Literature review

Cortisol modulators


According to some studies14, long-term phosphatidylserine (PS) can modulate stress induced stimulation of the HPA axis and buffer the over‑production of cortisol and ACTH. In one double‑blinded study15 using 800 mg of PS daily versus placebo for 2 weeks, researchers were able to show decreased post-exercise cortisol levels, less muscle soreness, and less psychological depression usually associated with overtraining. Another study16 using IV PS demonstrated blunting of ACTH and cortisol response to physical stress. Some studies show that the response is dose-dependent and not as prominent when a dose of less than 800 mg is used. However, another study17 did show a significant decrease in cortisol peaks for doses of 600 mg.


L-Theanine is an amino acid that increases dopamine, serotonin, and glycine in the brain. One cup of black tea has approximately 20 mg of L-Theanine. Low-dose L-Theanine can also have excitatory effects, suggesting a dose-dependent action. It can also induce alpha brainwave activity, which correlates with a relaxed state of the brain. Another study18 demonstrated that theanine administration caused a dose-dependent relaxed, yet alert, state of mind without sedation, beginning approximately 40 minutes after oral dosing. Another study19 determined that low doses of L-Theanine can also induce alpha wave activity on electroencephalography (EEG). In another study20, stress was induced by a math test and the effect was measured by heart rate and salivary immunoglobulin A IgA levels. It was demonstrated that the acute stress effect was reduced by using 200 mg of theanine.

Fish oil

Fish oil supplementation of 7.2 g daily has been shown to abolish the cortisol and adrenaline spike. In addition Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA) are also seen to lower noradrenaline in students experiencing stress as a result of exams.

Alpha-lipoic acid

Lipoic acid has been shown21 to prevent the accumulation of catecholamines in cardiac tissue secondary to stress and enhance elimination of catecholamine degradation products. Alpha-lipoic acid can partially restore hydrocortisone-induced suppression of T-cell activity.


Gamma-aminobutyric acid

GABA is a major inhibitory neurotransmitter. It mediates pre-synaptic inhibition of primary afferent fibres in the motor system. GABA acts like a ‘brake’ during times of runaway stress. Low GABA levels are associated with a number of psychiatric and neurological disorders; including anxiety, depression, and insomnia. Anti‑anxiety medications such as benzodiazepines work on GABA receptors, inducing relaxation.

[pull_quote align=”right” ]GABA is a major inhibitory neurotransmitter. It mediates pre-synaptic inhibition of primary afferent fibres in the motor system. GABA acts like a ‘brake’ during times of runaway stress. [/pull_quote]A small preliminary study22 of six subjects found gabapentin (structurally similar to GABA; increases brain GABA levels) to be effective for panic disorder. Natural therapies that produce relaxation also act, at least in part, by enhancing GABA levels. A controlled pilot study23 found brain GABA levels were significantly increased after a single 60 minute yoga session compared with a 60 minute reading session. Another study24 found valerenic acid, an active component of valerian, modulates GABA receptors. In a study25 comparing veterans with or without post-traumatic stress disorder (PTSD), the veterans with PTSD demonstrated reduced GABA–benzodiazepine receptor binding, demonstrated by positron emission tomography (PET) scan.

On an EEG, alpha waves are generated in a relaxed state, while beta waves are seen in stressful situations that make mental concentration difficult. Therefore, the ratio of alpha-to-beta waves is used as an indication of relaxation and better concentration. In general, the greater the alpha-to-beta ratio, the more relaxed and alert the person is. GABA produced significant effects on both increasing alpha waves and decreasing beta waves, resulting in a highly significant increase in the alpha‑to-beta wave ratio.

GABA receptors are highly expressed in the thalamus, a region of the brain involved with sleep processes. GABA-agonist drugs, such as Ambien (zolpidem) and Restoril (temazepam), are sedatives used to treat insomnia. The synthetic GABA-like drug gabapentin that increases brain GABA levels has been found to improve sleep disturbances associated with alcohol consumption. Owing to its relaxation effects, GABA may be considered as a sleep aid.


L-tryptophan, a large neutral amino acid essential for human metabolism, is the metabolic precursor of serotonin (a neurotransmitter), melatonin (a neuro‑hormone), and niacin (vitamin B3). It improves sleep latency. Even at low doses, it has been found to improve stage IV sleep and improve restfulness in obstructive sleep apnoea. It does not limit cognitive performance or inhibit arousal from sleep. 5-Hydroxytryptophan (5-HTP) acts primarily by increasing central nervous system (CNS) levels of serotonin. Other neurotransmitters and CNS chemicals, such as melatonin, dopamine, noradrenaline, and beta-endorphin, have also been shown to increase following oral administration of
5-HTP26–28. The decarboxylation of 5-HTP to serotonin is dependent on the presence of the active form of vitamin B6, pyridoxal 5’-phosphate (P5P), while the further conversion to melatonin requires S-adenosyl-L-methionine (SAMe). Owing to its enhancement of serotonin and then melatonin, 5-HTP benefits sleep disorders.


In humans, sustained and continuous work periods exceeding 12 hours, and often involving sleep loss and fatigue, can result in increased stress and anxiety, mood deterioration, and decreased performance. Studies suggest supplementation with tyrosine might, under circumstances characterised by psychosocial and physical stress, reduce the acute effects of stress and fatigue on task performance. Stress depletes the brain reserves of the catecholamine neurotransmitters noradrenaline and dopamine in animals; and it appears that depletion, especially of noradrenaline, is closely related to stress-induced performance decline in animals. Administration of tyrosine, an amino acid precursor of catecholamines, alleviates depletion of brain catecholamines and stress-induced decline in performance in these animals.

In humans, tyrosine supplementation appears to work in the same manner, alleviating stress-induced decline in nervous system noradrenaline, and subsequently enhancing performance under a variety of circumstances, including sleep deprivation, combat training, cold exposure, and unpleasant background noise.

According to one study29 tyrosine 150 mg/kg administration was able to offset decline in performance and vigilance for 3 hours in sleep-deprived candidates. In another study30 on cadets on a military combat training course, the group supplied with a tyrosine-rich drink performed better in tasks involving memory and tracking versus the group receiving placebo. Tyrosine supplementation has also been shown to decrease systolic blood pressure.

In another study31 that evaluated the negative influence of acute exposure to cold on short‑term memory, it was found that tyrosine supplementation returned performance to the level found at ambient temperature. Another study demonstrated that tyrosine (100 mg/kg) supplementation improved mood and memory in individuals subjected to a 4.5-hour exposure to cold and hypoxia. Individuals taking 300 mg/kg of tyrosine better resisted stress than placebo.

In a study in which subjects were given tyrosine while performing a number of stress‑sensitive tasks, while concurrently exposed to stress-inducing 90 dB background noise, tyrosine improved performance on two cognitive tasks and transiently decreased diastolic blood pressure. Tyrosine (100 mg/kg) also enhanced measured aspects of cardiovascular and cognitive performance in subjects exposed to stress-inducing low negative-pressure sessions (-50 mm Hg) for a maximum of 30 minutes.