Re: GABA 임상활용 : 고혈압, 스트레스, 성장호르몬 자극

[현준]

Oketch-Rabah HA, Madden EF, Roe AL, Betz JM. United States Pharmacopeia (USP) Safety Review of Gamma-Aminobutyric Acid (GABA). Nutrients. 2021 Aug 10;13(8):2742. doi: 10.3390/nu13082742. PMID: 34444905; PMCID: PMC8399837.

Abstract

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Gamma-amino butyric acid (GABA) is marketed in the U.S. as a dietary supplement. USP conducted a comprehensive safety eval‎uation of GABA by assessing clinical studies, adverse event information, and toxicology data. Clinical studies investigated the effect of pure GABA as a dietary supplement or as a natural constituent of fermented milk or soy matrices. Data showed no serious adverse events associated with GABA at intakes up to 18 g/d for 4 days and in longer studies at intakes of 120 mg/d for 12 weeks. Some studies showed that GABA was associated with a transient and moderate drop in blood pressure (<10% change). No studies were available on effects of GABA during pregnancy and lactation, and no case reports or spontaneous adverse events associated with GABA were found. Chronic administration of GABA to rats and dogs at doses up to 1 g/kg/day showed no signs of toxicity. Because some studies showed that GABA was associated with decreases in blood pressure, it is conceivable that concurrent use of GABA with anti-hypertensive medications could increase risk of hypotension. Caution is advised for pregnant and lactating women since GABA can affect neurotransmitters and the endocrine system, i.e., increases in growth hormone and prolactin levels.

GABA 보충제 섭취시 생길 수 있는 심각한 부작용은 보고되지 않았음

GABA 복용 용량에 대한 연구는 높은 용량으론 1일 18g 씩 4일간 , 장기간으론 1일 120mg씩 12주간 복용하고 큰 이상이 없었던 걸로 보고되어있음.

동물실험에서는 1g/kg/1일로 장기간 투여했지만 유의미한 독성은 발견되지 않았음

3.1. Natural Sources of GABA

GABA is ubiquitous in plants, where it is primarily synthesized from glutamic acid via the glutamate carboxylase enzyme [21]. It has been shown to increase significantly in plants following environmental and other stresses, such as drought, increased salinity, wounding, hypoxia, infection, and germination. A number of edible and medicinal plants contain GABA at different levels. For example, in tomato fruit (Solanum lycopersicum), it accumulates as the fruit matures until the ripening stage, when its catabolism is accelerated [22]. A study of GABA content of select uncooked foods found that some contain modest amounts of GABA. Brown rice germ (718 nmol/g), sprouted cereals (300–400 nmol/g), and spinach (414 nmol/g) had the highest levels of GABA [23,24]. Other studies demonstrated similar findings in sprouted or germinated beans, including adzuki beans (Vigna angularis (Willd.) Ohwi and H. Ohashi) [25], lupin (Lupinus angustifolius L.) [26], and soybean (Glycine max L.) [27] when compared to ungerminated beans. Similarly, grains, such as oats (Avena sativa L.), wheat (Triticum aestivum L.), and barley (Hordeum vulgare L.), have been shown to contain GABA [28]. In some fermented foods, GABA occurs at much higher levels. The traditional Korean food kimchi is reported to contain 2667 to 7225 nmol GABA/g [29], while Japanese green tea leaves have been reported to contain 9697–19,395 nmol of GABA/ g on a w/w basis [30]. Other lactic acid-fermented foods, such as cured meats and cheeses, also contain high amounts of GABA [31]. Humans have been exposed to GABA in fermented foods since people started consuming such foods.

GABA는 식물에 많이 들어있다.

GABA는 glutamate carboxylase enzyme에 의해 glutamic acid 로부터 합성된다.

GABA가 많이 들어있는 식품으론 발아현미, 발아곡물, 시금치 등이 있고

발효음식에는 더욱 많이 들어있다. 한국의 김치, 일본의 녹차

3.3. Metabolism of GABA

In animals, GABA is synthesized from glutamate via the GABA shunt pathway illustrated in Figure 3 [39]. The synthesis is catalyzed by the enzyme L-glutamic acid decarboxylase (GAD) with the help of pyridoxal phosphate, the active form of vitamin B6, as the co-factor. GABA is metabolized by gamma-aminobutyrate transaminase into an intermediate metabolite, succinate semi-aldehyde, which can then be reduced to gamma-hydroxybutyrate or oxidized to succinate and eventually converted to CO2 and water via the citric acid cycle [39].

Figure 3
In the GABA shunt, GABA is synthesized from glutamate in a process catalyzed by GAD. GABA is metabolized by GABA-T into succinate semi-aldehyde, which is then reduced to gamma-hydroxybutyrate or oxidized to succinate and eventually converted to CO2 and water via the TCA cycle. GAD, glutamatic acid decarboxylase; GABA-T, GABA transaminase; SSA, succinic semialdehyde; SSA-DH, succinic semialdehyde dehydrogenase; TCA cycle, tricarboxylic acid cycle. Green, enzymes; Orange, cofactor.

체내에선 GABA는 Glutamate로부터 합성된다.

작용하는 효소는 GAD = L-glutamic acid decarboxylase

보조인자는 비타민 B6

6.2. Effects of GABA on Blood Pressure

A double blind, placebo-controlled, parallel-design study examined the tolerability of GABA-enriched food in 177 hypertensive men and women who were not undergoing treatment for the hypertension [74]. Participants were randomly allocated to receive 8 mL of one of the following: low-salt soy sauce containing 120 mg of GABA, low-salt soy sauce (control), or regular soy sauce (control), daily each for 12 weeks. At the end of the study, the average systolic blood pressure (SBP) was lower by 4.6 mm Hg (p < 0.05) in the GABA-treated group compared to the control groups. Diastolic blood pressure (DBP) was not changed in all treatment groups, and average BP was above normal in all groups at the end of the study with no difference between groups. Additionally, significant changes were observed in lactate dehydrogenase (LDH), albumin, urea nitrogen, and calcium, although the changes were below a 10% difference and were considered within the historical reference range and thus clinically irrelevant. Incidence of adverse effects were similar between groups and not considered due to the GABA [74].

GABA는 혈압을 낮추는 효과가 있다.

6.3. Effects of GABA on Growth Hormone Levels

GABA has been reported to increase serum GH levels and has been considered an ergogenic aid. Many sports supplements include GABA as an ingredient.

GABA는 성장호르몬 수치를 높인다.

6.4. Effect of GABA on Sleep and Stress

A prospective, randomized, double-blind, and placebo-controlled trial eval‎uated the effects of GABA extracted from unpolished rice germ for improving sleep quality in 40 patients with insomnia [59]. Participants took 300 mg GABA or 300 mg maltodextrin (placebo) daily for 4 weeks. The 300-mg dose was selected based on an earlier study in which patients reported their subjective insomnia improved more with 300 mg of GABA compared to 150 mg [75]. Participants filled out a sleep questionnaire and underwent polysomnography before and after the study. After 4 weeks of GABA supplementation, sleep latency was significantly decreased (p = 0.001), and sleep efficacy was significantly increased (p = 0.018) compared to placebo. Three out of 10 subjects given GABA had either abdominal discomfort, headache, or drowsiness, which were classified as mild to moderate. The authors concluded that GABA supplementation may improve sleep quality without serious adverse effects [59].

In a study that eval‎uated the effects of GABA on heart rate variability and stress, there was no mention of adverse or untoward effects in healthy volunteers given a GABA-enriched oolong tea (2.01 mg of GABA per 200 mL tea, as analyzed using HPLC). Consumption of GABA-enriched tea was associated with an improved heart-rate variability and a significant decrease in the immediate stress score compared to volunteers given regular tea (not enriched with GABA). Adverse events were not reported as being monitored in this study, and the authors recommended that safety and tolerability of GABA intakes should be investigated in future studies [68].

GABA는 수면의 질을 개선시키고 스트레스 지수를 낮춘다.

6.6. Adverse Events Associated with GABA Intake

The clinical studies reviewed above did not associate any serious adverse events with GABA intake. Some adverse effects that were reported following intake of GABA included abdominal discomfort, headache, drowsiness, and transient burning sensation in the throat; these effects were classified as mild to moderate [50,59,61,67,75]. No case reports of AEs associated with GABA were found in the literature. Searches were conducted in various government reporting portals as described below.

GABA 섭취와 관련된 심각한 부작용은 보고되지 않았다.

GABA 섭취후 경미한 부작용으로 몇개의 증상이 보고되었다.

복부 불편감, 두통, 졸음, 목구멍의 화끈함

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9. Potential Interactions of GABA with Drugs

Some clinical studies [57,110,111] and animal experiments [110,112,113,114] have shown that ingestion of GABA may cause a drop in blood pressure, and thus it is conceivable that GABA may interact with antihypertensive medicines, such as propranolol, metoprolol, etc. GABA has been reported to cause a BP decrease of approximately 10%, but the effect was transient, with BP returning to baseline within a few days after stopping the GABA [74].

GABA 복용시 혈압이 약 10% 정도 감소한다. 다만, 이 효과는 일시적이다

Evidence from at least one clinical study shows that the bioavailability of GABA in the brain is improved significantly when taken concurrently with phosphatidylserine, and thus GABA may interact with medicines used to treat epilepsy [115]. It has been suggested that GABA supplementation could affect the enteric nervous system and possibly stimulate the endogenous production of GABA across the BBB [116,117].

GABA와 phosphatidylserine을 같이 먹으면 뇌의 GABA 사용률이 높아져

뇌전증 치료에 도움이 될 수 있다.

The oral administration of a mixture of GABA and L-theanine (100/20 mg/kg) to ICR mice was found to decrease sleep latency and prolong sleep duration compared to GABA or L- theanine treatment alone following an intraperitoneal injection with sodium pentobarbital. The authors concluded that GABA and L-theanine had a synergistic effect on the sleep behavior of mice [118].

GABA와 L-theanine 복합물은 수면지연을 줄이고 수면지속시간을 늘려줄 수 있다.

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시중 판매제품 

GABA 500mg + 비타민 B6

1일 2회~3회 투여권장

-> 1일 1g~1.5g GABA 섭취

GABA 100mg 캡슐

1회 1~2캡슐 1일 3회 복용

-> 1일 복용량 0.3g ~ 0.6g 섭취

GABA 500mg 캡슐

1회 1캡슐 1일 1~2회 복용

-> 1일 복용량 0.5g ~ 1g 섭취