Adverse reactions of dimethyl sulfoxide in humans: a systematic review (2024)

Bennedikte Kollerup Madsen, Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing,^a,1 Maria Hilscher, Data Curation, Formal Analysis, Investigation, Validation, Writing – Original Draft Preparation, Writing – Review & Editing,¹ Dennis Zetner, Conceptualization, Formal Analysis, Investigation, Methodology, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing,¹ and Jacob Rosenberg, Conceptualization, Formal Analysis, Investigation, Methodology, Project Administration, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing¹

Revised. Amendments from Version 1

In this updated version an additional table (Table 9) has been added with an overview of the different administration routes of DMSO used in the included studies.

Background: Dimethyl sulfoxide (DMSO) has been used for medical treatment and as a pharmacological agent in humans since the 1960s. Today, DMSO is used mostly for cryopreservation of stem cells, treatment of interstitial cystitis, and as a penetrating vehicle for various drugs. Many adverse reactions have been described in relation to the use of DMSO, but to our knowledge, no overview of the existing literature has been made. Our aim was to conduct a systematic review describing the adverse reactions observed in humans in relation to the use of DMSO.

Methods: This systematic review was reported according to the PRISMA-harms (Preferred Reporting Items for Systematic reviews and Meta-Analysis) guidelines. The primary outcome was any adverse reactions occurring in humans in relation to the use of DMSO. We included all original studies that reported adverse events due to the administration of DMSO, and that had a population of five or more.

Results: We included a total of 109 studies. Gastrointestinal and skin reactions were the commonest reported adverse reactions to DMSO. Most reactions were transient without need for intervention. A relationship between the dose of DMSO given and the occurrence of adverse reactions was seen.

Conclusions: DMSO may cause a variety of adverse reactions that are mostly transient and mild. The dose of DMSO plays an important role in the occurrence of adverse reactions. DMSO seems to be safe to use in small doses.

Registration: PROSPEROCRD42018096117.

Protocol and eligibility criteria

Our study-protocol is registered at PROSPERO (Registration number:CRD42018096117). The systematic review was performed according to PRISMA-harms (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines¹³.

No limitations were set on the date of publication. The language was restricted to English, Danish, Swedish, Norwegian, and Russian. We included all original studies that administered DMSO to humans and included five or more participants. There was no gender or age restriction. For a study to be included, the authors had to suspect that an observed adverse reaction could be caused by DMSO.

Primary outcome

The primary outcome was any adverse reaction seen in relation to the use of DMSO in humans.

Literature search

The search was performed inPubMed (1966-present),EMBASE (1980-present), and theCochrane Library. The databases were last searched on February 23, 2018. Our search strategy was formulated with the help of a medical research librarian.

The search string used in PubMed was: ((dimethyl sulfoxide) OR DMSO) AND ((((((administration and dosage) OR adverse reactions) OR alternate effects) OR secondary response) OR toxicology) OR side effects)). The search was restricted to humans. The search string was adapted to EMBASE and Cochrane Library using the same search-words as abovementioned.

The search string used in EMBASE was: ((dmso or dimethyl sulfoxide) and ((side effect or toxicology or secondary response or alternate effects or alternate reactions or (administration and dosage)) and (dmso or dimethyl sulfoxide))).mp. The search was restricted to humans, articles and Medline journals were excluded.

The search string used in Cochrane was: (adverse drug events and dimethyl sulfoxide). The search was restricted to trials.

Study selection and data extraction

Two authors (B.K.M. and D.Z.) independently screened title and abstract according to the eligibility criteria usingwww.covidence.org. Discrepancies were resolved by discussion. One author screened the full-text articles (B.K.M.). Russian articles were screened by an author fluent in Russian (M.H.). If M.H. was in doubt regarding inclusion of a study the results were presented to B.K.M. and then discussed until a mutual decision was made.

After the screening process was finished, all included studies were imported to an Excel sheet (Microsoft Excel 2016). Data extraction was performed by two authors (M.H. extracted from the Russian articles and B.K.M. extracted from the rest). Data extracted were: author, publication year, country, study characteristics (study design, sample size, size of comparison group if present, time to follow-up), use of DMSO (reason for use, treatment duration, administration route, dose of DMSO), and adverse reactions observed (number of persons experiencing an adverse reaction, method of assessing, and duration of adverse reaction).

Analysis

The Newcastle-Ottawa-Scale was used to assess the risk of bias in non-randomized observational studies¹⁴. Risk of bias in randomized controlled trials was assessed using the Cochrane Handbook “Risk of Bias” assessment tool¹⁵. Risk of bias was assessed at the outcome level.

The primary summary measure was percentage of persons experiencing an adverse reaction, as well as the range in which a reaction occurred in the studies included. No meta-analysis and further summery measures were planned due to the expected large heterogeneity of the studies.

Study selection

Our primary search identified 2599 studies (Figure 1). After the evaluation process, 109 studies were included in the final review^{2,4,6–9,16–118}.

Figure 1.

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PRISMA flow diagram.

Gastrointestinal reactions

Gastrointestinal adverse reactions were reported in 61 studies. Of these, 10 studies were randomized controlled trials^{16,30,33,55,57,59,67,79,93,95}, 49 were cohort studies^{2,4,7,9,18,19,23,25–27,29,35,38–43,45,46,48,50–54,58,60,66,68,69,71,73,83,85–88,90,94,97,98,101,104,105,112,113,115,118}, and 2 were case series^84,109. Most studies reported the number of patients experiencing an adverse reaction (Table 1). Other studies reported adverse reactions observed in relation to the number of treatments given (Table 2).

The most commonly reported gastrointestinal adverse reactions were nausea and vomiting. The incidence of nausea seems to be less common with the transdermal administration of DMSO compared with intravenous administration. The majority of studies reported an incidence of nausea between 2–14%, with the exception of one study, reporting an incidence of 32%². In one study that failed to specify the dose, 8 of 42 patients reported nausea and anorexia, but the symptoms disappeared in five of the eight patients when the dose of DMSO was reduced⁴⁵.

Often the studies had short follow-up periods (less than 24 hours), especially when DMSO was used as a cryoprotectant. The study reporting the highest incidence of nausea had a follow-up period of 5 days⁴⁸, and the authors concluded that the high incidence of nausea observed might be due to the long follow-up period⁴⁸. In another article using the same data¹¹⁹, it was suggested that the delayed nausea was due to gastrointestinal mucosal damage, and only the initial nausea could be related to DMSO, and therefore we decided only to include the data from the first 2 days after infusion⁴⁸.

Halitosis was reported in 29 studies^{4,9,16,19,29,30,35,42,43,45,50,52,55,57,58,66–68,79,83,85,88,94,95,97,98,109,112,113}. In five studies, patients discontinued treatment due to halitosis^9,45,83,94. In five studies, all patients experienced halitosis^9,45,83,94. Unlike halitosis, other gastrointestinal side effects were reported more often when DMSO was administered intravenously, than transdermally or intravesically.

One study reported a severe case of nausea, vomiting, and abdominal cramps in one patient with an acute allergic reaction⁵⁹. However, in most studies the reported gastrointestinal reactions were transient and mild, often lasting only minutes to a couple of hours^{16,38,41,68,85,87,90}. Several studies reported a relationship between the dose of DMSO and the occurrence of gastrointestinal adverse reactions^{26,33,53,73,83,85}.

Cardiovascular and respiratory reactions

Cardiovascular and respiratory adverse reactions were reported in 33 studies. Of these, two were randomized controlled trials^33,59, 30 were cohort studies^{7,18,23,25–27,36,39–41,51,54,61,65,66,68,73,74,80,85–87,90,100–102,104,115,117}, and one was a preliminary report⁹¹. Except for one study⁶⁶, all studies reporting cardiovascular and respiratory reactions administered DMSO intravenously (Table 3 andTable 4).

Bradycardia was defined as a heart rate less than 60 beats per minute^41,61 and was often transient^23,61,90,115, but cases where atropine was needed are described^49,96. A lowered heart rate not enough to be considered bradycardia was observed in four studies^39,41,54,61.

In some studies, hypertension did not require intervention^61,102, but cases where medication was needed to control the hypertension, or where treatment was stopped due to hypertension, are described^41,54,85. Hypotension was also described as transient most of the time^{18,23,68,87,104}, with some cases needing intervention^40,51,54.

One study reported 11 cases of transient extrasystoles in 22 patients receiving cryopreserved autologous blood stem cells, monitored with Holter during infusion⁷³. There were two studies reporting cases of asystole during embolization of dural arteriovenous fistulas with a substance called Onyx, a non-adhesive liquid embolic agent dissolved in DMSO^91,100.

Dyspnea was reported in seven studies^{18,25,27,54,66,68,85}. A single study reported eight patients with transient shock after stem cell transfusion⁵¹. Some of these patients developed loss of consciousness and cyanosis but recovered promptly and had no need for additional therapy, whereas the rest of the patients developed severe hypotension or transient dyspnea, which was described as the reason for the transient shock. Further description of the condition was not provided.

Several of the studies found a correlation between the dose of DMSO used and the incidence of cardiovascular adverse reactions^{41,67,71,75,78,85,86,93,101,115}.

Dermatological reactions

Dermatological side effects are common when DMSO is administered transdermally. Skin reactions or allergic reactions were reported in 58 studies. DMSO was applied transdermally in 43 studies^{2,4,6,17,19–22,24,28–32,37,44,45,52,55,57,63,64,66,67,69,72,75,76,78,79,82,83,88,89,93,95,96,106,108,109,111–113}, intravenously in 14 studies^{25,40,41,51,59,73,74,77,85,86,92,98,101,110} and intraarticular in one¹⁰³ (Table 5).

The most common skin reaction was a local burning sensation reported in 13 studies^{17,21,24,28,30,45,55,57,67,69,79,93,106}. In one study, all participants experienced this burning sensation⁴⁵. In the same study, four participants experienced a transient peripheral edema associated with itching and erythema⁴⁵. A single study described a burning sensation in four of 669 patients when DMSO was given as a local injection⁹²; another study described burning in two out of 17 patients when DMSO was injected intraarticularly¹⁰³.

Most skin reactions were transient, only lasting minutes^{17,24,32,67,72}, but some studies reported cases described as serious, causing discontinuation of treatment^{2,6,52,63,78,96}. There were two studies describing that skin reactions to DMSO would disappear after days of continuous treatment^45,83. Another study reported that 1 of 18 patients treated for psoriasis with DMSO was hospitalized due to exfoliative erythroderma⁶³. In another study, two patients, diagnosed with dermographia developed prominent areas of weals after DMSO application⁹⁵.

Acute allergic reactions due to use of DMSO were reported in six studies^{37,44,59,86,98,110}. One study reported that 63 of 144 patients experienced allergic reactions, which was not described as serious adverse events (bronchospasms, facial flushing, rash)⁸⁶. In two other studies, acute allergic reactions were characterized as serious adverse events^59,110.

Flushing was regarded as an allergic reaction in this review and was only reported when DMSO was administered intravenously^{25,40,41,51,54,73,74}. A total of four studies, not depicted inTable 5, reported 204 cases of flushing during 1439 stem cell infusions^25,40,51,74. Several studies observed a relationship between the dose of DMSO and the occurrence of adverse reactions^{67,75,78,83,88,93}.

Neurological reactions

Headache is the most common neurological adverse reaction reported. In one study, headache was the reason for withdrawal of 2 out of 21 patients being treated with DMSO¹¹⁶.

Three studies using DMSO as a cryoprotectant in stem cell transfusions described seizures after administration^18,36,47. Severe encephalopathy was observed in one patient⁹⁹, and transient cranial nerve III and IV palsy was observed in one patient after Onyx embolization³⁴. One study described neurological symptoms occurring during and after transfusion, but they did not define neurological symptoms in detail⁸⁶.

Urogenital reactions

Few urogenital reactions were described (Table 6 andTable 7). Hemoglobinuria was described as an adverse reaction seen after transfusion of stem cell products^39,51,56,73. However, hemoglobinuria is often attributed to erythrocyte debris in the transplant material and has thus not been interpreted as being caused by DMSO^39,73. The other urogenital reactions (Table 6 andTable 7) all occurred after DMSO instillation in the bladder^38,49,97.

Other reactions

Only one study in this review administered DMSO as eye-drops¹¹⁴. In this study, two patients experienced severe conjunctival hyperemia due to allergic reactions, and 25% of patients experienced a stinging sensation when eye-drops were applied¹¹⁴. Other studies performed eye examinations to determine whether DMSO caused changes in the lens; however, no such cases were observed^2,45.

Hyponatremia occurred in six patients after they received large doses of DMSO as treatment for cranial hypertension⁶². This adverse reaction was not reported in other studies (Table 8).

Very few cases of serious adverse reactions associated with DMSO have been described^18,36,51,59.

Overall, most studies administered DMSO intravenously or transdermally (Table 9)

Risk of bias within studies

In this review, we included 76 cohort studies, of which 64 were prospective^{2,4,6,7,20,22,24–27,29,31,32,34–38,40–45,48,50–54,56,58,60,63,65,66,68–70,72,73,77,80,81,83,85,88,90,92,94,97,98,101–104,107,108,110,112,115,117,118} and 13 were retrospective^{9,18,23,39,46,47,61,71,74,86,87,100,105}. Bias was assessed using The Newcastle-Ottawa-Scale¹⁴. Using this scale, studies were given zero to nine stars. A high number of stars equals low risk of bias and vice versa. The studies in this review had a median value of 5 stars, with a range of 2–8. No studies received the highest possible value of nine stars. Very few studies had a comparison group that did not receive DMSO, and often the occurrence of adverse reactions was poorly described. There were 24 randomized controlled trials (Figure 2). Many studies received an unclear risk of bias because often it was vaguely described how adverse reactions were reported.

Figure 2.

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Risk of bias in randomized controlled trials.

Overall, there was a high risk of bias when assessing the description of adverse reactions. Some studies were not assessed for bias due to being case-reports, preliminary trials, or because they included more than one study design^{17,19,28,62,84,91,99,109,111,113}.

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The manuscript is now suitable for indexing.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

The authors have adequately addressed my concerns.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

The authors have conducted a systematic review assessing reports of adverse reactions attributed to DMSO. The topic is interesting, and the authors have conducted their searches in a reasonable way. However, there are several flaws in this manuscript that need to be addressed:

Introduction

• The term “possible adverse reactions” is incorrect. Suspected adverse reactions is more reasonable

Methods

• If Russian articles were screened by only one author, how were discrepancies resolved in these cases? Specify which authors extracted the data, and whether this was done independently.

Results

• The term “possibly due” is incorrect. There are 4 levels in describing associations between medicines and suspected adverse reactions. The authors should revise their terminology.

• You state “in some studies patients discontinued treatments due to halitosis”; however, you have provided references for 5 studies – the report can be more precise.

Discussion

• How does “including Russian studies” strengthen the review? What about several other languages that have been omitted?

• You state that there seems to be a dose-response relationship, and have drawn similar conclusions. However, at no point in the results do you reportdata to support this claim. You state that studies reported associations between dose and the occurrence of adverse reactions, but fail to report the doses in question.

• Please enumerate the limitations of your review.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

Dear Igho J. Onakpoya,

Thank your for reviewing our manuscript “Adverse reactions of dimethyl sulfoxide in humans: a systematic review”. Your comments were very helpful and we appreciate the effort you put in to reviewing our manuscript. We have addressed the individual questions in the section below. We hope your find our replies satisfactory. Questions are written initalic and answers in plain.

Q1: The term “possible adverse reactions” is incorrect. Suspected adverse reactions is more reasonable.

A1: We have changed the paragraph in the introduction section to “suspected adverse reactions”.

Q2: If Russian articles were screened by only one author, how were discrepancies resolved in these cases? Specify which authors extracted the data, and whether this was done independently.

A1: We have clarified in the manuscript how the screening process was performed: “Two authors (B.K.M. and D.Z.) independently screened title and abstract according to the eligibility criteria using www.covidence.org. Discrepancies were resolved by discussion. One author screened the full-text articles (B.K.M.). Russian articles were screened by an author fluent in Russian (M.H.). If M.H was in doubt regarding inclusion of a study the results were presented to B.K.M and then discussed until a mutual decision was made. After the screening process was finished, all included studies were imported to an Excel sheet (Microsoft Excel 2016). Data extraction was performed by two authors (M.H. extracted from the Russian articles and B.K.M. extracted from the rest).”

Q3: The term “possibly due” is incorrect. There are 4 levels in describing associations between medicines and suspected adverse reactions. The authors should revise their terminology.

A3: We have rewritten the paragraph so it now states: “Gastrointestinal adverse reactions were reported in 61 studies. Of these, 10 studies were randomized controlled trials.”

Q4: You state “in some studies patients discontinued treatments due to halitosis”; however, you have provided references for 5 studies – the report can be more precise

A4: We have made our report more precise and it now states: “In five studies, patients discontinued treatment due to halitosis.”

Q5:How does “including Russian studies” strengthen the review? What about several other languages that have been omitted?

A5: A Russian Chemist, Dr. Alexander Saytzeff, identified DMSO in 1866, however it was not used for medical use at the time¹. But the fact that he was Russian might have been the reason why Russian scientists have made numerous studies using DMSO. We therefore thought it would be valuable to include Russian articles since many of these studies have never been translated, and therefore are not available to the international scientific society. Of course, we could have included many other languages, but we thought it most relevant to include Russian since we observed a large amount of articles in Russian during our initial examination of the subject.

Q6: You state that there seems to be a dose-response relationship and have drawn similar conclusions. However, at no point in the results do you reportdata to support this claim. You state that studies reported associations between dose and the occurrence of adverse reactions but fail to report the doses in question.

A6: As mentioned in our study several studies described a dose-response relationship between the amount of DMSO and the occurrence of adverse reactions (^{26,33,41,53,67,71,73,75,78,83,85,86,93,101,115} ). However, since the doses of DMSO and the route of administration differ between the studies, we were not able to give an exact dose. We can only say that an association seems likely.

Q7: Please enumerate the limitations of your review

A7: We have enumerated the limitations listed in the discussion in the manuscript.

With well over 20,000 patients receiving DMSO based autologous transplants annually in Europe alone, this is a timely review of the toxic effects of this valuable agent. It has been performed in an appropriate and scholarly manner and brings added value by including the Russian literature not easily accessible to the average English-speaking reader.

However there are ways in which the review might be improved and give added value to the reader.

It is not easy to ascertain the number of patients receiving DMSO intravenously and those receiving it by other routes. A small table could clarify this.

The side effect tables either as numbers of patients or numbers of treatments. If they cannot be presented as one combined set of data then some explanation of the two separate tables would be beneficial.

There seems to have been no attempt to quantify the dose of DMSO which patients have received or to characterize the severity of the reactions and relate these. Furthermore DMSO is usually a vehicle to facilitate giving the patient some other treatment e.g. a stem cell transplant or drug so the reasons for the use of DMSO are not clear. This also means there are side effects from the drug or treatment facilitated by the DMSO; is it possible to separate these effects in any way? Do the authors of the many papers selected for analysis recommend an upper limit to the amount of DMSO given or have a strategy for minimising the dose?

In their final paragraph the authors suggest that "reactions due to DMSO are often mild and transient". In their previous paragraph they admit that the case reports the less common and more severe side effects which did not meet the eligibility criteria of this review. However as long ago as 2005 it was possible to identify severe side effects in an appreciable number of cases (Windrumet al., 2005¹). Furthermore although they do not separate the factors responsible the authors of reference 7 record a SAE (Grades 3, 4 and 5) profilein excess of 3%. The authors should possibly be a little more circ*mspect in this paragraph particularly as they recommend the use of DMSO in (unspecified) small doses.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

References

Dear Curly Morris,

Thank for reviewing our manuscript: “Adverse reactions of dimethyl sulfoxide in humans: a systematic review”. We appreciate the effort put into reviewing our manuscript, and we have tried our best to use your comments to improve our manuscript. We have addressed the individual questions in the section below. We hope your find our replies satisfactory. Questions are written initalic and answers in plain.

Q1:It is not easy to ascertain the number of patients receiving DMSO intravenously and those receiving it by other routes. A small table could clarify this.

A1: We have added a table (Table 9) to our manuscript describing the route of administration of DMSO.

Q2 & 3:There seems to have been no attempt to quantify the dose of DMSO which patients have received or to characterize the severity of the reactions and relate these. Furthermore DMSO is usually a vehicle to facilitate giving the patient some other treatment e.g. a stem cell transplant or drug so the reasons for the use of DMSO are not clear. This also means there are side effects from the drug or treatment facilitated by the DMSO; is it possible to separate these effects in any way? Do the authors of the many papers selected for analysis recommend an upper limit to the amount of DMSO given or have a strategy for minimising the dose?

In their final paragraph the authors suggest that "reactions due to DMSO are often mild and transient". In their previous paragraph they admit that the case reports the less common and more severe side effects which did not meet the eligibility criteria of this review. However as long ago as 2005 it was possible to identify severe side effects in an appreciable number of cases (Windrum et al., 2005¹). Furthermore although they do not separate the factors responsible the authors of reference 7 record a SAE (Grades 3, 4 and 5) profilein excess of 3%. The authors should possibly be a little more circ*mspect in this paragraph particularly as they recommend the use of DMSO in (unspecified) small doses.

A2 & 3: DMSO is most often used as a vehicle in combination with other drugs. Therefore, it is not possible to separate completely the adverse reactions related to the use of DMSO and the adverse reactions related to other drugs, since adverse reactions such as nausea, vomiting, headache etc. are not specific for solely DMSO.

As described by the authors of reference 7⁷,it was difficult to isolate the effect of DMSO from side effects related to conditioning chemotherapy. The only adverse effect that can solely be attributed to DMSO is halitosis. Therefore, we could not conclude that DMSO was the cause of SAE’s in reference 7 and have not included it in our study. Correctly, Windrum et al.¹ describes several adverse reactions which may be contributed to DMSO. However, the study does not describe the seriousness of the adverse reactions.

As described in our study, it is very possible that some events are underrepresented in our study, which is a limitation.

The upper limit was not described by any studies; on the other hand several studies evaluated different doses of DMSO and found that a lesser amount of DMSO created fewer adverse reactions (^{61,86,120–122}.). Based on this observation, we feel confident that the use of small amounts of DMSO is recommendable, since DMSO works well as a vehicle. However, limiting the amount would always be desirable.