of the brain, while changes in GABA receptor properties can also impact the stress response._4,9,10 

However, several aspects of GABA-ergic neurotransmission may be obscured by endogenous steroid hormone derivatives whose synthesis is increased following stress._4,9,10 These compounds influence several aspects of the behavioral and neuroendocrine response to stress._9-10 Alterations in endogenous opioid neurotransmission are implicated in stress-related endocrine and autonomic responses._9,10

Alterations in the Stress Response

Stress can induce changes in CRH and AVP expression in the PVN, and stress can increase concentrations of ACTH in the systemic circulation. This results in desensitization of pituitary CRH receptors and blunted ACTH release._1-10 This dissociation between CRH hyperactivity and refractory corticotrophin responsiveness is a pathognomonic feature of stress-associated neuroendocrine dysregulation.₁₀

Beyond this, stress drastically affects growth hormone secretion, thyroid axis function, and reproductive function via decreased gonadotropin levels, suppressed gonadal steroids, increased circulating prolactin, disruption of the ovarian cycle, and decreased libido._1-10

Is Hypocortisolism A Protective Mechanism?

While elevated cortisol patterns are well recognized and understood, the process through which hypocortisolism evolves remains ill-defined. Although reduced availability of cortisol may be due to primary dysfunction of the adrenal glands, reductions in biosynthesis of hormones at different levels of the HPA axis likely play a greater role.

Integrity of HPA axis function and predictable patterns of daily cortisol release are essential for maintaining homeostasis during periods of chronic stress. Much of the available research on hypocortisolism and stress-induced disease has focused on disturbances in these mechanisms.

One developmental model presents hypocortisolism as developing via hypoactivity of the HPA axis after prolonged periods of chronic stress. After an initial period of HPA axis hyperactivity and hypercortisolism, hypocortisolism may ultimately develop as a type of maladaptive over compensation. This process involves the self-preservation mechanisms designed to protect metabolic machinery – the brain in particular – from the deleterious effects of persistent cortisol elevation.₁₂

An increase in hypothalamic release of CRF with subsequent adaptive down-regulation of CRF receptors at the level of the pituitary gland could also be involved in hypocortisolism. Although this has been demonstrated in animal studies, replication of such a process in human subjects has been difficult but may be indirectly implied. Some have postulated that an increase in the sensitivity of the HPA axis to hypercortisolism induces negative feedback control on further release of stimulating hormones, causing hypocortisolism.₁₃

The Neurodegenerative Model of Hypocortisolism

There is a central mechanism for low cortisol states via alterations in the CA1 and CA3 regions of the hippocampus. The hippocampus plays a central role in regulating the entirety of the stress response. While a primary purpose of this critical brain structure is to consolidate memories and assign importance to those memories, the hippocampus also maintains the highest concentration of cortisol receptors in the brain.₁₄

The hippocampus is therefore particularly vulnerable to high-stress states, with cortisol potentially playing a catabolic or damaging role that can lead to alterations in both function and structure of this brain center. The hippocampus serves a regulatory role to the HPA axis, and a damaged connection between hippocampus and HPA axis can lead to low cortisol states. Neuroinflammation and neurodegeneration associated with damaging effects of cortisol in the brain highlight the need for therapeutic strategies that limit injury of cortisol to key brain areas, reduce inflammation, and induce neurogenesis.

Intrinsic dysfunction of the adrenal gland is also linked to hypocortisolism, but data describing the link between intrinsic adrenal dysfunction and hypocortisolism is overall limited in comparison to other mechanisms. After reviewing studies on the effects of chronic stress on the adrenal glands, scientists conclude that “there is a considerable body of evidence of reduced adrenal gland activity and reactivity in human subjects living under conditions of chronic stress.”₁₅

Regardless of the underlying process, some believe the maladaptive physiological changes induced by hypocortisolism may actually be protective, to ensure survival: “Hypocortisolism is a protective response dampening chronic HPA axis activity and thereby reducing the damaging effects of the glucocorticoid response to daily hassles at the expense of symptoms such as high stress sensitivity, pain, and fatigue”.₁₈

In further support of this theory, researchers have observed comparable groups of pregnant women and found those with lower morning cortisol levels had higher daily stress compared to their counterparts experiencing normal or low daily stress loads. It could be that hypocortisolism is a counter-regulatory protective mechanism designed to protect placental CRF from maternal cortisol.₁₈

Hypocortisolism-enhanced stimulation of the immune system may be protective as well. In individuals suffering from recurrent or ongoing infectious assaults, reduced glucocorticoid signaling impairs the normally adaptive inhibitory mechanisms thereby promoting the body’s ability to mount adequate retaliatory defenses. The term “sickness response” was coined to describe the anorexia, fatigue, anhedonia, hyperesthesia, and concentration difficulties often accompanying the body’s response to infection via elevated immune activity.₁₉ 

Sickness response results from the body’s adaptive attempts to ration and prioritize its defenses to better eliminate the pathogen.₂₀ Many symptoms of the sickness response mimic those of stress-related bodily disorders, and an association between hypocortisolism-induced fibromyalgia (FMS) and the sickness response has been observed.

Hypocortisolism has been linked to fibromyalgia, post-traumatic stress disorder (PTSD), irritable bowel syndrome (IBS), lower back pain (LBP), burn-out, atypical depression, chronic pelvic pain (CPP), chronic fatigue syndrome (CFS), insomnia, and degenerative neurological diseases._2-7 Damaging effects on the immune system occur due to increased levels of pro-inflammatory cytokines and natural killer (NK) cells and T cells, which lower resistance to inflammatory and infectious diseases._1-7

Breast cancer patients demonstrate significant post-treatment exhaustion and have been shown to have significantly altered HPA axis activity in combination with elevated IL-6 levels, flattened cortisol curves, increased mortality, and metastases. Furthermore, the more flattened the cortisol curve is, the worse the prognosis and the earlier the mortality.

Additional studies have found elevations in interleukin-1β, natural killer cells, antinuclear autoantibodies, thyroid antibodies, and prostaglandins in patients with PTSD, in patients with intrusive traumatic memories, in sexually abused girls, and in patients with CFS, FMS, and chronic pelvic pain respectively.

The hypocortisol state also permissively allows an increase in sympathetic nervous system and catecholamine activity since normal cortisol-mediated suppression is lacking. Increased levels of catecholamines have been observed in patients with both PTSD and FMS.

Furthermore, exaggerations in sympathetic tone, in conjunction with underlying hypocortisolism, further fuels the production of pro-inflammatory cytokines. Associations between insulin resistance, obesity, diabetes, osteoporosis, mood disorders, and chronic pain have been described in patients with elevated levels of cytokines, particularly interleukin-6.

Alterations in rhythmicity of cortisol release have been associated with various negative outcomes, including tumor growth, early mortality in cancer, obesity, and disrupted glucose metabolism. Increased coronary artery calcification and metabolic syndrome have also been linked to circadian abnormalities in cortisol, particularly flattened cortisol curves.

Measuring the Stress Response

Emerging metabolic measures of stress biomarkers assist in evaluating the complex, multi-system, brain-body biological interactions that occur. These biomarkers can predict the risk of disease as well as the response to proposed interventions that can impact mental and physical wellness for a lifetime.₁₀

One of the key features of the HPA axis is its circadian rhythm that results in a predictable daily cortisol secretion pattern, whereby cortisol levels are naturally highest just before awakening, and decline over the course of the day.₂

The preferred method for measuring the stress response is a single-day, four-point cortisol test, with the most important measurements being the first morning cortisol or cortisol awakening response (CAR) measured 30 to 40 minutes after awakening and last sample prior to bedtime.₂

Clinicians may ask patients to refrain from exercise on day of testing to avoid mis-diagnosis of hypercortisolism or diurnal dysrhythmia.₂ CAR is used significantly more than the overall daily salivary cortisol to define stress-induced HPA axis abnormality as a miniature “stress test” as it is influenced by overall HPA reactivity and a person’s anticipation of stress.₂ A blunted cortisol response upon wakening is a sign of burnout or chronic fatigue, while higher CAR is can be indicative of depression.₂ Testing should be done on a “normal” day of anticipated stress.₂

Additionally, common abnormal diurnal patterns include persistently elevated cortisol throughout the day, hypercortisolism, and conversely abnormally low cortisol, or hypocortisolism.

Both hypercortisolism and hypocortisolism have been associated with a variety of symptomatic and clinical states, but hypocortisolism is thought to represent a more “injured” stress response and higher risk for morbidity and mortality overall, likely due to releasing of the immune response yielding higher baseline levels of inflammation.

Botanicals for Stress

Adaptogens

“Adaptogens” are a diverse group of herbs that restore overall balance and functioning of the body as a whole through normalizing unbalanced physiological processes: stimulation, relaxation, and improving focus and immune function. These herbs have been shown to clinically reduce self-reported stress, improve mood and energy, and strengthen the immune system.

Adaptogens are often particularly helpful in stress-related conditions due to their shielding effects on the brain, immune system, and cardiopulmonary systems. Some, such as ginseng, ashwagandha, and rhodiola, are specifically neuroprotective by blunting the impact of cortisol within the central nervous system by reducing neuroinflammation and even encouraging repair.

Astragalus (Astragalus membranaceus): Enhances mental and physical performance and learning ability; addresses stress and fatigue; provides resistance to cancer and diabetes, immune function, chemoprotective, increase oxygen to tissues

Ashwagandha (Indian ginseng, Poison Gooseberry, Winter Cherry): Strengthen immunity to colds and infections; improve physical and athletic ability; increase vitality, male fertility, and libido; regulate blood sugar; antioxidant; antibiotic; anti-inflammatory; rejuvenating; astringent; anti-anxiety; anti-tumor; diuretic; insomnia; reduce cholesterol; address arthritis; address asthma, leukoderma, bronchitis, backache, fibromyalgia, menstrual problems, hiccups, and chronic liver disease; balances cortisol; supports HPA axis; boosts thyroid hormones

Bacopa (Bacopa monniera): Supports cognitive function and concentration; addresses fatigue, anxiety, and epilepsy; antioxidant

Chaga mushroom: Strongest anti-cancer mushroom with an epochal effect in breast, liver, uterine, and gastric cancer; addresses hypertension and diabetes; addresses tuberculosis (TB) of the bones; strengthens immune system; anti-inflammatory; anti-ulcer; anti-tumor; supports DNA repair; anti-mutagenic

Cordyceps (Cordyceps sinensis): Immunosuppresive, anti-aging, antioxidant, decreases pro-inflammatory monoamine oxidase and lipid peroxidation activity, liver and lung protection (increase oxygenation), asthma, bronchitis, chemoprotective, anti-cancer, chronic renal failure, atherosclerosis, antiarrhythmic effects

Eleuthero root or Siberian ginseng (Eleutherococcus senticosus): Invigorate qi (chi or energy) or endurance, strengthen immune system, memory, chemoprotective, DNA repair, anti-inflammatory, normalize body function, particularly kidney, spleen and heart meridians, radiological protection, anti-cholesterolemic, antioxidant, angina, headache, insomnia, poor appetite, stress, fatigue, HPA-axis dysfunction

Licorice (Glycyrrhiza glabra): Adrenal stress, expectorant, phytoestrogen effects, food sweetener, reduces cholesterol manufacturing, antiviral

Holy basil (Tulsi, Ocimum tenuiflorum or Ocimum sanctum): Enhance body’s natural response to physical and emotional stress, reduce bloating and gas, antioxidant, support healthy adrenal function, cortisol release and immunity, radiation protection, lipid balance, blood sugar regulation, anti-inflammatory (COX-2 inhibitor), cancer prevention, slow age-related memory impairment, lower cholesterol

L-theanine: Found in green tea, induces relaxation through increased dopamine and serotonin, and improves sleep quality

Mastic (Pistacia lentiscus): Adrenal stress, expectorant, food sweetener, H. pylori infections, oral health/cancer, phytoestrogen effects

Mucuna pruriens (Cowhage, Velvet bean): Lower stress as a source of L-DOPA the precursor for dopamine, neuroprotective, Parkinson’s disease, antioxidant, blood sugar, weight loss, metabolic syndrome, male infertility

Muira Puama (Ptychopetalum olacoides): Neuroprotective, stress, libido, depression, mood

Panax ginseng: Mood, cognition, immunity, antifatigue, protection against mental, physical and environmental stress

Phosphatidylserine (PS)               : Decrease symptoms of mild depression in mood disorders

Rosa majalis: Anti-cancer, anti-oxidant, source for Vitamins A,C,E

Reishi or Lingzhi (Ganoderma lucidum): Mental, physical performance, learning, decrease stress and fatigue), blood pressure stabilizer, antioxidant, analgesic, kidney and nerve tonic, strengthen immune system, anti-inflammatory, anti-viral, anti-tumor, anti-parasitic, liver protectant, blood glucose regulation, chemoprotective

Rhaponticum: Strength or endurance or reduce fatigue, impotence or aphrodisiac

Rhodiola rosea (Golden root, Roseroot, Western roseroot, Aaron’s rod, Arctic root, King’s crown, Lignum Rhodium, Orpin Rose): Adaptogen, strength or endurance, reduce fatigue, mental and physical performance, decrease recovery time, antioxidant, learning, adrenal stress, depression, improve immunity, sleep patterns, mood stability, and motivation, resistance to cancer, type 2 diabetes, cardio-protective

Schisandra (Magnolia vine): Antioxidant, infection-resistant, increase skin health, liver protectant, stress/fatigue, enhance mental and physical performance, learning, adaptogen, improve resistance to cancer and diabetes, improve immune function, chemoprotective

Shiitake (Lentinus edodes): Enhances mental and physical performance, increases learning ability, and decreases stress and fatigue, may improve resistance to cancer and diabetes, immune function, antiviral, chemoprotective

Tongkat Ali (Eurycoma longifolia): Stress and cortisol balance, energy/fatigue, weight loss, erectile dysfunction, testosterone balance, infertility, athletic performance, antioxidant, anti-inflammatory

Valerian (Valeriana officianalis): Insomnia, anxiety, sedation, stress/sleep disorders

Nervines/Tonics

Nervines are a class of botanicals that reduce sympathetic overdrive, anxiety, and irritability by sedating the autonomic nervous system and inducing a sense of calm or relaxation. They can be used during the day to blunt a hyperaroused state, or in the evening for sleep induction.

Avena sativa (Oats): Antidepressant, anxiolytic, nervous system tonic and trophorestorative, nutritional, hypolipidemic (as food), cardiotonic, demulcent, emollient, vulnerary, antispasmodic

Bacopa monniera (Brahmi) Cognition and memory enhancer, nerve and brain tonic, mild anti-convulsant, antioxidant, anti-inflammatory, cardiotonic, vasoconstrictor, bitter, emetic, laxative & diuretic (leaf), aphrodisiac

Borago officinalis (Borage) Leaf: Diuretic, demulcent, emollient, refrigerant, adrenal restorative, galactagogue, expectorant.

Borago officinalis (Borage) Oil: inflammatory modulating, anti-atherosclerotic, anti-platelet, hypolipidemic, atopic dermatitis, dysmenorrhea, PMS, cyclic mastalgia, hypertension and diabetic neuropathy

Centella asiatica (Gotu kola): Strengthens nervous system, function, memory, relaxant, detoxifier, diuretic, topical antibiotic, peripheral vasodilator, anti-rheumatic, vulnerary, venotonic, keratolytic, anti-mycobacterial,  bitter, digestive, anti-inflammatory, laxative,  dermatological builder, connective tissue builder, cellulite, cirrhosis of the liver, keloids and hypertrophic scars, leprosy, scleroderma, varicose veins and venous insufficiency, and wound repair.

Hypericum perforatum (St. John’s Wort): Anti-depressant, anti-inflammatory, antimicrobial, astringent, nervine tonic, topical wound healing (burns)

Verbena officinalis (Blue vervain): Digestive tonic that increases intestinal motility, parasympathomimetic, anti-spasmodic, mild analgesic, nervous system tonic, hepatic stimulant, depression, melancholy

Vinca major/minor (Periwinkle): Astringent, cerebral circulatory stimulant, cytotoxic (anti-cancer), diabetes, glaucoma, stroke, brain trauma, poor memory, disordered thinking

Lavandula officinalis (Lavender): Carminative, nervous system relaxant, sedative, antispasmodic, anti-depressant, anti-septic,  aromatic, uterine stimulant, emmenagogue, diuretic, hypotensive, anti-rheumatic

Humulus lupulus (Hops): Sedative, hypnotic, diuretic, analgesic, topical antibacterial, astringent, antispasmodic, premature ejaculation, restlessness, nervous tension, headache, indigestion, restless leg syndrome, anxiety, phytoestrogen (PMS or menopause-related hormonal imbalances)

Melissa officinalis (Lemon Balm): Nervous system tonic and relaxant, carminative, sedative, diaphoretic, antidepressant, anti-viral, anti-microbial, hyperthyroidism choleretic, antispasmodic, antihistamine, mild analgesic, cardiotonic, hepatic, gout, herpes, rheumatism, neuralgias

Matricaria recutita (Chamomile): Nervous system sedative, antispasmodic, analgesic, anti-inflammatory, antiseptic, carminative, anti-microbial, anti-allergic, anti-ulcer, wound healing, neuralgia, rheumatic and muscular pains

Stachys officinalis (Betony): Sedative, mild diuretic, carminative, aromatic, skeletal muscle relaxant, astringent, alterative, circulatory tonic

Scutellaria laterifolia (Skullcap): Sedative, nervous system relaxant, antispasmodic, anticonvulsant, hypotensive

Passiflora incarnata (Passionflower): Antispasmodic, sedative, hypnotic, vasodilator, cardiotonic, analgesic, anxiolytic, relaxant, diuretic, anti-depressant, insomnia

Tilia europa (Lime flower, Linden tree): Anxiolytic, hypotensive, sedative, diaphoretic, anti-spasmodic, diuretic, emollient, immunomodulator, anti-inflammatory, expectorant, anti-coagulant, mild astringent, peripheral vasodilator

Lactuca virosa (Wild Lettuce): Nervous system relaxant, sedative, analgesic, hypnotic, narcotic, antispasmodic, whooping cough, rheumatism, aphrodisiac

Piper methysticum (Kava-kava): Sedative, nervous system, anticonvulsant, local anesthetic, analgesic, anti-fungal, anti-spasmodic, stimulant, anti-depressant, muscle relaxant, euphoric, anti-inflammatory, diaphroretic, carminative, diuretic, interstitial cystitis, restless leg syndrome, anxiety, cognition