Is Magnesium Better Absorbed Through The Skin?
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Effect of transdermal magnesium foam on serum and urinary magnesium levels in humans: A pilot study
- Lindsy Kass,
- Andrea Rosanoff,
- Amy Tanner,
- Keith Sullivan,
- William McAuley,
- Michael Plesset
ten
- Published: April 12, 2017
- https://doi.org/10.1371/journal.pone.0174817
Figures
Abstruse
Background
Oral magnesium supplementation is unremarkably used to back up a depression magnesium nutrition. This investigation set out to determine whether magnesium in a cream could be absorbed transdermally in humans to improve magnesium status.
Methods and findings
In this unmarried blind, parallel designed pilot report, n = 25 participants (aged 34.3+/-xiv.8y, height 171.5+/-11cm, weight 75.9 +/-14 Kg) were randomly assigned to either a 56mg/day magnesium cream or placebo cream grouping for two weeks. Magnesium serum and 24hour urinary excretion were measured at baseline and at fourteen days intervention. Food diaries were recorded for 8 days during this period. Mg examination and placebo groups' serum and urinary Mg did non differ at baseline. After the Mg2+ cream intervention there was a clinically relevant increase in serum magnesium (0.82 to 0.89 mmol/l,p = 0.29) that was not seen in the placebo grouping (0.77 to 0.79 mmol/50), simply was only statistically meaning (p = 0.02)) in a subgroup of non-athletes. Magnesium urinary excretion increased from baseline slightly in the Mg2+ group but with no statistical significance (p = 0.48). The Mgtwo+ group showed an 8.54% increase in serum Mgtwo+ and a 9.1% increase in urinary Mgii+ while these figures for the placebo group were smaller, i.e. +two.6% for serum Mg2+ and -32% for urinary Mgtwo+. In the placebo group, both serum and urine concentrations showed no statistically meaning modify after the application of the placebo foam.
Conclusion
No previous studies have looked at transdermal absorbency of Mg2+ in human subjects. In this pilot study, transdermal commitment of 56 mg Mg/day (a depression dose compared with commercial transdermal Mg2+ products available) showed a larger percentage rise in both serum and urinary markers from pre to mail intervention compared with subjects using the placebo cream, only statistical significance was achieved only for serum Mg2+ in a subgroup of not-athletes. Future studies should await at higher dosage of magnesium cream for longer durations.
Commendation: Kass Fifty, Rosanoff A, Tanner A, Sullivan K, McAuley West, Plesset M (2017) Effect of transdermal magnesium foam on serum and urinary magnesium levels in humans: A airplane pilot report. PLoS ONE 12(4): e0174817. https://doi.org/ten.1371/journal.pone.0174817
Editor: Yiqing Song, Indiana University Richard Grand Fairbanks School of Public Health, U.s.
Received: October 24, 2016; Accepted: March ten, 2017; Published: April 12, 2017
Copyright: © 2017 Kass et al. This is an open access article distributed under the terms of the Creative Eatables Attribution License, which permits unrestricted use, distribution, and reproduction in whatever medium, provided the original writer and source are credited.
Data Availability: All relevant information are inside the newspaper and its Supporting Data files.
Funding: The authors received no specific funding for this work.
Competing interests: In the future, Dr Andrea Rosanoff may receive royalties on a magnesium cream for which she has signed an agreement. The cream in which she will accept an involvement is dissimilar than the i used in this pilot written report equally the magnesium concentration is more than than double that used in the pilot study and it is a different formulation. The name of the cream is Natural At-home Cream. The U.S. Patent championship is: Cream Transdermal Magnesium Supplement. Publication No. United states-2016-0317576-A1. Publication Appointment: 11/03/2016. This does not modify our adherence to all the PLOS Ane policies on sharing information and materials.
Introduction
Mineral elements, such every bit magnesium (Mg2+), are required by the human body in modest amounts for the maintenance of health and the development of optimal functioning[one]). Mgii+ is an of import mineral element and it is the 4th near abundant cation in living organisms, with Mg2+ being a cofactor to over 325 enzymatic reactions within the body [2]. Around 99% of total body Mgtwo+ is located in the bone, muscles and non-muscular soft tissue [3]. Mgii+ supplementation has been shown to significantly improve blood pressure [4–6] as well as modifying vascular tone by regulating endothelium and shine muscle prison cell function [iv].
To maintain an adequate Mgii+ status humans must consume Mg2+ at regular intervals [vii]. The daily recommendation for Mg2+ is controversial, as the literature is conflicting and varies between countries, although values of ≥ 300 mg/day are unremarkably reported for healthy adults with adjustment for age, sex and nutritional status [vii].
Oral magnesium supplementation has been shown to affect various parameters, such as claret force per unit area [5,eight], immune function [9], cardiovascular system [10] and metabolic syndrome [11]. A contempo meta-assay by Zhang et al (2016) in the Journal of Diet [12] establish that in a healthy population grouping in that location was a dose dependent increase in both serum Mg concentration and urinary Mg excretion with supplemental oral magnesium intake ranging from 250–500mg/24-hour interval. Kass, Weekes and Carpenter (2012) identified that a supplement of >370 mg/24-hour interval of Mg+ shows greater efficacy than a lower dose in improving blood pressure and that magnesium supplementation gives a dose dependent response with regards to blood pressure [5].
An alternative method of maybe attaining recommended magnesium intakes might be through topical application. Current formulations include magnesium oils and trans-dermal creams, from which the magnesium may be absorbed beyond the skin and into the systemic circulation. However, in contrast to gastrointestinal epithelium, a master function of the skin is to deed equally a barrier, which restricts the absorption of exogenous chemicals into the trunk. The barrier part of the skin is idea to lie predominately in the outermost layer of the epidermis, the stratum corneum. The stratum corneum is idea to largely present a hydrophobic barrier to the absorption of transdermal creams. The dermis, immediately below the epidermis, contains the blood vessels that are able to transport substances that have permeated the skin into the systemic circulation.
Although less studied than organic molecules, metal ions are known to exist able to cantankerous the skin, with the literature having focussed on metals that are known to crusade irritant/toxic effects [13]. The lower resistance to permeation of the skin appendages, skin structures that serve a detail role including sensation, lubrication and estrus loss, and the ionised nature of metals means that their permeation beyond these skin appendages is considered to be the most likely route of absorption [thirteen,14]. However, the low surface area available for this in man pare means that metallic ion assimilation across skin is expected to be relatively low. Therefore, it has been questioned that a transdermal road of assistants might provide sufficient Mg2+ absorption to help see systemic Mgtwo+ requirements. This investigation aims to make up one's mind if transdermal absorption of Mg2+ from a topical cream occurs "in vivo" in humans.
To date, no study has investigated the absorbency of transdermal magnesium cream in man subjects. Commercially bachelor Mg2+ topical applications range from 75mg to 400mg depending on the dosage recommended by manufacturers. This ranges from five–thirty sprays of magnesium oil or 2–4 teaspoons of magnesium cream, which can exist applied in ane application or throughout the mean solar day. Disappointingly, many commercial topical creams and oils do not country the concentration of magnesium in the product.
This study was designed as a offset fourth dimension, airplane pilot study to ascertain whether such a topical Mg2+ preparation might affect urinary or serum Mgii+. Since less than 1% of magnesium is contained in the blood, cess by serum status may be problematic [three]. It is frequently considered that 24-hr urine excretion of Mgtwo+ may be a better indicator of intestinal absorption than serum concentration; however, urinary Mgtwo+ excretion is also highly variable and it is questionable whether it can exist used reliably to assess an individual'southward Mg2+ status [15]. However, serum Mg2+ can reflect a longer term dietary Mg2+ status over weeks or months whilst urinary Mg2+ can be a better marker of one'southward recent dietary intake [16]. These studies using serum and urinary Mgii+ markers in dietary Mg2+ enquiry could not be assumed to be helpful in the blueprint of this study. Djurhuus et al,[17], however, reported that although information technology is unlikely that a single decision of serum Mg2+ tin exist used in assessing whole-body Mg2+ condition in an private, serial determinations of serum Mg2+ might prove useful as an indicator of changes in whole body Mg2+ status. These authors likewise found that 24-hr urinary Mg2+ excretion is unlikely to be a reliable measure of whole body Mg2+ status and is not a proficient marker to measure out changes in whole body Mg2+ status. Nonetheless, we decided to use 24-hr urinary Mgii+ besides as serum Mgii+ in this pilot study.
Therefore, the purpose of this pilot study was to investigate whether a 56 mg/twenty-four hour period dose of magnesium in a cream, practical transdermally to humans, would touch on either serum magnesium levels or urinary excretion over a ii-week menstruum and to mensurate effect, if any, and variance to inform a properly powered futurity study, if warranted.
Methods
Recruitment
Subject recruitment started April 2014 and information collection and follow-up was completed by Feb 2015. The report was non registered on a CT Database at the fourth dimension of subject recruitment every bit trial registration in these kinds of studies is not commonly adept. The trial was subsequently registered in gild to comply with publication requirements co-ordinate to the WHO guidelines. The authors confirm that all ongoing and related trials for this intervention are registered.
Participants
Xx-five good for you adults (female = 13 male = 12) aged 34.iii+/-xiv.8y, meridian 171.5+/-11cm, weight 75.9 +/-xiv Kg, were recruited from the staff and student population of the University of Hertfordshire and give-and-take of rima oris to local residents and randomly assigned into either a magnesium cream or placebo foam group by random allotment. Randomisation was determined by allocation to a group selected from a box with equal amounts of newspaper stating either placebo or magnesium and selected at time of recruitment. The trial was single bullheaded with merely the lead investigator being aware of the content of the cream. One participant dropped out of study before completion. Participants were excluded if they were taking magnesium supplementation in any course within a calendar month of recruitment onto the trial, were under the age of 18y or above the age of 60y.There were no height or weight restrictions, Written informed consent was completed and ethical approval was granted by the University of Hertfordshire Health and Human Science Ethics Committee on 14th Apr 2014. Blood collection and blood and urine analysis was undertaken at the University of Hertfordshire Homo Physiology Laboratory.
Dietary magnesium intake was beneath the RNI in one of the placebo participants and three of the magnesium participants. This was not considered a bar to inclusion into the study as whatever change in serum or urinary Mg2+ from the cream could still be shown. High levels of physical exercise have been shown to deplete homo Mg2+ status ([18]. Iv participants were considered "athletes" as they engaged in at least 2hrs of physical exercise at least 5 days per week during the study, 3 who were assigned to the Mg2+ intervention group and 1 assigned to receive placebo. All other 20 participants who completed the study were considered "non-athletes", i.east. engaging in less than 2 hrs physical exercise per day for no more than than 3 days per week during the study. Participants were instructed not to practise 24h before claret draws, but "athletes" may have disregarded this education, so results were statistically analysed in two ways: one. "all subjects", including both athletes and non-athletes (n = 24 who completed the written report) and 2. "not-athletes" (n = 20) which excluded the 4 athletes. Baseline serum and urine Mg2+ concentrations as well as dietary Mg2+ recorded in the randomised intervention and placebo groups did not differ significantly from each other (P<0.05) (Tables 1 & 2) in either the "all subjects" or "non-athletes" groupings.
Baseline measurements
Baseline data consisted of a 24 hr urinary collection to assess baseline magnesium excretion and venous bloods to assess serum magnesium levels. (Tables i and 2). Urine was collected from the second urinary passing of the 24-hour interval until and including the first urinary passing of the next day. Blood collection could take place at whatsoever time of the day to adjust the participants but each participant had to return at that aforementioned timeslot for the second blood drove. No food was immune for the 3 hours before blood collection although water was immune.
Dietary analysis
Each participant recorded a iv-twenty-four hours food diary (3 midweek days and 1 weekend twenty-four hour period) prior to the intervention plus a 2d 4-day food diary at the end of the 12–14 mean solar day period, giving a total of viii days dietary analysis over the period of the intervention for each participant. This was analysed for Mgii+ intake using Diet Program six software (Forestfield Software Ltd., Westward Sussex, Uk). (Tables 1 and 2).
Intervention
After baseline measurements were taken, participants were randomly assigned to either the Mg2+ Cream or a placebo command cream and were instructed to utilize 2 x 5ml spoonfuls of cream per twenty-four hour period for two weeks. The resulting daily Mg2+ dose received by subjects in the Mg2+ grouping consisted of 56mg of Mg2+. This was manufactured, in the form of enquiry and evolution, for the Center for Magnesium Education & Research by Urist Cosmetics of Vancouver, B.C. Canada. For total ingredients come across S1 Text Ingredients list.
The placebo was a commercially bachelor aqueous foam containing no magnesium (by analysis) and creams were packaged identically. Instructions to participants suggested that Mgtwo+ or placebo cream be applied to the stomach and trunk in the outset instance and and so spread downwards to the legs. Time of twenty-four hours was not of import, but no showering or washing could have place for a minimum of 3 hours afterward application. After 12–14 days, terminal urine and claret samples were collected. The foam was practical upwardly to and including the twenty-four hour period of the concluding urine and blood collection. Participants were instructed to stop use of the cream if there was whatsoever agin reaction, of which there were none. At the end of the trial compliance was ensured from verbal communication as well of collection of the trans-dermal cream container to ensure full usage.
Sample collection
Serum blood samples were nerveless by venepuncture from the median cubital, basillic or cephalic vein. Serum separator vacutainers were inverted 10 times earlier beingness left to rest for thirty minutes. After, samples were centrifuged at 3000 rpm for 10 minutes. Serum was checked to be costless from haemolysis and was immediately pipetted and frozen at -80°C for subsequent assay
Urine was collected into three litre collection vessels over 24 hours. Urine was then decanted into a measuring vessel and volume of urine was recorded. The measuring vessel was then placed on a magnetic stirrer at 100rpm. To re-suspend the Mg2+, the pH was lowered to 3–3.25 by adding 5 M muriatic acid. Indistinguishable 1mL aliquots were frozen at -80°C for batch analysis.
Analyses
Urine and serum samples were analysed by colorimetric assay for magnesium (RX MONZA, Randox Laboratories Limited, County Antrim, United Kingdom). The motorcar was calibrated according to the manufacturer's instructions and results were calculated from the standard concentration curve generated using the manufacturer's calibration standard. Low urinary and serum Mg2+ were determined to exist below 3.0mmol/24h and 0.65mmol/fifty respectively [19].
All urine and serum samples were frozen and stored at -80°C for between 4–12 weeks.
Data assay
Serum and urinary Mg2+ data for both pre and post intervention were analysed for skewness and normality prior to statistical analysis. All information passed the normality examination so a standard two tailed, paired t-test was used to compare baseline to post-intervention values (serum and urinary Mg) for inside group analysis.
Statistical assay was conducted using SPSS V22 (IBM, New York, USA), with P value value of ≤0.05 accepted every bit statistically significant.
Results
Of the 29 subjects recruited, 1 was excluded for non coming together the criteria and 3 declined to participate afterwards baseline data was collected. 14 participants were allocated to the magnesium intervention grouping and completed the trial. Xi were allocated to the placebo intervention from which one dropped out due to agin reaction to the venepuncture at the baseline blood collection before foam had been administered. Fig 1 depicts the inclusion and exclusion of the participants in the study.
Urinary and serum response to trans-dermal magnesium application
Mean serum and 24-hour urinary Mg2+ concentrations were obtained for all participants before and after a 2-calendar week application menstruum of the magnesium or placebo trans-dermal foam. Baseline (Tables 1 & 2) serum Mgii+ values were below normal reference values (0.65mmol/fifty) in one magnesium intervention participant and one placebo participant (both non-athletes), whilst the baseline 24-hour urinary Mg2+ excretion was below normal (three.0mmol/24h) in 2 placebo participants (one non-athlete, one athlete) and three magnesium participants (two not-athletes, 1 athlete); these were different participants for both the serum and urine. Of the five participants with low urinary excretion, 3 had below the RNI for dietary Mg2+ intake however this was non the example for the low serum Mgii+ subjects.
All participants, Table 3
There was no statistically significant result of Mg2+ foam on either serum or urinary Mgtwo+ condition. However, after the Mgtwo+ cream intervention there was a clinically relevant increase [11, 19] in serum magnesium (0.82 to 0.89 mmol/l) that was not seen in the placebo group (0.77 to 0.79 mmol/L), but this was non statistically significant (p = 0.29). Similarly, in that location was a slight increase in magnesium urinary excretion in the Mg2+ grouping merely again no statistical significance (p = 0.48). A percentage increment of eight.54% for serum Mgii+ and nine.1% in urinary Mg2+ was seen in the Mg2+ group while for the placebo group these figures were smaller, i.east. +ii.6% for serum Mg2+ and -32% for urinary Mg2+. In the placebo group both serum and urine concentrations showed no statistically significant change after the application of the placebo cream.
Non-athletes, Tabular array 4
For non-athlete participants (n = 11 in Mg grouping plus n = ix in placebo group), there was a statistically significant ascent (P = 0.02) in serum Mg2+ in the intervention group which was not seen in the placebo grouping. Serum Mg2+ in the intervention showed a % change of +22.7% while that in the placebo grouping showed a +4.eleven% rise. Urinary Mgtwo+ did not show any significant change in either Mg2+ or placebo group although a large non-significant negative change could be seen in the placebo group (-32.50%) when compared with the xi.iii% increase in the intervention group.
Discussion
Transdermal Mg2+ consequence on serum Mg2+
Previous study of humans take shown that serial determinations of serum Mg2+ can prove useful as an indicator of changes in whole trunk Mg2+ status[17]. From this study, 56 mg/24-hour interval Mgtwo+ applied as transdermal cream for 12–14 days had no statistically significant effect on serum concentration in this small (northward = 25) homo study when both athletes and non-athletes were included in the statistical analyses. Withal, a tendency towards a rise in serum Mg2+ in the Mg2+ group could be seen with an increase of 0.07mmol/l, a clinically relevant rise in a measurement that is greater than many previous studies and a ascension that would take months to show change with oral Mgii+ therapy [xi, 19]. Zhang et al., [xi] reported that in 41 trials, 941 participants receiving a mean oral Mg supplement of 365 mg/twenty-four hours for a median of 12 weeks showed a mean rise of 0.05 mmol/Fifty circulating Mg (0.78 to 0.83 mmol/L). A meta-analysis of 27 trials by Zhang et al [8] investigating oral Mg2+ supplementation, showed a significant (p<0.001) rise in serum Mg with 200 mg/day oral Mg supplement or ane month supplement duration but that higher doses (≥ 300 mg/day) or durations of supplementation (≥2 months) were required to achieve a mean rise of 0.05 mmol/l in serum Mg2+. Additionally, studies included in the Zhang et al [8] meta-analysis prove a baseline mean C.V. for the 27 serum Mg2+ studies of ix.3% for Mg groups and ten.8% for placebo groups, i.due east. equally little equally half of the variance for baseline serum Mg2+ measurements in this written report (C.Five. = 21.9% and 17.3% for Mg2+ groups, all subjects and non-athletes respectively; C.5. = 20.7% and 12.3% for placebo groups, all subjects and not-athletes respectively). This pilot study of all subjects, both athletes and non-athletes, shows that transdermal Mg2+ may perhaps influence serum Mgii+ in a relatively short fourth dimension frame (12–14 days), but a higher concentration of Mg2+ cream, a larger number of subjects given the serum Mg2+ variance, and perhaps a longer written report is required to make any real conclusion.
Although participants were told to refrain from exercise for 24 hours before blood and urinary collection, 4 participants were undertaking regular high intensity training, the effects of which may touch Mg2+ parameters that can last longer than 24 hours [eighteen]. When the data from these four subjects were removed from the statistical analysis a significant outcome of the Mg2+ cream on serum Mgii+ concentrations could exist seen.(p = 0.02). Additionally, the %ascension in serum Mg2+ in the non-athletes (+22.seven%) was much larger than that shown in all subjects, i.e. both athletes and non-athletes (+8.54%). This is too small-scale a sample size to accomplish a firm conclusion but this increase in percentage modify in the not-athlete intervention grouping may exist due to an additional uptake of Mgtwo+.from the foam which may have been utilised during practise or for replenishment of Mg2+ stores rather than being transferred to serum in the athletic participants. This is an area of interest for farther report.
Farther, this assay of the serum Mg data for the not-athletes in the intervention group showed a mean increase from 0.75 to 0.92 mmol/l which may have clinical relevance in item with relation to cardiovascular disease. In a meta-analysis by Del Gobbo et al (2013)[20], information technology was found that a rise of 0.2 mmol/L circulating Mg was associated with a thirty% lower gamble of cardiovascular illness and fatal ischemic heart disease. In addition, Lutsey et al.(2014) [21] establish that after 20+ yrs follow up serum Mg showed a linear inverse association with the adventure of incident heart failure. Relative to those in the highest category of serum Mg, those in the everyman category were at ii.58 times greater risk of incident center failure after demographic adjustments. In these quintiles, the lowest serum Mg quintile was 0.7 mmol/L, the 2d was 0.75, the third was 0.8, the fourth was 0.85 and the highest was 0.ix mmol/L, i.eastward. each quintile was 0.05 mmol/l college than the next everyman quintile (these results were converted from mEq/50 past dividing by 2 to attain mmol/L). Our results testify a hateful rising of 0.05 mmol/Fifty serum Mg2+ with daily application of transdermal Mg2+ for only 2 weeks, and when because this Lutsey[21] report and the Del Gobbo[20] results, our finding suggests a possibly meaning favourable impact of transdermal Mg on risk of heart failure that needs full report.
Transdermal Mg effect on urinary Mg2+
Previous written report of humans has suggested that 24-60 minutes urinary Mg2+ excretion cannot be used as a measure of changes in whole body Mg2+ condition [17].
Upon analysis for all subjects, besides every bit for only non-athletes, use of the transdermal Mg2+ cream showed no pregnant ascension in urinary Mgii+, a measurement that reflects short term abdominal absorption of Mg2+. However, subjects in the Mgtwo+ group showed slight rises in urinary Mg2+ (+nine to 11%) while those in placebo grouping showed a substantial decrease in urinary Mgii+ (-32%). Possibly the decreased urinary Mgii+ excretion in the placebo cream group represents more than agile physiological Mgii+ memory processes that are not apparent in the Mg cream group ([xv,16]. It has been suggested that 24-60 minutes urine excretion of Mg2+ may be a better indicator of tissue status than the serum Mgtwo+ concentration, but information technology is highly variable and it is questionable whether it can be used to reliably assess a given individual's Mg2+ condition.
The trans-dermal foam independent 56 mg of Mgtwo+ administered daily. This is at the lower finish of creams sold commercially. The recommended dose of the few commercially available creams range betwixt 70mg/d to 400mg/d per day, therefore results of this study may represent an "underdose" of transdermal Mg2+.
Conclusion
No previous studies accept looked at effects of transdermal Mgtwo+ in human subjects. In this two-week pilot study, transdermal delivery of 56 mg Mg/day (a depression dose compared with commercial transdermal Mg2+ products available) showed a larger percentage change in both serum and urinary markers from pre to mail service intervention compared with subjects using the placebo cream. In addition, the ascent in mean serum Mg2+ seen in the Mg2+ group was clinically relevant although merely statistically meaning (p<0.05) when non-athletes were analysed separately.
Given the high variance in serum Mg2+ of these subjects, we propose that future inquiry focus on a larger number of human subjects given higher concentrations of Mg2+ cream awarding administered for longer durations to investigate whether transdermal application may bear witness a pregnant contribution to improvement in magnesium status. It would also be of interest to look at the effect of transdermal Mgtwo+ supplementation on athletes as compared to a sedentary population group.
Supporting information
Acknowledgments
Dr. Andrea Rosanoff declares a beneficial involvement in transdermal magnesium cream products.
Author Contributions
- Conceptualization: LK AR.
- Information curation: LK.
- Formal analysis: LK AR MP KS.
- Investigation: LK.
- Methodology: LK AR.
- Project assistants: LK.
- Resource: LK AR.
- Supervision: LK.
- Validation: LK AR.
- Visualization: LK AR.
- Writing – original draft: LK AR AT WM.
- Writing – review & editing: LK AR MP.
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Is Magnesium Better Absorbed Through The Skin?,
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