Re: 메틸설포닐메테인(MSM) 식이유황.. 치료효과...2017

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MSM (메틸설포닐메테인, 디메틸설폰) 
1) 제조 기준 
(1) 원재료 및 제조 및/또는 가공: DMSO(디메틸설폭시드)를 사용하여 산화시킨 후 증류, 정제, 여과, 농축 및 결정화 과정을 거쳐 식용 가능한 형태로 만들어야 합니다. 
(2) 기능성 화합물(또는 표지 화합물)의 함량: MSM은 980mg/g 이상 함유되어야 합니다. 
2) 규격 
(1) 외관: 독특한 색과 향, 잡맛과 잡내가 없음 
(2) MSM (가) 반가공 제품: 표시된 양 이상 (나) 최종 제품: 표시된 양의 80~120% 
(3) 중금속 (가) 납(mg/kg): 0.1 이하 (나) 카드뮴(mg/kg): 0.1(c) 수은(mg/kg) 이하: 0.5(d) 비소(mg/kg) 이하: 0.1(4) 대장균군: 음성 
3) 건강기능식품의 전제조건 
(1) 건강기능성 표시: 건강한 관절과 연골 유지에 도움이 될 수 있음 
(2) 1일 섭취량: MSM 1.5~2.0g 
4) 시험 방법 
(1) 외관: 제4장 2-7 외관 시험 방법 
(2) MSM: 제4장 3-67 MSM 
(3) 납, 카드뮴, 수은, 비소: [부록 표 4] 참조 
(4) 대장균: [부록 표 4] 참조

메틸설포닐메탄(MSM)은 인체에 유익한 유기 황 화합물로, 일반적으로 식물성 식품 속에 아주 소량 자연적으로 존재합니다. 다만, 특별히 MSM 농도가 매우 높은 한 종류의 식물이 “MSM이 풍부하다”라고 단정짓기는 어렵습니다. 아래는 이와 관련된 몇 가지 사항입니다.

일반적인 MSM 분포

대부분의 식물성 음식(과일, 채소, 곡물 등)에는 MSM이 미량 존재합니다.

자연 상태에서의 MSM 농도는 보충제로 제공되는 용량(수백 밀리그램 이상)과 비교하면 매우 낮은 수준입니다.

상대적으로 MSM 함량이 높을 가능성이 있는 식물군

일부 연구에서는 황 대사 경로가 활성화된 식물에서 MSM 또는 MSM 전구체(예를 들어, 다른 황 함유 화합물)의 농도가 다소 높을 수 있다고 제시합니다.

십자화과 식물(Brassicaceae) – 예를 들어, 브로콜리, 양배추, 콜리플라워 등은 일반적으로 유기 황 화합물을 풍부하게 포함하고 있어서 MSM의 전구체가 될 수 있는 성분들이 다른 채소에 비해 높을 수 있습니다.

Allium 계열 식물 – 마늘, 양파 등도 유기 황 화합물의 풍부한 공급원으로 알려져 있으나, 이들 식물에서 발견되는 황 성분은 주로 알리신과 그 유도체 등으로, MSM과는 화학적 구조나 생리활성 면에서 차이가 있습니다.

결론

자연식품에서 MSM은 여러 식물에 아주 소량 존재하며, 단일 식물에서 “풍부하다”라고 보기보다는 다양한 식물성 식품을 균형 있게 섭취할 때 MSM을 포함한 유기 황 화합물의 이점을 얻을 수 있습니다.

실제 MSM 보충제는 이러한 미량의 자연 MSM보다 훨씬 높은 농도로 합성되어 제공되므로, 식물을 통해 섭취하는 MSM의 양은 매우 한정적이라고 할 수 있습니다.

따라서, 특별히 “MSM이 풍부한” 한 종류의 식물을 꼽기는 어렵지만, 황 함유 화합물의 전구체가 비교적 많이 포함된 식물군은 십자화과 채소와 마늘, 양파와 같은 Allium 계열 식물이라고 할 수 있습니다. 그러나 이들 식물의 자연 MSM 함량은 보충제로 섭취하는 MSM의 양과는 상당한 차이가 있음을 유념해야 합니다.

Nutrients

. 2017 Mar 16;9(3):290. doi: 10.3390/nu9030290

Methylsulfonylmethane: Applications and Safety of a Novel Dietary Supplement

Matthew Butawan 1, Rodney L Benjamin 2, Richard J Bloomer 1,*

• Author information
• Article notes
• Copyright and License information

PMCID: PMC5372953  PMID: 28300758

Abstract

Methylsulfonylmethane (MSM) has become a popular dietary supplement used for a variety of purposes, including its most common use as an anti-inflammatory agent. It has been well-investigated in animal models, as well as in human clinical trials and experiments. A variety of health-specific outcome measures are improved with MSM supplementation, including inflammation, joint/muscle pain, oxidative stress, and antioxidant capacity. Initial evidence is available regarding the dose of MSM needed to provide benefit, although additional work is underway to determine the precise dose and time course of treatment needed to provide optimal benefits. As a Generally Recognized As Safe (GRAS) approved substance, MSM is well-tolerated by most individuals at dosages of up to four grams daily, with few known and mild side effects. This review provides an overview of MSM, with details regarding its common uses and applications as a dietary supplement, as well as its safety for consumption.

초록

메틸설포닐메테인(MSM)은 

항염증제로 가장 많이 사용되는 것을 비롯하여 

다양한 목적으로 사용되는 인기 있는 건강 보조 식품이 되었습니다. 

동물 실험과 인간 대상 임상 시험 및 실험을 통해 

그 효능이 잘 입증되었습니다. 

메틸설포닐메테인(MSM 유황)보충제를 섭취하면 

염증, 관절/근육통, 산화 스트레스, 항산화 능력 등 

건강과 관련된 다양한 결과가 개선됩니다. 

이점을 제공하기 위해 필요한 MSM의 용량에 대한 초기 증거가 있지만, 

최적의 이점을 제공하기 위해 필요한 정확한 용량과 치료 기간을 결정하기 위한 

추가 작업이 진행 중입니다. 

일반적으로 안전한 것으로 인정된 물질(GRAS)인 

MSM은 하루 최대 4g의 용량으로 대부분의 사람들이 잘 견디며, 

알려진 부작용이 거의 없고, 

부작용이 경미합니다. 

이 리뷰는 

MSM에 대한 개요를 제공하며, 

식이 보충제로서의 일반적인 용도와 적용에 관한 세부 사항과 섭취 안전성에 관한 정보를 제공합니다.

Keywords: methylsulfonylmethane, MSM, dimethyl sulfone, inflammation, joint pain

1. Description and History of MSM

Methylsulfonylmethane (MSM) is a naturally occurring organosulfur compound utilized as a complementary and alternative medicine (CAM) under a variety of names including dimethyl sulfone, methyl sulfone, sulfonylbismethane, organic sulfur, or crystalline dimethyl sulfoxide [1]. Prior to being used as a clinical application, MSM primarily served as a high-temperature, polar, aprotic, commercial solvent, as did its parent compound, dimethyl sulfoxide (DMSO) [2]. Throughout the mid-1950s to 1970s, DMSO was extensively studied for its unique biological properties including its membrane penetrability with and without the co-transport of other agents, its antioxidant capabilities, its anti-inflammatory effects, its anticholinesterase activity, and its ability to induce histamine release from mast cells [3]. After Williams and colleagues [4,5] studied the metabolism of DMSO in rabbits, others postulated that some of the biological effects attributed to DMSO may in part be caused by its metabolites [6].

In the late 1970s, Crown Zellerbach Corporation chemists, Dr. Robert Herschler and Dr. Stanley Jacob of the Oregon Health and Science University, began experimenting with the odorless MSM in search of similar therapeutic uses to DMSO [7]. In 1981 Dr. Herschler was granted a United States utility patent for the use of MSM to smooth and soften skin, to strengthen nails, or as a blood diluent [8]. In addition to the applications laid out in the first Herschler patent, subsequent Herschler patents claimed MSM to relieve stress, relieve pain, treat parasitic infections, increase energy, boost metabolism, enhance circulation, and improve wound healing [9,10,11,12,13,14,15,16], though there is little supporting scientific evidence [17]. On the other hand, the scientific literature does suggest that MSM may have clinical applications for arthritis [18,19,20] and other inflammatory disorders such as interstitial cystitis [21], allergic rhinitis [22,23], and acute exercise-induced inflammation [24].

Although MSM research has expanded since the patents of Herschler and one MSM product (OptiMSM®; Bergstrom Nutrition, Vancouver, WA, USA) was granted the Generally Recognized As Safe (GRAS) status by the Food and Drug Administration in 2007 [25], the use of MSM remained largely unchanged from 2002 to 2012 [26]. For example, according to the 1999–2004 National Health and Nutritional Examination Survey (NHANES), the weighted percentage of regular MSM users was 1.2% [27]. A 2007 study using a subjective survey reported that 9.6% of survey completers had tried MSM [28]; however, the sample of those who completed the survey was not diverse. More recent analysis of past data from the National Health Interview Surveys (NHIS) asserts that MSM use had dropped 0.2 percent points between 2007 and 2012 [26]. In more recent years, it appears that MSM use is on the rise, based on current MSM sales data.

1. MSM에 대한 설명과 역사

메틸설포닐메테인(MSM)은

디메틸설폰, 메틸설폰, 설포닐비스메탄, 유기황 또는 결정성 디메틸설폭사이드 등

다양한 이름으로 보완대체의학(CAM)으로 활용되는

자연 발생 유기황 화합물입니다 [1].

임상 응용 프로그램으로 사용되기 전에,

MSM은 주로 고온, 극성, 비극성, 상업용 용매로 사용되었으며,

그 모체 화합물인 디메틸설폭사이드(DMSO)도 마찬가지였습니다 [2].

1950년대 중반부터 1970년대까지,

DMSO는 다른 약물의 공동 수송 유무에 따른

막 투과성, 항산화 능력, 항염증 효과, 항콜린에스테라제 활성,

비만 세포에서 히스타민 방출을 유도하는 능력 등

독특한 생물학적 특성을 연구하는 데 광범위하게 사용되었습니다 [3].

윌리엄스와 동료 연구진[4,5]이 토끼에서 DMSO의 대사를 연구한 후,

다른 연구자들은 DMSO에 기인하는 생물학적 효과 중 일부가 부분적으로

그 대사 산물에 의해 야기될 수 있다고 가정했습니다[6].

1970년대 후반,

오리건 보건과학대학의 로버트 허슐러(Robert Herschler) 박사와 스탠리 제이콥(Stanley Jacob) 박사는

크라운 젤러바흐(Crown Zellerbach)사의 화학자로서

DMSO와 유사한 치료 용도를 찾기 위해 무취 MSM을 실험하기 시작했습니다 [7].

1981년 허슐러 박사는

MSM을 사용하여 피부를 매끄럽고 부드럽게 하고,

손톱을 강화하거나,

혈액 희석제로 사용하는 것에 대한 미국 실용 특허를 받았습니다 [8].

첫 번째 허쉬러 특허에 명시된 응용 프로그램 외에도,

이후 허쉬러 특허는 MSM이

스트레스 해소, 통증 완화, 기생충 감염 치료, 에너지 증가, 신진대사 촉진, 혈액순환 개선, 상처 치유 개선에

도움이 된다고 주장했습니다 [9,10,11,12,13,14,15,16],

하지만 이를 뒷받침하는 과학적 증거는 거의 없습니다 [17].

한편,

과학 문헌에 따르면

MSM은 관절염[18,19,20]과

간질성 방광염[21],

알레르기성 비염[22,23],

급성 운동 유발 염증[24]과 같은

기타 염증성 질환에 임상적으로 적용될 수 있는 것으로 나타났습니다.

허쉬러의 특허와 MSM 제품(OptiMSM®; Bergstrom Nutrition, Vancouver, WA, USA)이 2007년 미국 식품의약국(FDA)으로부터 GRAS(Generally Recognized As Safe) 지위를 부여받은 이후 MSM 연구가 확대되었지만, MSM의 사용은 2002년부터 2012년까지 크게 변하지 않았습니다[25]. 예를 들어, 1999-2004년 국민건강영양조사(NHANES)에 따르면, 일반 MSM 사용자의 가중 비율은 1.2%였습니다[27]. 주관적 설문조사를 사용한 2007년 연구에 따르면, 설문조사에 참여한 사람들 중 9.6%가 MSM을 시도한 적이 있다고 보고했습니다[28]; 그러나 설문조사를 완료한 사람들의 표본은 다양하지 않았습니다. 최근 미국 국민건강면접조사(NHIS)의 과거 데이터 분석에 따르면, 2007년과 2012년 사이에 남성 동성애자 사용이 0.2% 포인트 감소했다고 합니다 [26]. 최근 몇 년 동안, 남성 동성애자 사용이 증가하고 있는 것으로 보입니다. 현재 남성 동성애자 판매 데이터를 기반으로 합니다.

1.1. MSM Synthesis—The Sulfur Cycle

MSM is a member of the methyl-S-methane compounds within the Earth’s sulfur cycle. Natural synthesis of MSM begins with the uptake of sulfate to produce dimethylsulfoniopropionate (DMSP) by algae, phytoplankton, and other marine microorganisms [29]. DMSP is either cleaved to form dimethyl sulfide (DMS) or undergoes demethiolation resulting in methanethiol, which can then be converted to DMS [30]. Approximately 1%–2% of the DMS produced in the oceans is aerosolized [29].

Atmospheric DMS is oxidized by ozone, UV irradiation, nitrate (NO3), or hydroxyl radical (OH) to form DMSO or sulfur dioxide [30,31,32,33,34,35]. Atmospheric levels of DMSO and MSM appear to be dependent upon the season with a maxima in the spring/summer and minima in the winter [36], possibly due to DMS production and volatility being temperature dependent. Oxidized DMS products like sulfur dioxide contribute to increased condensation and cloud formation [37,38], thus providing a vehicle for DMSO to return to Earth dissolved in precipitation where it can undergo disproportionation to either DMS or MSM [39].

Once absorbed into the soil, DMSO and MSM will be taken up by plants [40] or utilized by mutualistic soil bacterium such as the bioremediative additive, Pseudomonas putida, in order to improve soil conditions [41,42,43,44,45,46]. MSM is broadly expressed in a number of fruit [40,47], vegetable [40,47,48], and grain crops [47,49], though the extent of MSM bioaccumulation is dependent upon the plant. At this point, MSM and the other sulfur sources are consumed as a plant product and excreted, released as a by-product of plant respiration in the form of sulfide, or eventually decompose as the plant dies. The non-aerosolized sulfur sources can then be oxidized to sulfate and incorporated into minerals, which undergo erosion and return to the oceans, thus completing this sulfur sub-cycle.

Alternatively, synthetically produced MSM is manufactured through the oxidation of DMSO with hydrogen peroxide (H2O2) and purified by either crystallization or distillation. While distillation is more energy intensive, it is recognized as the preferred method [50] and utilized for manufacture of the GRAS OptiMSM® (Bergstrom Nutrition, Vancouver, WA, USA) [25]. Biochemically, this manufactured MSM would have no detectable structural or safety differences from the naturally produced product [51]. Since the concentration of MSM is in the hundredths ppm in food sources, synthetically produced MSM makes it possible to ingest bioactive quantities without having to consume unrealistic amounts of food.

1.1. MSM 합성 - 황의 순환

MSM은

지구의 황의 순환에 속하는

메틸-S-메탄 화합물의 일종입니다.

MSM의 자연 합성은

조류, 식물성 플랑크톤, 기타 해양 미생물에 의해 황산염이 흡수되어

디메틸설포노프로피오네이트(DMSP)가 생성되는 것으로 시작됩니다 [29].

DMSP는

디메틸설파이드(DMS)를 형성하기 위해 분해되거나 메탄티올로 전환되어

DMS로 전환될 수 있는 메탄티올로 전환됩니다 [30].

바다에서 생성되는 D

MS의 약 1% - 2%가 에어로졸화됩니다 [29].

대기 중의 DMS는

오존, 자외선 조사, 질산염(NO3), 또는 수산기(OH)에 의해 산화되어

DMSO 또는 이산화황으로 변합니다 [30,31,32,33,34,35].

대기 중의 DMSO와 MSM의 농도는

계절에 따라 달라지는 것으로 보이며,

봄/여름에 최대치, 겨울에 최소치를 보입니다 [36].

이는 DMS의 생산과 휘발성이 온도에 따라 달라지기 때문일 수 있습니다.

이산화황과 같은 산화된 DMS 제품은

응축과 구름 형성을 증가시키는 데 기여합니다 [37,38],

따라서

DMSO가 지구로 돌아와 강수량에 용해되어

DMS 또는 MSM으로 불균형하게 분해될 수 있는 수단을 제공합니다 [39].

DMSO와 MSM은 일단 토양에 흡수되면

식물[40]에 흡수되거나,

토양 상태를 개선하기 위해 생물학적 개선 첨가제인 슈도모나스 푸티다(Pseudomonas putida)와 같은

공생 토양 박테리아에 의해 활용됩니다[41,42,43,44,45,46].

MSM은

과일 [40,47], 채소 [40,47,48], 곡물 작물 [47,49] 등

다양한 작물에서 광범위하게 발견되지만,

MSM의 생체 축적 정도는 식물에 따라 다릅니다.

이 시점에서,

MSM과 다른 황 공급원은 식물성 제품으로 소비되고 배설되거나,

황화물의 형태로 식물 호흡의 부산물로 방출되거나,

결국 식물이 죽으면서 분해됩니다.

비산화 황원은

황산염으로 산화되어 광물에 포함될 수 있으며,

이 광물은 침식을 거쳐 바다로 돌아가 이 황의 하위 순환을 완성합니다.

또는 합성으로 생산된 MSM은

DMSO를 과산화수소(H2O2)로 산화시켜 제조하고,

결정화 또는 증류로 정제합니다.

증류는 에너지 집약적이지만,

선호되는 방법으로 인정받고 있으며 [50] GRAS OptiMSM®(Bergstrom Nutrition, 미국 워싱턴주 밴쿠버) [25]의 제조에 사용됩니다.

생화학적으로, 이렇게 제조된 MSM은

자연적으로 생산된 제품과 구조적 또는 안전성 측면에서 차이가 없을 것입니다 [51].

식품 원료에 함유된 MSM의 농도는

100분의 1ppm이기 때문에,

합성으로 생산된 MSM을 섭취하면 비현실적인 양의 식품을 섭취하지 않고도

생체 활성량을 섭취할 수 있습니다.

1.2. Absorption and Bioavailability

Exogenous sources of MSM are introduced into the body through supplementation or consumption of foods like fruits [40,47], vegetables [40,47,48], grains [47,49], beer [47], port wine [52], coffee [47], tea [47,53], and cow’s milk [47,54]. Along with MSM, absorbed methionine, methanethiol, DMS, and DMSO can be used by the microbiota to contribute to the MSM aggregate within the mammalian host [55,56,57]. Diet-induced microbiome changes have been shown to affect serum MSM levels in rats [58] and gestating sows [59]. That said, the gut flora is readily manipulated by diet [60], exercise [61], or other factors and likely affects bioavailable MSM sources, as suggested in pregnancy [62].

Pharmacokinetic studies indicate that MSM is rapidly absorbed in rats [63,64] and humans [65], taking 2.1 h and <1 h, respectively. Similar studies utilizing DMSO in monkeys demonstrate rapid conversion of DMSO to MSM within 1–2 h after delivery via oral gavage [66]. Humans ingesting DMSO oxidized approximately 15% to MSM by hepatic microsomes in the presence of NADPH2 and O2 [56].

In rats, between 59% and 79% of MSM is excreted the same day as administration in urine, either unchanged or as another S-containing metabolite [64]. Urine is the most common form of excretion as MSM has been detected in urine of rats [63,67], rabbits [4,5], bobcats [68], cheetahs [69], dogs [70], monkeys [66], and humans [4,62,71,72]. Additionally, excretion of MSM can be contained in feces [63,64] or several other biofluids including cow’s milk [54,73], red deer tail gland secretion [74], and human saliva [75].

The remaining MSM exhibits fairly homogeneous tissue distribution and a biological half-life of approximately 12.2 h in rats [63]. Tissue distribution in humans is also likely widespread as it has been detected in cerebrospinal fluid and evenly distributed between the gray and white matter of the brain [76,77,78,79,80]. Moreover, the biological half-life within the brain is an estimated 7.5 h [79], while the general half-life is suggested to be greater than 12 h [65]. The persisting systemic MSM comprises the bioavailable source.

MSM is a common metabolite with a steady state concentration dependent upon an assortment of individual-specific factors including, but not limited to, genetics [55,67,81] and diet [58,59,82]. In 1987 the first reported baseline MSM levels were 700–1100 ng/mL or 7.44–11.69 µmol/L [83]. Similar results have been observed with levels in the low micromolar range of 0–25 µmol/L [55]. More recently, a possible discrepancy has been noted in a study report listing baseline MSM levels ranging from 13.3 to 103 µM/mL [65]. In a recent human study involving daily ingestion of MSM at 3 g by 20 healthy men for a period of four weeks, it was noted that serum MSM was elevated in all men following ingestion, with a further increase at week 4 versus week 2 in the majority of men [84]. These data indicate that oral MSM is absorbed by healthy adults and accumulates over time with chronic intake.

1.2. 흡수 및 생체 이용률

외인성 MSM의 공급원은

과일[40,47], 채소[40,47,48], 곡물[47,49], 맥주[47], 포트 와인[52], 커피[47], 차[47,53], 우유[47,54]와 같은

식품의 섭취나 보충제를 통해 체내에 유입됩니다.

미생물 군집은

MSM과 함께 흡수된 메티오닌, 메탄티올, DMS, DMSO를 사용하여

포유류 숙주 내의 MSM 집합체에 기여할 수 있습니다 [55,56,57].

식이 유발 미생물 군집 변화는 쥐의 혈청 MSM 수준에 영향을 미치는 것으로 나타났습니다 [58] 및 임신한 모돈 [59].

그렇지만,

장내 세균총은 식이요법[60], 운동[61], 또는 다른 요인에 의해 쉽게 조작될 수 있으며,

임신에 관한 연구에서 제시된 바와 같이 생체 이용 가능한

MSM 공급원에 영향을 미칠 가능성이 있습니다[62].

약동학 연구에 따르면,

MSM은 쥐[63,64]와 인간[65]에서 각각 2.1시간과 1시간 이내에 빠르게 흡수됩니다.

DMSO를 원숭이에게 투여한 유사한 연구에 따르면,

경구 투여 후 1-2시간 내에

DMSO가 MSM으로 빠르게 전환되는 것으로 나타났습니다 [66].

인간이 NADPH2와 O2가 존재하는 상태에서

간 미세소체에 의해 DMSO를 섭취하면

약 15%가 MSM으로 산화됩니다 [56].

쥐의 경우,

투여 당일 소변으로 배설되는 MSM의 59%에서 79%가 변하지 않은 상태이거나

다른 S 함유 대사 산물로 배설됩니다 [64].

소변은

배설물 중에서 가장 흔한 형태입니다.

MSM은

쥐[63,67], 토끼[4,5], 살쾡이[68], 치타[69], 개[70], 원숭이[66], 그리고

인간[4,62,71,72]의 소변에서 검출되었습니다.

또한,

MSM의 배설은

대변 [63,64] 또는 젖소 우유 [54,73], 붉은 사슴 꼬리샘 분비물 [74], 그리고

사람의 타액 [75]을 포함한 여러 다른 생물학적 체액에 포함될 수 있습니다.

나머지 MSM은

상당히 균일한 조직 분포를 나타내며,

쥐의 경우 약 12.2시간의 생물학적 반감기를 보입니다 [63].

인간의 조직 분포도

광범위할 것으로 보입니다.

뇌척수액에서 검출되었으며,

뇌의 회백질과 백질 사이에 고르게 분포되어 있기 때문입니다 [76,77,78,79,80].

또한, 뇌 내에서의 생물학적 반감기는

약 7.5시간으로 추정되며[79],

일반적인 반감기는 12시간 이상인 것으로 알려져 있습니다[65].

지속되는 전신 MSM은

생체 이용 가능한 공급원으로 구성됩니다.

MSM은

유전학[55,67,81]과 식습관[58,59,82]을 포함하되

이에 국한되지 않는 다양한 개인별 요인에 따라

정상 상태 농도가 달라지는 일반적인 대사 산물입니다.

1987년에 보고된 최초의 기준 MSM 수준은

700-1100 ng/mL 또는 7.44-11.69 µmol/L[83]이었습니다.

마이크로몰 단위로 환산했을 때 0-25 µmol/L의 낮은 수준에서도

유사한 결과가 관찰되었습니다 [55].

최근에는 기준 MSM 수준이 13.3~103 µM/mL인 연구 보고서에서 가능한 불일치가 발견되었습니다 [65].

최근 4주 동안 20명의 건강한 남성에게

매일 3g의 MSM을 섭취하게 한 인간 대상 연구에서,

섭취 후 모든 남성에서 혈청 MSM이 증가했으며,

대부분의 남성에서 2주차에 비해 4주차에 더 많이 증가하는 것으로 나타났습니다 [84].

이 데이터는

경구 MSM이 건강한 성인에게 흡수되고

만성 섭취 시 시간이 지남에 따라 축적된다는 것을 나타냅니다.

2. Mechanisms of Actions

Due to its enhanced ability to penetrate membranes and permeate throughout the body, the full mechanistic function of MSM may involve a collection of cell types and is therefore difficult to elucidate. Results from in vitro and in vivo studies suggest that MSM operates at the crosstalk of inflammation and oxidative stress at the transcriptional and subcellular level. Due to the small size of this organosulfur compound, distinguishing between direct and indirect effects is problematic. In the sections to follow, an attempt will be made to describe each mechanism within a focused scope.

2.1. Anti-Inflammation

In vitro studies indicate that MSM inhibits transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [85,86] by impeding the translocation into the nucleus while also preventing the degradation of the NF-κB inhibitor [86]. MSM has been shown to alter post-translational modifications including blocking the phosphorylation of the p65 subunit at Serine-536 [87], though it is unclear whether this is a direct or indirect effect. Modifications to subunits such as these contribute heavily to the regulation of the transcriptional activity of NF-κB [88], and thus more details are required to further understand this anti-inflammatory mechanism. Traditionally, the NF-κB pathway is thought of as a pro-inflammatory signaling pathway responsible for the upregulation of genes encoding cytokines, chemokines, and adhesion molecules [89]. The inhibitory effect of MSM on NF-κB results in the downregulation of mRNA for interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α) in vitro [90,91]. As expected, translational expression‎ of these cytokines is also reduced; furthermore, IL-1 and TNF-α are inhibited in a dose-dependent manner [90].

MSM can also diminish the expression‎ of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) through suppression of NF-κB; thus lessening the production of vasodilating agents such as nitric oxide (NO) and prostanoids [86]. NO not only modulates vascular tone [92] but also regulates mast cell activation [93]; therefore, MSM may indirectly have an inhibitory role on mast cell mediation of inflammation. With the reduction in cytokines and vasodilating agents, flux and recruitment of immune cells to sites of local inflammation are inhibited.

At the subcellular level, the nucleotide-binding domain, leucine-rich repeat family pyrin domain containing 3 (NLRP3) inflammasome senses cellular stress signals and responds by aiding in the maturation of inflammatory markers [94,95]. MSM negatively affects the expression‎ of the NLRP3 inflammasome by downregulating the NF-κB production of the NLRP3 inflammasome transcript and/or by blocking the activation signal in the form of mitochondrial generated reactive oxygen species (ROS) [90]. The mechanisms by which MSM demonstrates antioxidant properties will be discussed in the following section.

2. 작용 기전

MSM의 막 투과 능력이 향상되어 신체 전체에 침투할 수 있기 때문에,

MSM의 완전한 기계적 기능은 세포 유형의 집합을 포함할 수 있으며,

따라서 설명하기가 어렵습니다.

체외 및 체내 연구 결과에 따르면,

MSM은

전사 및 세포 내 수준에서 염증과 산화 스트레스의 교차 작용을 통해 작용합니다.

이 유기황 화합물의 크기가 작기 때문에

직접적인 영향과 간접적인 영향을 구분하는 것이 어렵습니다.

다음 섹션에서는 각 메커니즘을 집중적으로 설명하려고 합니다.

2.1. 항염증

시험관 내 연구에 따르면,

MSM은 핵으로의 전좌를 방해하고

NF-κB 억제제의 분해를 방지함으로써

활성화된 B 세포의 핵 인자 kappa-light-chain-enhancer(NF-κB)의 전사 활성을 억제합니다[85,86].

MSM은

번역 후 변형에 영향을 미치는 것으로 밝혀졌는데,

그 중에서도 세린-536에서의 p65 서브유닛의 인산화(phosphorylation)를 차단하는 것이 포함됩니다[87].

그러나 이것이 직접적인 영향인지 간접적인 영향인지는 확실하지 않습니다. 이와 같은 서브유닛의 변형은 NF-κB의 전사 활동 조절에 크게 기여하므로[88], 이 항염증 메커니즘을 더 자세히 이해하기 위해서는 더 많은 정보가 필요합니다.

전통적으로,

NF-κB 경로는

사이토카인, 케모카인, 그리고 접착 분자를 암호화하는 유전자의 상향 조절을 담당하는

전염증성 신호 전달 경로로 간주되어 왔습니다 [89].

MSM이

NF-κB에 미치는 억제 효과는

체외에서 인터루킨(IL)-1, IL-6, 그리고 종양 괴사 인자-α(TNF-α)에 대한

mRNA의 하향 조절을 초래합니다 [90,91].

예상대로,

이러한 사이토카인의 번역 발현도 감소합니다.

또한, IL-1과 TNF-α는 용량 의존적으로 억제됩니다 [90].

또한,

MSM은

NF-κB의 억제를 통해 유도성 산화질소 합성효소(iNOS)와 사이클로옥시게나제-2(COX-2)의 발현을 감소시킬 수 있으므로,

산화질소(NO)와 프로스타노이드와 같은 혈관 확장제의 생산을 감소시킬 수 있습니다 [86].

NO는

혈관 긴장도를 조절할 뿐만 아니라 [92]

비만 세포의 활성화를 조절합니다 [93];

따라서,

MSM은 간접적으로 비만 세포 매개 염증에 대한 억제 역할을 할 수 있습니다.

사이토카인과 혈관 확장제의 감소로 인해

국소 염증 부위에 대한 면역 세포의 유입과 유동이 억제됩니다.

세포 내 수준에서

뉴클레오티드 결합 도메인, 류신-풍부 반복 패밀리 피린 도메인 3(NLRP3) 염증성 복합체는

세포 스트레스 신호를 감지하고 염증성 마커의 성숙을 돕는 방식으로 반응합니다 [94,95].

MSM은

NLRP3 인플라미소좀 전사체의 NF-κB 생산을 하향 조절하거나

미토콘드리아에서 생성된 활성 산소 종(ROS)의 형태로 활성화 신호를 차단함으로써

NLRP3 인플라미소좀의 발현에 부정적인 영향을 미칩니다 [90].

MSM이 항산화 특성을 나타내는 메커니즘은 다음 섹션에서 설명합니다.

2.2. Antioxidant/Free-Radical Scavenging

Although an excess of ROS can wreak havoc on a number of intracellular components, a threshold amount is required to activate the appropriate pathways in phenotypically normal cells [96]. The antioxidant effect of MSM was first noticed when the neutrophil stimulated production of ROS was suppressed in vitro but unaffected in a cell free system [97]; for that reason, it was proposed that the antioxidant mechanism acts on the mitochondria rather than at the chemical level.

MSM influences the activation of at least four types of transcription factors: NF-κB, signal transducers and activators of transcription (STAT), p53, and nuclear factor (erythroid-derived 2)-like 2 (Nrf2). By mediating these transcription factors, MSM can regulate the balance of ROS and antioxidant enzymes. It is important to note that each of these is also, in part, activated by ROS.

As mentioned previously, MSM can inhibit NF-κB transcriptional activity and thus reduce the expression‎ of enzymes and cytokines involved in ROS production. Downregulation of COX-2 and iNOS reduces the amount of superoxide radical (O2−) and nitric oxide (NO), respectively [86]. Additionally, MSM suppresses the expression‎ of cytokines such as TNF-α [86,90,91], which may reduce any stimulated mitochondrial generated ROS [98]. Decrements in cytokine expression‎ may also be involved in reduced paracrine signaling and activation of other transcription factors and pathways.

MSM has been shown to repress the expression‎ or activities of STAT transcription factors in a number of cancer cell lines in vitro [99,100,101]. The janus kinase (Jak)/STAT pathway is involved in regulation of genes related to apoptosis, differentiation, and proliferation, all of which generate ROS as a necessary signaling component [102,103,104]. Signaling through the Jak/STAT pathway may also be stifled by reduced cytokine expression‎. Downregulation of the Jak/STAT pathway may further reduce ROS generation by decreasing expression‎ of oxidases [105] and B-cell lymphoma-2 (Bcl-2) [106].

In macrophage-like cells, pre-treatment with MSM in vitro was found to decrease accumulation of the redox sensitive p53 transcription factor [107]. This p53 exhibits dichotomous oxidative function depending on the intracellular ROS levels, whereby, in a general sense, p53 exerts antioxidative functions at low intracellular ROS levels and prooxidative functions at high ROS levels [108]. The antioxidative function of p53 upregulates scavenging enzymes like Sestrin, glutathione peroxidase (GPx) and aldehyde dehydrogenase (ALDH). The prooxidative function of p53 upregulates oxidases while also suppressing antioxidant genes. For a more in depth summary of p53 and oxidative stress, please see the review by Liu and Xu [108].

Murine neuroblastoma cells cultured with human immunodeficiency virus type 1 transactivating regulatory protein (HIV-1 Tat) displayed reduced nuclear translocation of Nrf2; however, co-culturing with MSM returned Nrf2 translocation to the nucleus to control levels [109]. Nrf2 is well documented for its association with antioxidant enzymes including glutamate-cysteine ligase (GCL), superoxide dismutases (SODs), catalase (CAT), peroxiredoxin (Prdx), GPx, glutathione S-transferase (GST), and others [110]. Though it is unclear what direct effect MSM has on Nrf2, it is worth mentioning that Nrf2 can also be regulated by p53 expression‎ of p21 or Jak/STAT expression‎ of B-cell lymphoma-extra large (Bcl-XL) [111].

2.2. 항산화/자유 라디칼 소거

ROS가 과도하게 생성되면 세포 내 여러 구성 요소에 혼란을 야기할 수 있지만, 표현형적으로 정상적인 세포에서 적절한 경로를 활성화하기 위해서는 임계량이 필요합니다 [96]. MSM의 항산화 효과는 호중구가 ROS 생성을 자극했을 때 시험관 내에서는 억제되었지만 무세포 시스템에서는 영향을 받지 않았을 때 처음 발견되었습니다 [97]; 이러한 이유로 항산화 메커니즘이 화학 수준이 아닌 미토콘드리아에서 작용한다고 제안되었습니다.

MSM은 적어도 네 가지 유형의 전사 인자(transcription factor)의 활성화에 영향을 미칩니다:

NF-κB,

신호 변환기 및 전사 활성화 인자(STAT),

p53, 그리고

핵 인자(erythroid-derived 2)-like 2(Nrf2).

이러한 전사 인자를 매개함으로써,

MSM은 ROS와 항산화 효소의 균형을 조절할 수 있습니다.

이 중 각각은 부분적으로 ROS에 의해 활성화된다는 점에 유의해야 합니다.

앞서 언급한 바와 같이,

MSM은

NF-κB 전사 활성을 억제하여

ROS 생산에 관여하는 효소와 사이토카인의 발현을 감소시킬 수 있습니다.

COX-2와 iNOS의 하향 조절은

각각 슈퍼옥사이드 라디칼(O2−)과 산화질소(NO)의 양을 감소시킵니다 [86].

또한,

MSM은 TNF-α와 같은 사이토카인의 발현을 억제합니다 [86,90,91],

자극된 미토콘드리아에서 생성된 ROS를 감소시킬 수 있습니다 [98].

사이토카인 발현의 감소는

또한 감소된 파라크린 신호 전달과 다른 전사 인자와 경로의 활성화에 관여할 수 있습니다.

MSM은 체외에서 여러 암세포주에서 STAT 전사 인자의 발현 또는 활동을 억제하는 것으로 나타났습니다 [99,100,101].

자누스 키나제(Jak)/STAT 경로는

세포 사멸, 분화, 증식과 관련된 유전자 조절에 관여하며,

이 모든 과정에서 ROS가 필수 신호 전달 요소로 생성됩니다 [102,103,104].

Jak/STAT 경로를 통한 신호 전달은

사이토카인 발현 감소로 인해 억제될 수도 있습니다.

Jak/STAT 경로의 하향 조절은

산화효소[105]와 B-세포 림프종-2(Bcl-2)[106]의 발현을 감소시킴으로써

ROS 생성을 더욱 감소시킬 수 있습니다.

대식세포와 유사한 세포에서 체외에서 MSM을 사용한 전처리가 산화 환원 민감성 p53 전사 인자의 축적을 감소시키는 것으로 밝혀졌습니다 [107]. 이 p53은 세포 내 ROS 수준에 따라 이분법적인 산화 기능을 나타내는데, 일반적으로 p53은 낮은 세포 내 ROS 수준에서는 항산화 기능을 발휘하고 높은 ROS 수준에서는 산화 촉진 기능을 발휘합니다 [108]. p53의 항산화 기능은 세스트린, 글루타티온 퍼옥시다아제(GPx), 알데히드 탈수소효소(ALDH)와 같은 청소 효소를 활성화합니다. p53의 산화 촉진 기능은 항산화 유전자를 억제하는 동시에 산화 효소를 활성화합니다. p53과 산화 스트레스에 대한 보다 자세한 요약은 Liu와 Xu의 리뷰를 참조하시기 바랍니다 [108].

인간 면역결핍 바이러스 1형 트랜스액티베이팅 조절 단백질(HIV-1 Tat)로 배양된 쥐 신경아세포종 세포는 Nrf2의 핵 전좌가 감소하는 것으로 나타났습니다. 그러나 MSM과 함께 배양하면 Nrf2의 핵 전좌가 정상 수준으로 회복되었습니다. [109] Nrf2는 글루타메이트-시스테인 리가제(GCL), 슈퍼옥사이드 디스뮤타제(SOD), 카탈라제(CAT), 퍼옥시레독신(Prdx), GPx, 글루타티온 S-트랜스퍼라제(GST) 등 항산화 효소와 연관되어 있다는 사실이 잘 알려져 있습니다 [110]. MSM이 Nrf2에 직접적인 영향을 미치는지는 확실하지 않지만, Nrf2는 p53의 p21 발현 또는 B세포 림프종-초대형(Bcl-XL)의 Jak/STAT 발현에 의해 조절될 수 있다는 점을 언급할 가치가 있습니다 [111].

2.3. Immune Modulation

Stress can trigger an acute response by the innate immune system and an ensuing adaptive immune response if the stressor is pathogenic. Sulfur containing compounds including MSM play a critical role in supporting the immune response [112,113,114]. Through an integrated mechanism including those mentioned above, MSM modulates the immune response through the crosstalk between oxidative stress and inflammation.

Chronic exposure to stressors can have detrimental effects to the immune system as it becomes desensitized or over-stressed and unable to elicit a typical immune response. The broad effects of IL-6 have been implicated in the maintenance of chronic inflammation [115]. MSM has been shown to reduce IL-6 in vitro, which may mitigate these chronic deleterious effects [86,87,90]. Pre-treatment with MSM, prior to exhaustive exercise, prevented the over-stress of immune cells as lipopolysaccharide (LPS)-treated blood was still able to mount a response through the secretion of cytokines ex vivo, an effect not observed in the placebo group [24].

The adjacent vasculature plays a role in mediating the acute immune response primarily through the activation of mast cells. Histamine release from mast cells is inhibited by DMSO [116]; however, the effects of MSM on histamine release remain unexplored. Previous studies indicate that MSM has an inhibitory role on vascular function [117,118]. Other in vitro studies demonstrate that MSM has the ability to dampen the expression‎ of vasodilating agents such as NO and prostanoids [86]. A reduction in NO protects macrophages against NO stimulated apoptosis [107].

Additionally, MSM may serve other immune modulatory effects related to cell cycle and cell death. In vitro studies indicate that MSM can induce apoptosis in gastrointestinal cancer cells [119], hepatic cancer cells [120], and colon cancer cells [121]. Contrary to these findings, MSM did not induce apoptosis in murine breast cancer cells [122]. Rather, MSM was shown to restore normal cellular metabolism to both metastatic murine breast cancer and murine melanoma cells [123]. Cell cycle arrest has also been observed in gastrointestinal cancer cells [119] and myoblasts [124]. These alterations to cell survival may arise from cyclin production modulations to the p53 and Jak/STAT pathways.

Though few studies have examined the effectiveness of MSM on wound healing, the innate immune system may also benefit from enhanced wound closure, as assessed by the scratch test in vitro [124,125,126]. Future studies would be needed to confirm‎ these results in vivo.

2.3. 면역 조절

스트레스는 선천성 면역체계에 의해 급성 반응을 유발할 수 있으며, 스트레스 요인이 병원성일 경우 적응성 면역 반응이 뒤따릅니다. MSM을 포함한 황 함유 화합물은 면역 반응을 지원하는 데 중요한 역할을 합니다 [112,113,114]. 위에서 언급한 메커니즘을 포함한 통합 메커니즘을 통해, MSM은 산화 스트레스와 염증 사이의 교차 작용을 통해 면역 반응을 조절합니다.

스트레스 요인에 만성적으로 노출되면 면역 체계가 둔감해지거나 과도한 스트레스를 받아 일반적인 면역 반응을 일으키지 못하게 되어 면역 체계에 해로운 영향을 미칠 수 있습니다. IL-6의 광범위한 영향은 만성 염증의 유지와 관련이 있습니다 [115]. MSM은 체외에서 IL-6를 감소시키는 것으로 나타났으며, 이는 이러한 만성적인 해로운 영향을 완화할 수 있습니다 [86,87,90]. 격렬한 운동 전에 MSM으로 전처리를 하면, LPS(lipopolysaccharide)로 처리된 혈액이 생체 외에서 사이토카인 분비를 통해 반응을 일으킬 수 있었기 때문에 면역 세포의 과도한 스트레스를 예방할 수 있었습니다. 이는 위약 그룹에서는 관찰되지 않은 효과입니다 [24].

인접한 혈관계는 주로 비만세포의 활성화를 통해 급성 면역 반응을 매개하는 역할을 합니다. DMSO는 비만 세포에서 히스타민 방출을 억제합니다 [116]; 그러나, MSM이 히스타민 방출에 미치는 영향은 아직 밝혀지지 않았습니다. 이전 연구에 따르면, MSM은 혈관 기능에 억제 역할을 하는 것으로 나타났습니다 [117,118]. 다른 시험관 내 연구에 따르면, MSM은 NO 및 프로스타노이드와 같은 혈관 확장제의 발현을 억제하는 능력이 있는 것으로 나타났습니다 [86]. NO의 감소는 NO 자극에 의한 세포 자멸사로부터 대식세포를 보호합니다 [107].

또한, MSM은 세포주기 및 세포 사멸과 관련된 다른 면역 조절 효과를 제공할 수 있습니다. 체외 연구에 따르면, MSM은 위장암 세포[119], 간암 세포[120], 대장암 세포[121]에서 세포 사멸을 유도할 수 있습니다. 이러한 연구 결과와는 반대로, MSM은 쥐의 유방암 세포[122]에서 세포 사멸을 유도하지 못했습니다. 오히려, MSM은 전이성 쥐 유방암과 쥐 흑색종 세포 모두에서 정상적인 세포 대사를 회복시키는 것으로 나타났습니다 [123]. 또한, 위장암 세포 [119]와 근아세포 [124]에서도 세포 주기 정지가 관찰되었습니다. 이러한 세포 생존의 변화는 사이클린 생산 조절에서 p53 및 Jak/STAT 경로로 인해 발생할 수 있습니다.

MSM이 상처 치유에 미치는 효과에 대한 연구는 많지 않지만, 체외 스크래치 테스트를 통해 평가한 바에 따르면, 선천성 면역 체계도 향상된 상처 봉합으로 혜택을 볼 수 있습니다 [124,125,126]. 이러한 결과를 생체 내에서 확인하기 위해서는 향후 연구가 필요합니다.

2.4. Sulfur Donor/Methylation

MSM has long been thought of as a sulfur donor for sulfur containing compounds such as methionine, cysteine, homocysteine, taurine, and many others. Guinea pigs fed radiolabeled MSM incorporated labeled sulfur into serum proteins containing methionine and cysteine [127]. This study suggested that microbial metabolism may be responsible for the utilization of MSM to form methionine and subsequent synthesis to cysteine. More recent in vivo studies with radiolabeled MSM suggest that this compound is metabolized rapidly in a homogenous distribution of tissues [63,64]. These studies reportedly collected most labeled sulfur as metabolites of MSM in urine but did not determine the metabolites. Further study regarding the activity of MSM as a sulfur donor is ongoing.

In humans, no MSM dose-dependent trends are observed between individuals for plasma sulfate and homocysteine changes [65]. With microorganisms largely responsible for sulfur utilization throughout the sulfur cycle, MSM as a sulfur donor may be dependent on the existing microbiome with mammalian hosts.

MSM is reportedly a non-alkylating agent and does not methylate DNA [128]. In a letter by Kawai et al., the parent compound of MSM, DMSO, can methylate DNA in the presence of hydroxyl radical (OH) [129], which also has the potential to aid in the oxidation of DMSO to MSM [32,35]. Although it is uncertain whether MSM alkylates DNA, MSM does not appear to cause chromosome aberration in vitro or micronucleation in vivo according to two final study reports. Future studies are needed to determine whether MSM is a methyl donor.

2.4. 유황 공여체/메틸화

MSM은 메티오닌, 시스테인, 호모시스테인, 타우린 등 유황을 함유한 화합물의 유황 공여체로 오랫동안 여겨져 왔습니다. 방사성 표지된 MSM을 먹인 기니피그는 메티오닌과 시스테인을 함유한 혈청 단백질에 표지된 유황을 통합했습니다 [127]. 이 연구는 미생물 대사가 MSM을 메티오닌으로 전환하고, 그 후 시스테인으로 합성하는 데 관여할 수 있다고 제안했습니다. 최근에 방사성 표지된 MSM을 이용한 생체 내 연구에 따르면, 이 화합물은 조직에 균일하게 분포되어 빠르게 대사된다고 합니다 [63,64]. 이 연구에서 대부분의 표지된 유황은 소변에서 MSM의 대사 산물로 수집되었지만, 대사 산물은 확인되지 않았습니다. 유황 기증자로서의 MSM의 활동에 관한 추가 연구가 진행 중입니다.

인간에서는 혈장 황산염과 호모시스테인 변화에 대한 MSM의 용량 의존적 경향이 관찰되지 않습니다 [65]. 유황 순환 전반에 걸쳐 유황 활용에 크게 기여하는 미생물과 관련하여, 황 기증자로서의 MSM은 포유류 숙주의 기존 미생물 군집에 의존할 수 있습니다.

MSM은 비알킬화제로 알려져 있으며 DNA를 메틸화하지 않습니다 [128]. Kawai 등의 연구에 따르면, MSM의 모체 화합물인 DMSO는 하이드록실 라디칼(OH)이 존재하는 상태에서 DNA를 메틸화할 수 있습니다 [129]. 또한, DMSO가 MSM으로 산화되는 것을 돕는 잠재력도 가지고 있습니다 [32,35]. MSM이 DNA를 알킬화할 수 있는지는 확실하지 않지만, 두 건의 최종 연구 보고서에 따르면 MSM은 체외에서 염색체 이상이나 체내에서 소핵을 유발하지 않는 것으로 나타났습니다. MSM이 메틸 기증자인지 여부를 확인하기 위해서는 향후 연구가 필요합니다.

3. Common Uses

As a therapeutic agent, MSM utilizes its unique penetrability properties to alter physiological effects at the cellular and tissue levels. Furthermore, MSM has the ability to act as a carrier or co-transporter for other therapeutic agents, even furthering its potential applications.

3.1. Arthritis and Inflammation

Arthritis is an inflammatory condition of the joints that currently affects approximately 58 million adults, with an estimated increase to 78.4 million by 2040 [130]. This inflammation is characterized by pain, stiffness, and a reduced range of motion with regards to the arthritic joint(s). MSM is currently a CAM treatment alone and in combination for arthritis and other inflammatory conditions. MSM, as a micronutrient with enhanced penetrability properties, is commonly integrated with other anti-arthritic agents including glucosamine, chondroitin sulfate, and boswellic acid.

As mentioned previously, a number of in vitro studies suggest that MSM exerts an anti-inflammatory effect through the reduction in cytokine expression‎ [86,87,90,91]. Similar results have been observed with MSM in experimentally induced-arthritic animal models, as evidenced by cytokine reductions in mice [131] and rabbits [86,87,90,91,132]. Additionally, MSM in a combinatorial supplement with glucosamine and chondroitin sulfate effectively reduced C-reactive protein (CRP) in rats with experimentally-induced acute and chronic rheumatoid arthritis [133].

To date, most arthritic human studies have been non-invasive and assess joint condition through the use of subject questionnaires such as the Western Ontario and McMaster Universities Arthritis Index (WOMAC), 36-Item Short Form Survey (SF36), Visual Analogue Scale (VAS) pain, and the Lequesne Index. In his overview of MSM, Dr. Stanley Jacob references eleven case studies of patients suffering from osteoarthritis who experienced improved symptoms following supplementation with MSM [7]. Clinical trials suggest MSM is effective in reducing pain, as indicated by the VAS pain scale [18,134], WOMAC pain subscale [18,19,135,136], SF36 pain subscale [18,136], and Lequesne Index [134]. Concurrent improvements were also noted in stiffness [18,135,136] and swelling [134]. Furthermore, in the study conducted by Usha and Naidu [134], MSM in combination with glucosamine potentiated the improvements in pain, pain intensity, and swelling.

Other human studies utilizing combination therapies report similar results. For instance, arthritis associated pain and stiffness was significantly improved through the use of Glucosamine, Chondroitin sulfate, and MSM (GCM) [137,138]. Only marginal improvements in pain and stiffness were observed when a GCM combination was supplemented on top of modifications to diet and exercise in sedentary obese women diagnosed with osteoarthritis (OA) [139]. MSM was also shown to be effective in reducing arthritis pain when used in combination with boswellic acid [140] and type II collagen [141].

In addition to arthritis, MSM improves inflammation in a number of other conditions. For example, MSM attenuated cytokine expression‎ in vivo for induced colitis [142], lung injury [143], and liver injury [143,144]. Hasegawa and colleagues [131] reported that MSM was useful in protecting against UV-induced inflammation when applied topically and acute allergic inflammation after pre-treatment with a 2.5% aqueous drinking solution.

MSM is effective at reducing other inflammatory pathologies in humans as well. In a physician’s review of clinical case studies, MSM was an effective treatment for four out of six patients suffering from interstitial cystitis [21]. Additionally, MSM is also suggested to alleviate the symptoms of seasonal allergic rhinitis [22,23]. Though the reduction in systemic exercise-induced inflammation by MSM has been observed [24], human studies have not explored the inflammatory effects directly at the cartilage or synovium, as seen in the reduced synovitis inflammation in mice given MSM [145].

3.2. Cartilage Preservation

Cartilage degradation has long been thought of as the driving force of osteoarthritis [146]. Articular cartilage is characterized by a dense extracellular matrix (ECM) with little to no blood supply driving nutrient extraction from the adjacent synovial fluid [147]. Pro-inflammatory cytokines, particularly IL-1β and TNF-α, are implicated in the destructive process of cartilage ECM [148]. With minimal blood supply and possible hypoxic microenvironments, in vitro studies suggest that MSM protects cartilage through its suppressive effects on IL-1β and TNF-α [86,90,91] and its possibly normalizing hypoxia-driven alterations to cellular metabolism [123].

Disruption of this destructive autocrine or paracrine signaling by MSM has also been observed in surgically-induced OA rabbits by the reduction in cartilage and synovial tissue [132], TNF-α, and the protected articular cartilage surface during OA progression. Histopathology of a rheumatoid arthritis (RA) rat model supplemented with a GCM combination demonstrated decreased synovium proliferation and the development of an irregular edge at the articular joint [133]. Furthermore, MSM supplementation in OA mice significantly decreased cartilage surface degeneration [149]. In fact the protective effects of MSM can be seen as far back as 1991, when Murav’ev and colleagues described the decreased knee joint degeneration of arthritic mice [150]. Interestingly, endogenous serum MSM becomes elevated in sheep post-meniscal destabilization caused osteoarthritis [151]; however, the magnitude of this physiological response was not large enough to protect against cartilage erosion.

3.3. Improve Range of Motion and Physical Function

With the aforementioned improvements in inflammation and cartilage preservation, not surprisingly beneficial changes in overall physical function have also been noted through the use of subjective measurements [18,19,135,136]. In studies with osteoarthritic populations given MSM daily, significant improvements in physical function were observed, as assessed through the WOMAC [18,19,135,136], SF36 [19,135,136], and Aggregated Locomotor Function (ALF) [135]. Objective kinetic knee measurements following eccentric exercise-induced muscle damage were not conclusive but suggest that MSM may aid in maximal isometric knee extensor recovery [152].

MSM has been used in a number of combination therapies with positive results. Supplementation with glucosamine, chondroitin sulfate, MSM, guava leaf extract, and Vitamin D improved physical function in patients with knee osteoarthritis based on the Japanese Knee OA Measure [137]. A GCM supplement was successful in increasing functional ability and joint mobility [138]. MSM in combination with boswellic acid was also shown to improve knee joint function as assessed through the Lequesne Index [140]. MSM with arginine l-α-ketoglutarate, hydrolyzed Type I collagen, and bromelain taken for three months daily post-rotator cuff repair improved repair integrity without affecting objective functional outcomes [153].

Other studies exploring the uses of MSM in combination therapies failed to show significant improvements. In one such study in geriatric horses, a GCM combination supplement given orally for three months failed to show significant changes in gait characteristics [154]. In humans, MSM and boswellic acid reduced the need for anti-inflammatory drugs but was not more effective than the placebo as a treatment for gonarthrosis [155]. However, when a GCM combination supplement was administered in addition to dietary and exercise interventions, no significant improvements were noted when compared to the non-supplemented group [139].

Subjects with lower back pain undergoing conventional physical therapy with supplementation of a glucosamine complex containing MSM reported an improvement in their quality of life [156]. A 2011 systematic review of GCM supplements as a treatment for spinal degenerative joint disease and degenerative disc disease failed to come to a conclusion on efficacy due to the scarcity of quality literature [157].

3.4. To Reduce Muscle Soreness Associated with Exercise

Prolonged strenuous exercise can result in muscle soreness caused by microtrauma to muscles and surrounding connective tissue leading to a local inflammatory response [158]. MSM is alluded to be an effective agent against muscle soreness because of its anti-inflammatory effects as well as its possible sulfur contribution to connective tissue. Endurance exercise-induced muscle damage was reduced with MSM supplementation, as measured by creatine kinase [159]. Pre-treatment with MSM reduced muscle soreness following strenuous resistance exercises [152,160,161] and endurance exercise [162].

3.5. Reduce Oxidative Stress

In vitro studies suggest that MSM does not chemically neutralize ROS in stimulated neutrophils but instead suppresses mitochondrial generation of superoxide, hydrogen peroxide, and hypochlorous acid [97]. Additionally, MSM is able to restore the reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio to normal levels, decrease NO production, and reduce neuronal ROS production following HIV-1 Tat exposure [109]. Animal studies using MSM as the primary treatment for experimentally induced injuries show reductions in malondialdehyde (MDA) [142,143,144,163,164,165], GSSG [165], myeloperoxidase (MPO) [142,143,163], NO [164], and carbon monoxide (CO) [164] and/or increases in GSH [142,143,163,164,165,166], CAT [142,143,144,165], SOD [143,144,163,165], and GPx [165]. Treatment modalities for these animal studies were either an acute one time dose or pre-treatment prior to inducing injury [144,163,165].

In humans, MSM pre-treatment prior to endurance exercise results in acute attenuation of induced protein oxidation [167,168], bilirubin [159,168], lipid peroxidation [167], creatine kinase [159], oxidized glutathione [167], and uric acid [168] and also an increase in total antioxidant capacity [159,168]. Following endurance exercise, reduced glutathione was elevated with 10 days of pre-treatment [167] but was insignificantly affected by a single oral dose just prior to exercise [168].

Pre-treatment with MSM in subjects undergoing resistance exercise exhibits more variability. Supplementation for 28 days with 3.0 g/day prior to exhaustive resistance exercise showed an increase in Trolox equivalent antioxidant capacity (TEAC) and a decrease in homocysteine [161]; whereas, supplementation for 14 days at the same dosage reported no significant changes in TEAC or homocysteine [160]. The longer period of supplementation may have allowed bioavailable MSM stores to reach a level where it could upregulate Nrf2 enough to produce a more significant rise in antioxidant enzymes.

Combination therapies including MSM have become more popular recently, particularly with ethylenediaminetetraacetic acid (EDTA) due to the permeability enhancement provided by MSM [169]. For instance, topical EDTA-MSM is effective at reducing oxidative damage in the form of protein-lipid aldehyde adducts [170,171,172]. EDTA-MSM reduced lens opacification in diabetic cataract [172] but was ineffective in reversing experimentally induced intraocular pressure in rats [170]. In humans, EDTA-MSM lotion significantly improved pitting edema symptoms after two weeks of application, with circulating total antioxidant capacity and MDA reductions noted [173].

Humans studies show promise for MSM as an antioxidant with similar results noted, including reductions in MDA [19,167,168], protein carbonyls (PC) [167,168], and uric acid [168] and increases in GSH [167] and TEAC [159,161,168]. Contrary to previous literature, Kantor et al. reported that MSM users experienced reduced lymphocyte DNA repair capacity at 60 min. [174]. This conflicting result may be explained by the samples being collected at different points in the day, since the circadian clock can modulate this measure [175].

3.6. Improve Seasonal Allergies

In an eval‎uation of MSM on seasonal allergies, 2.6 g/day PO MSM for 30 days improved upper and total respiratory symptoms as well as lower respiratory symptoms by week 3 [23]. All these improvements were maintained throughout the 30 days of supplementation. A drawback of this study was the lack of reporting on pollen counts and a symptoms questionnaire [176]. This was later corrected when Barrager and Schauss published the additional requested data [22]. Barrager et al. used a subsection of this sample population to measure histamine release but found no significant changes in plasma IgE or histamine levels [23].

3.7. Improve Skin Quality and Texture

Since the initial patent awarded to Herschler in 1981, MSM has been suggested to have therapeutic uses for the improvement of skin quality and texture by acting as a sulfur donor to keratin. According to one final study report, MSM is non-irritating to the skin of rabbits via an occlusive patch. Another final study report indicated that MSM may be slightly irritating to skin of guinea pigs. Using a lotion containing EDTA and MSM, mild improvement in burn sites on rats were noticed following three days of topical application every 8 h [171].

Skin appearance and condition after MSM treatment significantly improved as assessed by expert grading, instrumental analysis, and participant self-assessment [177]. Human combination studies with four peeling sessions using pyruvic acid and MSM once every two weeks improved the degree of pigmentation of melisma, skin elasticity, and the degree of wrinkling [178]. A combination treatment of silymarin and MSM proved useful in managing rosacea symptoms [179]. A case study of a 44 year old man with severe X-linked type ichthyosis showed improvement of symptoms after four weeks of topical moisturizer containing amino acids, vitamins, antioxidants, and MSM [180].

3.8. MSM and Cancer

An emerging area of MSM research deals with the anti-cancer effect of the organosulfur compound. In vitro studies using MSM alone or in combination have eval‎uated the metabolic and phenotypic effects of a number of cancer cell lines including breast [100,101,122,123,126,181], esophagus [119], stomach [119], liver [119,120], colon [121], bladder [99], and skin cancers [123,125] with promising results. MSM independently has been shown to be cytotoxic to cancer cells by inhibiting cell viability through the induction of cell cycle arrest [119,122,123], necrosis [119], or apoptosis [100,101,119,120,121]. The inhibition of cell growth and proliferation may be attributed to the metabolic alterations induced by MSM at the transcriptional and/or post-translational stages. For instance, MSM has been shown to inhibit expression‎ and DNA binding of transcription factors such as STAT3 [100,101] and STAT5b [100,101,181]; meanwhile, the p53 transcription factor is maintained by MSM [100] and does not induce apoptosis [121]. Though MSM inhibition of DNA binding by STAT3 may be an indirect effect of the phosphorylation of Jak2 [99]. Nonetheless, by inhibiting the binding of STAT3 and STAT5b to promoters, the reduced expression‎ of oncogenic proteins such as vascular endothelial growth factor (VEGF) [99,100,101,123], heat shock protein (HSP)90α [100], and insulin-like growth factor-1 receptor (IGF-1R) [99,100,101] has been observed. The reduced expression‎ of IGF-1R and VEGF may help prevent the development of tumors by reducing the insulin-like growth factor-1 (IGF-1)-mediated cell survival and proliferation pathways and preventing tumor-induced angiogenesis [182,183]. These metabolic alterations contribute to profound alterations at the cellular level as well.

In vitro studies with cancer cell lines suggest that MSM has the ability to stimulate phenotypic changes more closely resembling non-cancerous cells. Treatment with MSM results in the induction of contact inhibition and cell senescence [122,123,125,126], anchorage-dependent growth [122,125], reduced migration of metastatic lines [101,122,125,126], and normalized wound healing [122,125]. This could in part be attributed to the robust changes to cellular filaments, including the disassembly and indirect reassembly of microtubules [123] and reorganization of actin localization [125]. While preventing angiogenesis may prompt a state of hypoxia, MSM has also been shown to reduce levels of HIF-1α under hypoxic conditions [100,123] and prevent or improve various metastatic biomarkers in response to hypoxia [123]. In vitro MSM studies have also been supported by additional xenograft and in vivo studies confirm‎ing the results.

When cancer cells are xenotransplanted into animal models treated with MSM, tumor growth suppression has been observed [99,100,101], though two of these studies included a combination treatment of MSM and AG490 [99] or Tamoxifen [101]. Tumor tissue from mice treated exclusively with MSM exhibited reduced expression‎ of IGF-1, STAT3, STAT5b, and VEGF without significant suppression of IGF-1R [100]. Tissues isolated from xenografted mice treated with combination treatments both displayed downregulation of STAT5b and IGF-1R signaling [99,101]. Previous studies also suggest that pre-treatment with MSM for approximately one week prior to inducing cancer in rats results in a significant reduction in the mean time to tumor onset [184,185]. Human trials with MSM as a cancer treatment have not been conducted to date; however, one study suggests that MSM use may be associated with a decreased risk of lung and colorectal cancer [186]. In vitro and in vivo results warrant further investigation of MSM as a treatment for cancer.

4. Safety Profile

MSM appears to be well-tolerated and safe. A number of toxicity studies have been conducted in an array of animals including rats [184,185,187,188,189], mice [190], and dogs [191,192]. In a preliminary toxicity study report, a single mortality was reported in a female rat given an oral aqueous dose of 15.4 g/kg after two days; however, a post-mortem necropsy examination showed no gross pathological alterations. Other technical reports indicate that mild skin and eye irritation have been observed when MSM is applied topically. Nonetheless, under the Food and Drug Administration (FDA) GRAS notification, MSM is considered safe at dosages under 4845.6 mg/day [25]. A summary of the toxicity studies is listed in Table 1.

Table 1.

Methylsulfonylmethane (MSM) Toxicity Data.

SpeciesRouteDurationNOAELReference

Acute ≤15 days
Mice	Oral	Not stated (acute)	5 g/kg	Kocsis et al. (1975) [6]
Mice	Intraperitoneal	Not stated (acute)	5 g/kg	Kocsis et al. (1975) [6]
Mice	Oral gavage	15 days	5 g/kg	Takiyama et al. (2010) [190]
Rat	Intraperitoneal	Not stated (acute)	5 g/kg	Kocsis et al. (1975) [6]
Rat	Oral gavage	15 days	2 g/kg	Horvath et al. (2002) [187]
Subacute
Gestating Rat	Oral gavage (14 days)	21 days	1 g/kg/day	Magnuson et al. (2007) [188]
Subchronic
Mice	Oral	91 days	1.5 g/kg/day	Takiyama et al. (2010) [190]
Rat	Oral	90 days	1.5 g/kg/day	Horvath et al. (2002) [187]

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MSM and Alcohol

Much anecdotal evidence from web forums and videos exists regarding chronic MSM use and increased sensitivity to alcohol. Since other sulfur containing molecules, such as disulfiram, are used to combat alcoholism by causing adverse reactions when consuming alcohol [193], it is worth mentioning there have been no studies to date examining the effects of MSM usage on alcohol metabolism or addiction pathways. As mentioned previously, MSM readily crosses the blood brain barrier and becomes evenly distributed throughout the brain [76,77,78,79,80]; however, studies have not focused on the metabolic effects on the different neural pathways. Further studies are needed to assess the safety of MSM use with recreational alcohol use.

5. Conclusions

MSM is a naturally occurring organosulfur compound with broad biological effects. Human absorption and biosynthesis of this compound likely depends heavily on the co-metabolism between microbiota and host. Whether naturally produced or manufactured, MSM exhibits no biochemical differences in its ability to intermediate oxidative stress and inflammation. This micronutrient is well tolerated for arthritis and a number of other conditions related to inflammation, physical function, and performance. Emerging research suggests that MSM may one day aid in the treatment of various types of cancer [49,99,100,101,119,120,121,122,123,125,126,181,184,185,186,194] or metabolic syndromes [195].

Acknowledgments

Funding for this work was provided by The University of Memphis.

Abbreviations

ALDH	Aldehyde Dehydrogenase
ALF	Aggregated Locomotor Function
Bcl-2	B-cell lymphoma 2
Bcl-XL	B-cell lymphoma-extra large
BW	Body Weight
CAM	Complementary and Alternative Medicine
CAT	Catalase
CO	Carbon Monoxide
COX	Cyclooxygenase
CRP	C-Reactive Protein
DMS	Dimethyl Sulfide
DMSO	Dimethyl Sulfoxide
DMSP	Dimethylsulfoniopropionate
DNA	Deoxyribose Nucleic Acid
ECM	Extracellular Matrix
EDTA	Ethylenediaminetetraacetic acid
GCL	Glutamate-Cysteine Ligase
GCM	Glucosamine, Chondroitin Sulfate, and Methylsulfonylmethane
GPx	Glutathione Peroxidase
GRAS	Generally Recognized As Safe
GSH	Reduced Glutathione
GSSG	Oxidized Glutathione
GST	Glutathione S-Transferase
H2O2	Hydrogen Peroxide
HIF-1α	Hypoxia Inducible Factor-1α
HIV-1 Tat	Human Immunodeficiency Virus Type 1 Transactivating regulatory protein
HSP	Heat Shock Protein
IGF-1	Insulin-like Growth Factor-1
IGF-1R	Insulin-like Growth Factor-1 Receptor
IL	Interleukin
iNOS	Inducible Nitric Oxide Synthase
Jak	Janus Kinase
LD50	Lethal Dose
LPS	Lipopolysaccharide
MDA	Malondialdehyde
MPO	Myeloperoxidase
MSM	Methylsulfonylmethane
NADPH2	Reduced Nicotinamide-Adenine Dinucleotide Phosphate
NF-κB	Nuclear Factor Kappa-light-chain-enhancer of activated B cells
NHANES	National Health and Nutritional Examination Survey
NHIS	National Health Interview Surveys
NLRP3	Nucleotide-binding domain, Leucine-Rich repeat family Pyrin domain containing 3
NO	Nitric Oxide
NO3	Nitrate
NOAEL	No Observed Adverse Effect Level
Nrf2	Nuclear factor (erythroid-derived 2)-like 2
O2	Molecular Oxygen
O2-	Superoxide Radical
OA	Osteoarthritis
OH	Hydroxyl Radical
ppm	Parts per million
Prdx	Peroxiredoxin
ROS	Reactive Oxygen Species
SF36	36-Item Short Form Survey
SOD	Superoxide Dismutase
STAT	Signal Transducers and Activators of Transcription
TEAC	Trolox Equivalent Antioxidant Capacity
TNF-α	Tumor Necrosis Factor-alpha
UV	Ultraviolet
VAS	Visual Analogue Scale
VEGF	Vascular Endothelial Growth Factor
WOMAC	Western Ontario and McMaster Universities Arthritis Index

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Author Contributions

M.B., R.J.B. and R.L.B. contributed to the literature search as well as the writing and editing of the manuscript.

Conflicts of Interest

M.B. has no conflicts of interest to disclose. R.L.B. is an employee of Bergstrom Nutrition. R.J.B. has received research funding from and acted as a consultant to dietary supplement companies, including those who sell MSM. All authors read and approved of the final manuscript.

References

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