TEPZZ 

55  ZZB_T
(19)

(11) EP 2 552 200 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.:

of the grant of the patent: A61K 31/10 (2006.01) A61P 25/00 (2006.01)
14.10.2015 Bulletin 2015/42
(86) International application number:
(21) Application number: 11763467.5 PCT/US2011/030806

(22) Date of filing: 31.03.2011 (87) International publication number:

WO 2011/123695 (06.10.2011 Gazette 2011/40)

(54) DIMETHYL SULFOXIDE (DMSO) FORMULATIONS FOR TREATING AUTISM

DIMETHYLSULFOXID (DMSO-)FORMULIERUNGEN ZUR BEHANDLUNG VON AUTISMUS
FORMULATIONS DE DIMÉTHYLSULFOXYDE (DMSO) POUR TRAITER L’AUTISME

(84) Designated Contracting States: (56) References cited:

AL AT BE BG CH CY CZ DE DK EE ES FI FR GB WO-A1-2007/049262 WO-A2-2008/091704
GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO US-A- 4 514 421 US-A1- 2007 180 544
PL PT RO RS SE SI SK SM TR US-A1- 2008 249 082 US-A1- 2009 312 273
US-A1- 2009 324 784
(30) Priority: 31.03.2010 US 319827 P
• Adams J B: "Summary of Biomedical Treatments
(43) Date of publication of application: for Autism", ARI Publication 40, 1 April 2007
06.02.2013 Bulletin 2013/06 (2007-04-01), pages 1-28, XP002700806,
Retrieved from the Internet: URL:http://
(73) Proprietor: Abela Pharmaceuticals, Inc. autism.com/pdf/providers/adams_ biomed_
Lake Forest, CA 92630 (US) summary.pdf [retrieved on 2013-07-10]
• RAMÍREZ E ET AL: "Dimethyl sulfoxide in the
(72) Inventors: treatment of mental patients.", ANNALS OF THE
• JACOB, Stanley NEW YORK ACADEMY OF SCIENCES 15 MAR
Portland, OR (US) 1967, vol. 141, no. 1, 15 March 1967 (1967-03-15),
• COZEAN, Jesse pages 655-667, XP002700807, ISSN: 0077-8923
Lake Forest, CA (US) • Prater G: "Products", , 1 September 1999
• COZEAN, Colette (1999-09-01), pages 1-3, XP002700808, Retrieved
Lake Forest, CA (US) from the Internet: URL:http://www.lef.org/
magazine/mag99/sep9 9-products.htm [retrieved
(74) Representative: Rees, Kerry on 2013-07-10]
WP Thompson
55 Drury Lane
London WC2B 5SQ (GB)
EP 2 552 200 B1

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent
Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the
Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been
paid. (Art. 99(1) European Patent Convention).

Printed by Jouve, 75001 PARIS (FR)

 1 EP 2 552 200 B1 2

Description [0008] Dimethyl sulfoxide (DMSO; (CH3)2(SO)) is a po-

lar, aprotic solvent widely used as a solvent. It is frequent-
BACKGROUND ly used in various chemical and biological reactions and
as a cryoprotectant for cell storage. The strong unpleas-
Field of the Invention 5 ant odor of DMSO, among other side effects, has ad-
versely impacted the use of DMSO in medical applica-
[0001] Embodiments of the invention relate generally tions.
to formulations comprising dimethyl sulfoxide (DMSO) to [0009] RAMÍREZ E ET AL: ("Dimethyl sulfoxide in the
treat behavioral disorders, communication delays, and treatment of mental patients.", ANNALS OF THE NEW
developmental delays. Several formulations disclosed 10 YORK ACADEMY OF SCIENCES 15 MAR 1967, pages
herein are useful for treating broad autism phenotype 655-667) discloses therapeutic effects of DMSO in men-
disorder, including autism spectrum disorders (e.g., au- tal patients and proposes the compound for the treatment
tism). of autism.

Description of the Related Art 15 SUMMARY

[0002] Behavioral disorders and neurodevelopmental [0010] There is a need in the art for an efficacious treat-
disorders are broad categories of disorders typically used ment of neurodevelopmental disorders, such as broad
to describe the perceived behavior and developmental autism phenotype. The phrase "broad autism pheno-
difficulties of children and adolescents. Such disorders 20 type", as used herein, shall be given its ordinary meaning
are often difficult to diagnose due to their varied etiolo- and shall include autism spectrum disorders (such as
gies, differing degrees of severity, and varied times of autism, Asperger syndrome, and atypical autism), disor-
onset. ders characterized by personality, language and social-
[0003] Behavioral symptoms are used to diagnose pa- behavioral disorders that fall below the threshold of an
tients and may include qualitative in social interaction, 25 autism diagnosis, and disorders having an underlying
impairment in communication, restricted and/or repetitive genotype associated with autism spectrum disorders.
behavior. Symptoms include lack of social or emotional [0011] Described herein is a formulation comprising
reciprocity, stereotyped or repetitive use of language, id- dimethyl sulfoxide (DMSO) to treat the behavioral and
iosyncratic language, panic attacks, impaired use of non- physical symptoms associated with autism spectrum dis-
verbal behavior, balance and coordination problems, and 30 orders. Alternatively, DMSO may be combined with
other generalized sensory problems. methylsulfonylmethane (MSM) and/or other related com-
[0004] For example, autism is a neurodevelopmental pounds to treat the behavioral and physical symptoms
disorder that is reported to affect one of every one hun- associated with broad autism phenotype and other neu-
dred children in the United States. It is a pervasive de- rodevelopmental disorders, including but not limited to
velopmental disorder affecting social, communicative 35 Attention Deficit Disorder (ADD), Attention Deficit Hyper-
and compulsive/repetitive behaviors characterized by activity Disorder (ADHD), hyperactivity, Asperger’s syn-
stereotypic complex body movements (stimming) and drome Tourette syndrome, Obsessive Compulsive Dis-
difficulties with normal social interaction. Children with order (OCD), Pervasive Developmental Disorder (PDD),
autism may have trouble using their imagination, have a tic disorders, and learning disorders. In accordance with
limited range of interests, and may show repetitive pat- 40 the invention DMSO and MSM are used to treat broad
terns of behavior or body movements. Autism can se- autism phenotype disorders. In several embodiments,
verely impact both the affected individual and the family the formulations described herein are protective and are
members. useful for the prevention or progression of the disorders
[0005] Once a patient is diagnosed with a behavioral identified herein. In several embodiments, the formula-
and/or neurodevelopmental disorder, many current treat- 45 tions described herein act as antioxidants, aid in myeli-
ment regimes strive to lessen associated deficits and nation, and/or facilitate neurotransmission.
family distress, and to increase quality of life and func- [0012] Formulations according to several embodi-
tional independence of the affected individuals. ments herein reduce one or more of stimming, repetitive
[0006] Methylsulfonylmethane (MSM; (CH3)2SO2)), behavior, ameliorate gastrointestinal distress, improve
also known as dimethyl sulfone or methylsulfonylmeth- 50 toilet training and/or other learned skill sets, improve lan-
ane, is an organosulfur compound that is a metabolite of guage function (ability to speak as well as desire to
DMSO and certain sulfur-containing amino acids. MSM speak), reduce social deficits, and/or improve the invol-
has been marketed primarily as a dietary supplement. untary gag reflex suffered by many individuals having
[0007] Adams J B: ("Summary of Biomedical Treat- autism or other broad autism phenotype disorders.
ments for Autism", ARI Publication 40, 1 April 2007 pages 55 [0013] In several embodiments, the invention compris-
1-28, URL:http://autism.com/pdf/provid- es use of a formulation suitable for administration to a
ers/adams_biomed_summary.pdf) discloses p.o. MSM subject having a broad autism phenotype disorder for the
in a dose of 0.5 to 2 g for the treatment of autism. treatment of the disorder, wherein the formulation com-

2
 3 EP 2 552 200 B1 4

prises DMSO and MSM. In several embodiments, the able for intravenous, sublingual, nasal, or topical admin-
broad autism phenotype disorder is one or more of At- istration to a subject. Other routes of administration may
tention Deficit Disorder (ADD), Attention Deficit Hyper- also be used, including but not limited to, subcutaneous
activity Disorder (ADHD), hyperactivity, Asperger’s syn- injection, direct injection into a tissue site, enteric admin-
drome, Tourette syndrome, Obsessive Compulsive Dis- 5 istration, epidural, intracerebral, intracerebroventricular,
order (OCD), Pervasive Developmental Disorder (PDD), intradermal, intramuscular, intraperitoneal, or intravesic-
tic disorders, and learning disorders. ular. In one embodiment, the formulation is suitable for
[0014] In several embodiments, the invention compris- oral administration.
es a formulation comprising, consisting essentially of, or [0019] In several embodiments, a formulation compris-
consisting of a combination of DMSO and MSM, and op- 10 ing DMSO in an amount ranging from about 0.1 g to about
tionally including other ingredients. In some embodi- 0.5 g is provided. In several embodiments, DMSO is
ments, DMSO is present in an amount ranging from about present in an amount ranging from about 0.1 g to about
0.01 g to about 5 g. In several embodiments, MSM is 5 g. In several embodiments, MSM is present in an
present in an amount ranging from about 1 g to about 10 amount ranging from about 1 g to about 5 g. In several
g. In several embodiments, the formulation is configured 15 embodiments, DMSO is present in an amount ranging
for administration of the DMSO and the MSM individually. from about 0.005 to about 0.1 g/kg of the subject’s body
In several embodiments, the formulation is configured weight and the MSM is present in an amount ranging
for the administration of the DMSO and the MSM togeth- from about 0.1 to about 0.8 g/kg of the subject’s body
er. In several embodiments, the formulation further com- weight. In several embodiments, DMSO is present in a
prises vitamins and/or dietary supplements, including but 20 concentration of about 0.1%-23% and the MSM is
not limited to omega-3, fatty acids (such as medium chain present in a concentration of about 10%-25% of the total
fatty acids, lauric acid, oleic acid, coconut oil, etc.), vita- volume of the formulation. In some embodiments, ratio
mins A-E, antioxidants, amino acids, neurotransmitter of MSM to DMSO is between about 20:1 to 500:1. In
precursors, herbal supplements (e.g., Lion’s mane, (Her- several embodiments wherein the formulation comprises
icium erinaceus) mycelium, cistanche extract; lemon 25 one or more additional compounds or nutrients, the ratio
balm (Melissa officinalis), Passiflora, St. John’s wort, of MSM and/or DMSO may be higher or lower than the
Chamomila), growth factors), and combinations thereof. range of ratios disclosed above. In some embodiments,
[0015] In some embodiments, the formulation further the MSM:DMSO ratio is altered to account for the inclu-
comprises a serotonin reuptake inhibitor. In some em- sion of one or more additional compounds or nutrients in
bodiments, the formulation further comprises risperi- 30 the formulation. In some embodiments, however, no
done. In some embodiments, the formulation further change in the MSM:DMSO ratio is made.
comprises urea. In some embodiments, the formulation [0020] In one embodiment, the formulation is config-
further comprises a sulfur binding agent. In some em- ured for a single administration to the subject for every
bodiments, the formulation further comprises one or 24 hours. In several embodiments, the formulation is con-
more nutrients that reduce one or more side effects as- 35 figured for multiple administrations to the subject over a
sociated with the components of the formulation. 24 hour period. In one embodiment, the formulation is
[0016] In several embodiments, the formulation is in a suitable for administration between 1 and 4 times daily.
solid form. In one embodiment, administration of the solid In still additional embodiments, multiple formulations are
formulation results in timed release of the DMSO, of the provided, such that administration times can be varied
MSM, of both DMSO and MSM, and/or of an optionally 40 based on a subject’s schedule (e.g., dosing is adaptable
included additional compound. In several embodiments, to the patterns within the circadian rhythm of a subject
the timed release of each compound is substantially sim- having a broad autism phenotype or other neurodevel-
ilar, while in some embodiments, the solid formulation opmental disorder). For example, in some embodiments
allows for individual release times of one or more com- a liquid formulation is administered one or more times
ponents of the formulation. 45 during the daytime to a subject, and a solid, time release
[0017] In several embodiments, the MSM reduces formulation is administered in the early evening, such
odor associated with administration of DMSO and/or the that a subject need not be woken up during their natural
metabolism of DMSO post-administration. In several em- sleep times in order to receive an additional dose of the
bodiments, MSM reduces one or more additional unde- formulation.
sired side effects caused by the DMSO. Such DMSO- 50 [0021] In several embodiments, the formulation is suit-
related side effects include, but are not limited to gas- able for co-administration with one or more additional
trointestinal irritation, skin reactions (e.g., irritation at the compounds, including, but not limited to amphetamines,
site of administration, injection, or application), dry skin, pemoline, methylphenidate, sertraline, atomoxetine, clo-
headache, dizziness, drowsiness, nausea, vomiting, di- mipramine, buspirone, bupropion, venlafaxine, imi-
arrhea, constipation, breathing problems, vision prob- 55 pramine, fluvoxamine, paroxetine, fluoxetine, nefazo-
lems, blood problems (e.g., hemoloysis), and allergic re- done, doxepin, clozapine, haloperidol, quetiapine, thior-
actions. idazine, lanzapine, carbamazepine, lithium citrate, and
[0018] In several embodiments, the formulation is suit- valproic acid. In one embodiment co-administration com-

3
 5 EP 2 552 200 B1 6

prises administration of the formulation to the subject pri- MSM and a serotonin reuptake inhibitor is provided. In
or to administration of the one or more additional com- several embodiments, a formulation for treating one or
pounds to the subject. In one embodiment, co-adminis- more symptoms associated with broad autism phenotype
tration comprises administration of the formulation to the disorder comprising DMSO, MSM, and risperidone is pro-
subject concurrently with administration of the one or 5 vided. In several embodiments, the invention comprises
more additional compounds to the subject. In one em- a formulation for treating one or more symptoms associ-
bodiment, co-administration comprises administration of ated with broad autism phenotype disorder, the formula-
the formulation to the subject after administration of the tion comprising DMSO, MSM, and one or more com-
one or more additional compounds to the subject. pounds selected from the group consisting of: ampheta-
[0022] In several embodiments, the formulation is suit- 10 mine, pemoline, methylphenidate, sertraline, atomoxet-
able for the treatment of a hyperactive gag reflex. In sev- ine, clomipramine, buspirone, bupropion, venlafaxine,
eral embodiments, the formulation is suitable for the imipramine, fluvoxamine, paroxetine, fluoxetine, nefazo-
treatment of anti-social behavior. In several embodi- done, doxepin, clozapine, haloperidol, risperidone,
ments, the formulation is suitable for improving language quetiapine, thioridazine, lanzapine, carbamazepine, lith-
skills in a developmentally delayed subject. In several 15 ium citrate, and valproic acid. In some embodiments, the
embodiments, the formulation is suitable for the treat- DMSO is provided in a dose of about .01 g to about 10
ment of stimming and/or other repetitive behavior (e.g., g, and wherein the MSM is provided in a dose of about
excessive double-checking, excessive hand-washing, 1 g to about 20 g.
anti-social outbursts, counting, tapping, repeating words, [0027] In some embodiments, the DMSO is combined
hoarding, etc.). In several embodiments, the formulation 20 with the MSM, and wherein the combination exists as a
is suitable for improving social interaction in a subject. In solid form at room temperature.
several embodiments, the formulation is suitable for im- [0028] In some embodiments, the DMSO and MSM is
proving the ability of a subject to focus his or her attention provided in a liquid formulation, wherein the liquid formu-
on a task or process for an increased period of time. In lation optionally comprises a flavoring. In some embod-
some embodiments, the increased attention span further 25 iments, the formulation comprises a flavoring and where-
improves the social interaction, language development, in the flavoring reduces or masks an unpleasant taste
or anti-social behavior of a subject. associated with the formulation.
[0023] In several embodiments, there is provided a for- [0029] In some embodiments, the DMSO is combined
mulation for the treatment of a broad autism phenotype with the MSM and/or an additional compound, and
disorder or symptoms associated with a broad autism 30 wherein the combination reduces an odor associated
phenotype disorder suitable for administration to a sub- with DMSO. In one embodiment the additional compound
ject having such a disorder or such symptoms, the for- comprises urea. In one embodiment the additional com-
mulation comprising DMSO in an amount ranging from pound comprises a nutrient.
about 0.01 g to about 5 g and comprising MSM. [0030] In one embodiment, the invention comprises a
[0024] In one embodiment, the formulation comprises 35 method for treating a broad autism phenotype disorder
MSM, which is present in an amount ranging from about comprising identifying a subject having a broad autism
1 g to about 10 g. In one embodiment, the formulation phenotype disorder (e.g., autism), and providing DMSO
comprises MSM, which is present in a concentration of and MSM to the subject. In several embodiments, the
about 10%-25% and the DMSO is present in a concen- invention comprises a method for treating one or more
tration of about 0.1%-3% of the total volume of the for- 40 of the following conditions: hyperactive gag reflex, stim-
mulation. In several embodiments, the formulation fur- ming behavior, repetitive behavior, anti-social behavior,
ther comprises an additional compound or nutrient that violent behavior, delayed language development, and
reduces an undesired side effect of the formulation. In delayed learned skills (e.g., toilet training) that may occur
one embodiment, the additional compound or nutrient is in subjects having broad autism phenotype, ADD, ADHD
a sulfur-binding agent. In one embodiment, the additional 45 or other developmental and/or behavioral diagnoses. In
compound or nutrient is urea. some embodiments, the method comprises identifying a
[0025] In several embodiments, the formulation is suit- subject having said condition(s), and providing DMSO
able for co-administration with one or more additional and MSM to the subject. In one embodiment, DMSO is
compounds to the subject, wherein the additional com- provided in a dose of about .01 g to about 10 g, and MSM
pound includes but is not limited to, amphetamines, 50 is provided in a dose of about 1 g to about 50 g. In one
pemoline, methylphenidate, sertraline, atomoxetine, clo- embodiment, DMSO is provided in a dose of about .1 g
mipramine, buspirone, bupropion, venlafaxine, imi- to about .5 g daily. In one embodiment, DMSO is provided
pramine, fluvoxamine, paroxetine, fluoxetine, nefazo- in a dose of about 3 g to about 5 g daily. In one embod-
done, doxepin, clozapine, haloperidol, risperidone, iment, MSM is provided in a dose of about 1 g/kg to
quetiapine, thioridazine, lanzapine, carbamazepine, lith- 55 about .8 g/kg of the subject’s body weight. In one em-
ium citrate, and valproic acid. bodiment, DMSO is provided in a daily dose of .01 g to
[0026] In several embodiments, a formulation for treat- about 5 g; and MSM is provided in a dose of about 1 g
ing broad autism phenotype disorder comprising DMSO, to about 10 g daily. In one embodiment, DMSO is pro-

4
 7 EP 2 552 200 B1 8

vided in a range of about .01 g to about 5 g, and MSM is SO is combined with MSM, wherein the combination ex-
provided in a range of about 1 g to about 10 g. ists as a solid form at room temperature. In one embod-
[0031] In one embodiment, DMSO and MSM are pro- iment, the solid combination is administered to a subject
vided in an oral form of about 1-10 ml daily, wherein the with broad autism phenotype disorder or any of the symp-
DMSO is in a concentration of about 0.1%-2% and the 5 toms associated with that disorder.
MSM is provided in a concentration of about 10%-25% [0037] In several embodiments of the invention, a for-
of the total volume. DMSO and MSM are individually pro- mulation for treating one or more symptoms associated
vided in an oral form in one embodiment. In other em- with broad autism phenotype disorder is provided. In one
bodiments, DMSO and MSM are provided in a combined embodiment, the formulation comprises DMSO and
oral formulation. The oral formulation is provided in a 10 MSM and one or more additional compounds selected
liquid form in one embodiment. Flavorings or other addi- from the group consisting of: amphetamine, pemoline,
tives are provided in some embodiments. In some em- methylphenidate, sertraline, atomoxetine, clomipramine,
bodiments, DMSO and MSM are provided in an intrave- buspirone, bupropion, venlafaxine, imipramine, fluvox-
nous, sublingual, nasal, or topical form. In one embodi- amine, paroxetine, fluoxetine, nefazodone, doxepin,
ment, DMSO and MSM are administered topically, and 15 clozapine, haloperidol, risperidone, quetiapine, thiori-
the combination reduces any skin irritation that may be dazine, lanzapine, carbamazepine, lithium citrate, and
experienced by using DMSO alone. In one embodiment, valproic acid. In one embodiment, DMSO is provided in
DMSO and MSM are administered orally, and the com- a dose of about .01 g to about 10 g, and MSM is provided
bination reduces any gastrointestinal side effects that in a dose of about 1 g to about 20 g. The additional com-
may be experienced by using DMSO alone. 20 pound is provided in a dose of about .25 mg to about 100
[0032] According to some embodiments, the invention mg in some embodiments.
comprises a formulation or therapeutic regimen consist- [0038] In one embodiment, the formulation comprises
ing or consisting essentially of DMSO and MSM for the an oral dose of DMSO and MSM in solid or liquid form,
treatment of a broad autism phenotype disorder (e.g., and a separate dose of the additional compound. Alter-
autism). In some embodiments, the invention comprises 25 natively, the formulation comprises a single dose com-
a therapeutic regimen comprising DMSO and MSM for prising, consisting, or consisting essentially of DMSO,
the treatment of a broad autism phenotype disorder (e.g., MSM, and at least one additional compound. In one em-
autism), wherein said MSM and DMSO are suitable for bodiment, DMSO is combined with MSM and an addi-
delivery separately or combined and/or sequentially or tional compound, wherein the combination reduces an
simultaneously. In one embodiment, DMSO and MSM 30 odor or other side effect associated with DMSO.
are delivered separately at different times (e.g., on dif-
ferent days or other time periods). In some embodiments, DETAILED DESCRIPTION
DMSO is delivered orally, and MSM is delivered topically,
or vice versa. [0039] In several embodiments, therapeutic formula-
[0033] In several of the embodiments disclosed herein, 35 tions for treating broad autism phenotype disorder, are
DMSO and MSM are provided in a single dose in a 24- provided. In one embodiment, a formulation comprising
hour period. Multiple doses in a 24-hour period are pro- an oral dosage of about 1-10 g/day MSM and about
vided in another embodiment. 0.01-2 g/day DMSO is provided. In one embodiment, a
[0034] In several embodiments disclosed herein, DM- formulation comprising an oral dosage of 4.7 g/day MSM
SO and MSM are additionally provided with one or more 40 and 0.025 or 0.25 g/day DMSO is provided. The oral dos-
additional compounds, including but not limited to am- age may be in the form of a liquid solution, capsule, pow-
phetamine, pemoline, methylphenidate, sertraline, ato- der, effervescent, or any other form suitable for oral de-
moxetine, clomipramine, buspirone, bupropion, venla- livery.
faxine, imipramine, fluvoxamine, paroxetine, fluoxetine, [0040] Non-oral doses are provided according to some
nefazodone, doxepin, clozapine, haloperidol, risperi- 45 embodiments. In some embodiments, DMSO and MSM
done, quetiapine, thioridazine, lanzapine, car- are provided intravenously, topically, buccally, nasally
bamazepine, lithium citrate, and valproic acid, or combi- (e.g., via drops or a spray), and/or subcutaneously. Sub-
nations thereof. In one embodiment, DMSO and MSM lingual doses are provided in several embodiments. In
enhances the absorption or bioavailability of the addition- several embodiments, the oral dosages of DMSO and
al compound. 50 MSM disclosed herein are supplemented with topical
[0035] In several embodiments, formulations de- DMSO, MSM, or a combination thereof.
scribed herein are used to supplement one or more non- [0041] Broad autism phenotype (e.g., autism) includes
drug therapies, including but not limited to cognitive ther- neurodevelopmental disorders characterized by, in some
apy, neuromodulation, occupational therapy, physical cases, cerebral hypoperfusion, neuro-inflammation and
therapy, behavior modification, biofeedback, etc. In 55 gastrointestinal inflammation. In several embodiments,
some embodiments, supplementing with DMSO and formulations disclosed herein are used to treat neurode-
MSM provides a synergistic effect. velopmental disorders. In several embodiments, formu-
[0036] In several embodiments disclosed herein, DM- lations disclosed herein are used to treat one or more

5
 9 EP 2 552 200 B1 10

the following: cerebral hypoperfusion, neuro-inflamma- including about 0.025 g/kg, about 0.03 g/kg, about 0.05
tion and gastrointestinal inflammation. In several embod- g/kg, about 0.1 g/kg, about 0.125 g/kg, about 0.15 g/kg,
iments, formulations comprising DMSO and MSM in- about 0.175 g/kg, about 0.20 g/kg, about 0.25 g/kg, about
clude one or more of the following compounds: dimethyl 0.30 g/kg, about 0.35 g/kg, and overlapping ranges there-
sulfide (DMS), L-arginine, fructose 1, 6-diphosphate, L- 5 of. Likewise, DMSO, in some embodiments, is adminis-
lysine, L-aspartate, and urea. In some embodiments, for- tered in a daily amount ranging from about 0.0001 g/kg
mulations comprising DMSO and MSM include sulfur- to about .2 g/kg including about 0.0002 g/kg, about
binding compounds, amino acids, and/or other nutrients. 0.0003 g/kg, about 0.0005 g/kg, about 0.0007 g/kg, about
In some embodiments, the additional compounds are 0.0009 g/kg, about 0.001 g/kg, about 0.002 g/kg, about
provided in a range of percentages from about 5% to 10 0.003 g/kg, about 0.004 g/kg, 0.008 g/kg, 0.012 g/kg,
about 50% by weight of the DMSO and MSM (e.g., about 0.015 g/kg, 0.02 g/kg, 0.04 g/kg, 0.06 g/kg, 0.10 g/kg,
5%- 10%, 10% - 15%, 15% - 20%, 20% - 30%, 30% - 0.12 g/kg, 0.15 g/kg, 0.175 g/kg, and overlapping ranges
40%, 40% - 50%, and overlapping ranges thereof). Rang- thereof.
es of about 1% - 5% and over 50% are used in certain [0045] In several embodiments, the invention compris-
embodiments. 15 es an oral formulation comprising a ratio of MSM to DM-
[0042] In one embodiment, the invention comprises a SO ranging from about 600:1 to about 40:1. In certain
method of treating the symptoms of broad autism phe- such embodiments, the MSM:DMSO ratio ranges from
notype disorders, wherein the method comprises daily about 100:1 to about 250:1, including 120:1, 140:1,
administration of a 10-100 ml formulation comprising 160:1, 170:1, 180:1, 185:1, 190:1, 200:1, 220:1, and
10%-15% MSM and 0.1%-10% DMSO and optional in- 20 240:1, and overlapping ranges thereof. In other embod-
termittent (e.g., weekly, monthly) administration of a iments, the invention comprises an oral formulation hav-
10-100 ml formulation comprising 10%-90% DMSO. In ing a ratio of MSM to DMSO ranging from about 600:1
some embodiments, the invention comprises a method to about 5:1. Such embodiments include formulations
of treating the symptoms of broad autism phenotype dis- with ratios ranging from about 10:1 to about 50:1, includ-
orders, wherein the method comprises regular adminis- 25 ing 20:1, 25:1, 27.5:1, 29:1, 30:1, 31:1, 32:1, 33:1, 33.5:1,
tration of a 10-100 ml formulation comprising 5%-50% 35:1 and 40:1, and overlapping ranges thereof. In yet
MSM and 0.1%-20% DMSO and optional intermittent other embodiments, the formulation comprises a ratio of
(e.g., weekly, monthly) administration of a 10-100 ml for- MSM to DMSO ranging from about 600:1 to 0.2:1. In such
mulation comprising 50%-100% DMSO, and optionally embodiments, the ratio may range from 0.2:1 to 2:1 in-
MSM. In some embodiments, DMSO and MSM regulate 30 cluding 0.3:1, 0.4:1, 0.5:1, 0.7:1, 0.9:1, 1.0:1, 1.1:1, 1.2:1,
neurotransmitter activity. 1.3:1, 1.5:1, 1.7:1, and 2.0:1, and overlapping ranges
[0043] In several embodiments, the combined use of thereof.
MSM reduces or eliminates the odor normally associated [0046] The ratio of MSM to DMSO in several embodi-
with DMSO. This is surprisingly beneficial in several em- ments is surprisingly advantageous because MSM syn-
bodiments because many practitioners have avoided us- 35 ergistically improves the efficacy of DMSO. Thus, DMSO,
ing DMSO in high concentrations (or in any amount) be- which may have side effects (e.g., odor, gastrointestinal
cause of its unpleasant odor. effects) when administered at certain concentrations,
[0044] In some embodiments, a formulation compris- may be provided at lower concentrations to offer the
es, consists or consists essentially of an oral dosage of same or better therapeutic efficacy. In some embodi-
about 2 g to 6 g daily MSM and about 0.01 g to 0.05 g 40 ments, the use of DMSO enhances the efficacy and/or
daily of DMSO. In another embodiment, a formulation lowers the amount of MSM needed. In one embodiment,
comprises, consists or consists essentially of an oral dos- DMSO reduces the side-effects and/or enhances the bi-
age of about 2 g to 6 g daily MSM and about 0.01 g to oavailability (or absorbability) MSM.
0.2 g daily of DMSO. In another embodiment, a formu- [0047] In some embodiments, the invention comprises
lation comprises, consists or consists essentially of an 45 a method of managing the symptoms of neurodevelop-
oral dosage of about 2 g to 6 g daily MSM and about 0.01 mental disorders, such as autism, by administering an
g to 5.0 g daily of DMSO. In some embodiments, about oral dosage of DMSO and MSM daily for a period of days,
0.1 g to about 0.5 g of MSM is administered to a subject weeks, months or longer. In certain embodiments, a short
daily in, for example, single or multiple doses. In some term regimen comprises an increased daily dose of DM-
embodiments, about 0.001 g to about 0.1 g of DMSO is 50 SO. In some embodiments, duration of use ranges from
administered to a subject daily in, for example, single or about 1 day to about 30 days (e.g., 7 days, 14 days, 20
multiple doses. In several embodiments, dosage of MSM days, etc.)
and DMSO is determined based on the body weight of a [0048] Formulations comprising DMSO and MSM are
subject. For example, in one embodiment, the mass of administered multiple times per day in certain embodi-
MSM and DMSO administered are based on the weight 55 ments. In some embodiments, dosing occurs two, three,
of a subject in kilograms (or other unit of measure). Thus, four or more times daily, depending on age and cooper-
in some embodiments, MSM is administered in a daily ation of the patient. In other embodiments, formulations
amount ranging from about 0.01g/kg to about 0.4 g/kg, are taken only once per day.

6
 11 EP 2 552 200 B1 12

[0049] In several embodiments, the combination of compounds. According to one embodiment, compounds
DMSO and MSM in a single formulation results in a syn- such as MSM are provided to reduce the odor associated
ergistic effect, thereby lowering the concentration of DM- with DMSO use by reducing the formation of DMSO me-
SO, MSM, or both needed to effectively reduce one or tabolites or by binding to DMSO metabolites (e.g., DMS).
more symptoms of autism or other neurodevelopmental 5 [0056] In some embodiments, the odor of DMSO (or
disorders According to one embodiment, the use of MSM its metabolites) is reduced by about 10-20%, about
reduces the amount of DMSO needed. In one embodi- 20-30%, about 30-40%, about 40-50%, about 50-75%,
ment, the use of DMSO reduces the amount of MSM about 75-95%, about 95%-100%, or overlapping ranges
needed. In one embodiment, a combined DMSO and thereof, when MSM is combined with DMSO. In one em-
MSM therapy results in reduced concentrations of both 10 bodiment, an odor reduction of at least 50% is achieved
DMSO and MSM. when MSM is combined with DMSO. In one embodiment,
[0050] Further, the synergistic effects of certain em- 10% MSM reduces the odor of 90% DMSO when MSM
bodiments reduce the amount of time from inception of is added to the DMSO prior to the administration of the
treatment to amelioration of symptoms associated with combination to a subject. In one embodiment, MSM in a
broad autism phenotype. In some embodiments, this time 15 concentration of at least 5% reduces the odor of DMSO
period is reduced several fold, for example from the order in concentrations up to 95% when MSM is added to the
of several months down to the order of several weeks. DMSO prior to the administration of the combination to
In certain embodiments, the synergistic effects result in a subject. In one embodiment, sulfur binding compounds,
symptomatic improvement within 3 to 6 weeks, and in DMSO (or DMSO metabolite) receptor agonists or an-
some embodiments, improvement is accomplished with- 20 tagonists are used to reduce the odor.
in days. [0057] Because the administration of DMSO to pa-
[0051] In several embodiments, DMSO combined with tients with broad autism phenotype may result in an odor
MSM is particularly advantageous because, in some em- that prevents treatment for patients that are attending
bodiments, DMSO enhances the bioavailability of MSM school, the reduction of odor in several embodiments dis-
by, for example, allowing MSM to more effectively pen- 25 closed herein is particularly advantageous. In one em-
etrate a desired target tissue or cell. In several embodi- bodiment, DMSO treatment combined with MSM can by
ments, DMSO is not used as a simple vehicle to enhance administered daily to a patient, instead of waiting until
penetration or transportation of another agent, but rather vacations. Because of the odor-reducing properties in
exhibits its own bioactivity. several embodiments, patient compliance with the for-
[0052] In several embodiments, formulations compris- 30 mulations is increased.
ing DMSO and MSM exhibit reduced odor than formula- [0058] In some embodiments, a coated or uncoated
tions comprising DMSO alone. Formulations in liquid, gel, formulation is provided. In some embodiments, the coat-
solid, and/or gaseous forms exhibit reduced odor when ing provides a time-release effect (e.g., sustained-re-
DMSO is combined with MSM in some embodiments. lease, sustained-action, extended-release, controlled-
[0053] As used herein, "compound" shall be given its 35 release, or continuous-release). Coatings, in some em-
ordinary meaning and shall include, but not be limited to, bodiments, incorporate a flavor additive, such that there
molecules, ingredients, atoms, substances and ele- is no chalky or medicinal-tasting residue remaining after
ments. consuming the solid formulation. DMSO and MSM, may
[0054] In some embodiments, the combination of DM- be provided in the form of oral capsules, gel-caps, tablets,
SO and MSM unexpectedly reduces the unpleasant odor 40 powders, and effervescents, or topical gels, lotions, and
normally experienced with DMSO use. For example, in creams. Other forms may also be manufactured. Liquid
certain embodiments, DMSO/MSM formulations pro- formulations comprising flavorings, colorings or other ad-
duce no perceptible odor after use. In some embodi- ditives are provided in several embodiments. Confection-
ments, formulations comprising DMSO and urea, and aries comprising DMSO and MSM are provided in some
MSM are provided to reduce odor. In several embodi- 45 embodiments. For example, in one embodiment, a hard
ments in which odor is reduced, odors associated with candy, chew or lollipop is provided to enhance the pal-
the oxidation, metabolism, degradation or other conver- atability of the formulation to children and/or to provide
sion of DMSO are reduced. For example, in one embod- controlled release. Formulations, according to several
iment, odors associated with methylthiomethane (DMS) embodiments herein, may also be incorporated into
are reduced. 50 foods and beverages.
[0055] In several embodiments in which odor is re- [0059] In several embodiments, a formulation compris-
duced, odors associated with the oxidation, metabolism, ing MSM and DMSO is encapsulated to, for example,
degradation or other conversion of DMSO are reduced. facilitate delivery, bioactivity, absorption, time-release,
In some embodiments, odors are reduced through the and/or palatability. In several embodiments, non-encap-
binding of odiferous compounds. In some embodiments, 55 sulated powders facilitate delivery, bioactivity, absorp-
odors are reduced by reducing the production of odor- tion, time-release, and/or palatability.
causing compounds. In some embodiments, odors are [0060] In some embodiments, one or more additional
reduced by increasing the degradation of odor-causing active compounds are provided with a DMSO/MSM com-

7
 13 EP 2 552 200 B1 14

bination. In certain embodiments, a formulation compris- pharmaceuticals are contraindicated.

ing DMSO and MSM further comprises vitamins and sup- [0063] In one embodiment, preventative doses of DM-
plements, including but not limited to omega-3 fatty acids SO and MSM are provided to individuals who have a
(such as medium chain fatty acids, lauric acid, oleic acid, predisposition (e.g., biological or environmental) for neu-
coconut oil, etc.), vitamins A-E, antioxidants, and com- 5 rodevelopmental disorders (e.g., broad autism spectrum
binations thereof. In some embodiments, a formulation disorders), but who have not yet exhibited symptoms. In
comprising DMSO and MSM further comprises stimu- some embodiments, preventative doses are in the range
lants, antidepressants, anti-psychotics and/or mood sta- of about .5 g to about 5 g of MSM and about .01 g to
bilizers (including, but not limited to, serotonin reuptake about 0.5 g DMSO. Lower or higher ranges may be used
inhibitors). In some embodiments, a formulation compris- 10 depending on the extent of risk, age, or weight of individ-
ing DMSO and MSM further comprises one or more of ual.
the following medications: amphetamine, pemoline, [0064] In several embodiments, a formulation compris-
methylphenidate, sertraline, atomoxetine, clomipramine, ing DMSO and MSM is used to positively affect one or
buspirone, bupropion, venlafaxine, imipramine, fluvox- more of the following symptoms displayed by autistic in-
amine, paroxetine, fluoxetine, nefazodone, doxepin, 15 dividuals: stimming behavior (daytime and nighttime);
clozapine, haloperidol, risperidone, quetiapine, thiori- gastrointestinal distress, including but not limited to se-
dazine, lanzapine, carbamazepine, lithium citrate, and vere constipation; delayed toilet training; communication
valproic acid. In some embodiments, the additional active function; social deficits; and hyperactive gag reflex. In
compounds are provided in a range of percentages from several embodiments, formulations described herein im-
about 5% to about 50% by weight of the DMSO and MSM 20 prove mitochondrial function and/or facilitate oxygen
(e.g., about 5% - 10%, 10% - 15%, 15% - 20%, 20% - transport in the body and are useful to treat broad autism
30%, 30% - 40%, 40% - 50%, and overlapping ranges phenotype, ADD, ADHD, hyperactivity and other neu-
thereof). Ranges of about 1% - 5% and over 50% are rodevelopmental or behavioral disorders. In several em-
used in certain embodiments. In some embodiments, the bodiments, formulations described herein reduce inflam-
ratio of MSM:DMSO by weight is 20:1 to 500:1. In some 25 mation, including but not limited to neuro-inflammation,
embodiments, the ratio of MSM and DMSO combined as and are useful to treat broad autism phenotype, ADD,
compared to another agent (such as a medication listed ADHD, hyperactivity and other neurodevelopmental or
above) by weight is 100:1 to 1000:1. In some embodi- behavioral disorders.
ment, the formulation comprises about 2-10 g [0065] In some embodiments, improvements in stim-
MSM, .01-1 g DMSO, and 2-500 mg of one or more phar- 30 ming are measured using the Repetitive Behavior Scales
maceuticals, such as a serotonin reuptake inhibitor, ris- (RBS). The RBS were designed detect the presence and
peridone, or other compound. In some embodiments, the severity of abnormal repetitive behaviors associated with
formulation comprises about 2-10 g MSM, .01-1 g DM- psychiatric, neurodevelopmental, and behavioral disor-
SO, and .5-50 g of one or more nutrients, such as a fatty ders. The RBS has four separate subscales, each meas-
acid, anti-oxidant, vitamin, etc. 35 uring a different type of repetitive behavior: Stereotyped
[0061] In several embodiments, combination therapy Behavior, Self-injurious Behavior, Compulsive Behavior,
of DMSO and one or more of the medications identified and a listing of all other aberrant behaviors. Each scale
above (or other medications used to treat autism) is par- has two sections, one of which lists the observable move-
ticularly advantageous because lowers doses of the ments, behaviors, or actions that are examples of the
medication can be used to achieve a comparable effect. 40 disorder, and a standard 7-item severity scale for each
Lowering the dose is particularly beneficial in some em- behavior. Formulations according to several embodi-
bodiments because side effects are concomitantly re- ments disclosed herein improve at least one of the re-
duced, which may be particularly advantageous for chil- petitive behavior types on the RBS subscales and are
dren. In one embodiment, DMSO acts to enhance pen- useful for treating psychiatric, neurodevelopmental, and
etration of one or more of said medications (or other med- 45 behavioral disorders, including but not limited to broad
ications used to treat autism). In one embodiment, DMSO autism phenotype, ADD, ADHD, hyperactivity, Asperg-
acts to catalyze the therapeutic reaction exerted by one er’s syndrome, Tourette syndrome, OCD, PDD, tic dis-
or more of said medications (or other medications used orders, and learning disorders. In some embodiments,
to treat autism). In several embodiments, DMSO, MSM formulations according to several embodiments herein
and one or more of said medications (or other medica- 50 reduce repetitive behavior by more than about 25%, 50%,
tions used to treat autism) provide a synergistic effect. 75%, 90%, 95% or 100%, in either frequency, duration,
[0062] In several embodiments, treatment of neurode- intensity, or a combination thereof.
velopmental disorders (e.g., broad autism spectrum dis- [0066] In certain embodiments, improvements in gas-
orders) are accomplished only with DMSO and MSM, trointestinal distress, including but not limited to severe
without the need for pharmaceuticals having undesired 55 constipation, are measured using the Visual-Analog
side-effects. In one embodiment, a formulation compris- Scale (VAS), which assesses the frequency and consist-
ing DMSO and MSM is particularly suitable for children ency of bowel movements. Formulations according to
under the age of 6, ages at which many of the traditional several embodiments disclosed herein improve the inci-

8
 15 EP 2 552 200 B1 16

dence of gastrointestinal distress, including reductions for the quantitative analysis of the entirety of the patient’s
in constipation. autistic behaviors, and scores can be directly compared
[0067] In certain embodiments, improvements in lan- before and after treatment to discern the effects and ben-
guage function are measured using the Mullen Scales of efits of DMSO/MSM treatment. Formulations according
Early Learning, testing both Expressive Language and 5 to several embodiments disclosed herein improve the
Receptive Language. The Mullen Scales of Early Learn- patient’s score in at least one of the CARS criteria.
ing were designed to measure a child’s early intellectual [0071] Furthermore, qualitative measures are used to
development, school readiness, and communication evaluate the effectiveness of DMSO/MSM therapy. Such
abilities, The Mullen Scales consist of five different rat- qualitative measures include, but are not limited to gen-
ings: Gross Motor, Fine Motor, Expressive Language, 10 eral improvements autism-associated deficits, reduc-
Receptive Language, and Visual Reception. Formula- tions family distress, increased quality of life, and in-
tions according to several embodiments disclosed herein creased functional independence of the affected individ-
improve the performance of a patient in at least one of uals. Conclusions of improvements using the
the Mullen Scales. In some embodiments, formulations scales/scores and qualitative indices as described may
improve a subject’s sign or oral language skills, including 15 be made between pre- and post-treatment evaluation of
but not limited to, learning a greater quantity of words, a patient, or between a post-treatment patient and an
expediting learning, learning longer words, forming sen- accepted average patient population with a similar de-
tences, understanding context, comprehending instruc- gree of symptoms.
tions, etc. Social skills are improved in several embodi- [0072] Specific embodiments will be described with
ments. 20 reference to the following nonlimiting examples, which
[0068] In certain embodiments, improvements in social should be regarded in an illustrative rather than a restric-
deficits are measured using the Social Responsiveness tive sense.
Scale (SRS). The SRS is a 65-item rating scale that
measures the severity of autism spectrum symptoms as EXAMPLE
they occur in natural social settings. The SRS provides 25
a clear picture of a patient’s social impairments, assess- [0073] A male patient, diagnosed with an autism spec-
ing social awareness, social information processing, ca- trum disorder at 24 months of age, was treated with a
pacity for reciprocal social communication, social anxie- combination of MSM and DMSO, beginning at the age
ty/avoidance, and autistic preoccupations and traits. It of 3. As described below, the patient exhibited marked
measures these traits in five different subsections: Re- 30 improvements in the areas of stimming, gastrointestinal
ceptive, Cognitive, Expressive, and Motivational aspects distress, verbalization and communication, social inter-
of social behavior, as well as Autistic Preoccupations, to action, and hyperactive gag reflex. In some embodi-
provide a balanced look at the patient’s improvements in ments, combination of MSM and DMSO unexpectedly
social interactions. Formulations according to several improve one or more symptoms associated with autism,
embodiments disclosed herein improve the performance 35 as compared to administration of MSM or DMSO individ-
of a patient in one or more SRS criteria. According to ually. In several embodiments, in addition to the benefi-
some embodiments, treatment with DMSO and/or MSM, cial therapeutic effects, the combination of MSM and DM-
alone or combined, improve anti-social and/or violent be- SO reduces one or more of the side effects typically as-
havior. sociated with DMSO administration (e.g., odor, gastroin-
[0069] Formulations according to several embodi- 40 testinal distress). In some embodiments, these unex-
ments disclosed herein reduce the severity and/or fre- pected effects are the result of the continued (e.g., daily)
quency of a patient’s hyperactive gag reflex. In several administration of MSM/DMSO, while in other embodi-
embodiments, DMSO and MSM are used to treat patients ments, these effects are long-term (e.g., persist beyond
with hyperactive gag reflex, regardless of whether neu- the period of continued administration of MSM/DMSO).
rodevelopmental symptoms are present. In some em- 45 Moreover, in certain embodiments, combinations of
bodiments, formulations disclosed herein are used to MSM and DMSO result in synergistic therapeutic effects
treat disorders in oropharyngeal response. Formulations for one or more of the symptoms of autism. In some em-
according to several embodiments herein reduce hyper- bodiments, these synergistic effects are the result of the
active gag reflex by more than about 25%, 50%, 75%, continued (e.g., daily) administration of MSM/DMSO,
90%, 95% or 100%, in either frequency, duration, inten- 50 while in other embodiments, these effects are long-term
sity, or a combination thereof. (e.g., persist beyond the period of continued administra-
[0070] Additionally, for adolescent patients, overall im- tion of MSM/DMSO).
provement in autism may be measured according to the [0074] The patient’s symptoms include stimming,
Childhood Autism Rating Scale (CARS). The CARS is nighttime stimming, hyperactive gag reflex, impaired so-
used to diagnose the presence and severity of autism 55 cial interaction, a lack of vocalization and communication,
symptoms. The scale uses fifteen different criteria, rated delayed success with toilet training, and constipation.
1 to 4, to objectively score a patient’s behavior, interac- DMSO/MSM treatment was initiated for patient. The pa-
tion, and emotional responses. Use of this scale allows tient was treated with 4.7 grams of oral MSM solution

9
 17 EP 2 552 200 B1 18

daily (4© teaspoons daily of a 15% solution). Within 12 positions disclosed herein are used as a chronic treat-
weeks, stimming (especially night-time stimming) was re- ment for an autism phenotype, and/or for counteracting
duced by about 90% and incidents of hyperactive gag one or more symptoms associated therewith. In some
reflex were reduced from multiple times per day to only embodiments, chronic treatment is not necessary, as the
a few times per month. The patient was also treated with 5 positive therapeutic effects persist beyond the period of
4.7 grams of MSM and .025 grams of DMSO in an oral administration.
solution (4 © teaspoons daily of 15% MSM and .1% DM- [0079] Social Interaction: At 18 months of age, the pa-
SO). Stimming and hyperactive gag reflex continued to tient would not engage with his parents, fighting any at-
improve as compared both to pre-treatment and treat- tention given to him. Within three months of DMSO/MSM
ment with MSM alone. 10 treatment, the patient showed great social development,
[0075] The patient was also treated with two short term and became more engaging with others (e.g., giving
bolus treatments with increased amounts of DMSO. In more eye contact, and is instigating affection in the form
addition to the 4.7 g of MSM and .025 g of DMSO in an of hugs and kisses.
oral solution, the patient received an additional 4.8 g/day [0080] When beginning school, the patient was placed
of DMSO for a short duration of 10 days (1 teaspoon, 15 in a one-on-one environment with the teacher, who felt
90% oral solution). The patient’s ability to vocalize im- that he was unable to participate in the routines of a reg-
proved dramatically, as did his attempts to communicate ular class. After six months of DMSO/MSM treatment,
and interact. The patient’s chronic constipation was also the patient was introduced into a classroom with other
eliminated during these treatment cycles of higher doses children, where he now sits attentively and participates
of DMSO. 20 appropriately.
[0076] The patient was further treated with an oral for- [0081] Communication: Before beginning DM-
mulation comprising 4.7 g of MSM and .25 g of DMSO. SO/MSM therapy, the patient struggled to communicate.
Improvements in communication, social interaction, and He knew one sign (for the word "more"). He would give
constipation continued at this dosage. a high-five when prompted, and would wave and imitate
[0077] Specific examples of improvements associated 25 dance moves from a favorite TV show. He was non-verbal
with several embodiments of the invention are set forth and non-vocal, with humming being his primary sound.
below. After one month of 4.7 grams of MSM treatment daily,
[0078] Stimming: The patient began exhibiting stim- the patient began to engage in an activity for 8-10 minutes
ming behavior at 18 months of age, beginning with head- at a time, a marked improvement. He also gained an
shaking and spinning. At 20 months, the patient began 30 additional sign ("my turn") and became more vocal. Fur-
running up and down the hall while humming in anticipa- ther, the patient vocalized using language-like sounds,
tion of bedtime. When put to bed, the patient would kick rather than just humming.
his crib and jump in the crib for hours at a time before [0082] Within about three months of DMSO/MSM
falling asleep from exhaustion. Often, the patient would treatment, the patient learned 20 sign language signs.
wake up in the middle of the night and continue jumping. 35 The patient began writing out his numbers, ABCs, and
After commencing treatment with a dose of 4.7 grams his name. After continued treatment, the patient had the
MSM daily (15% MSM solution, 4© oral teaspoons daily), ability to write out his numbers from 1-20 and the entire
improvement was noted within 12 weeks. The patient alphabet.
was going directly to bed, lying down, and no longer kick- [0083] After the patient was treated with a larger dose
ing. His nightly stimming was reduced from every night 40 of DMSO for 10 days in addition to his normal treatment,
to once every two or three weeks. Upon waking, the pa- the patient began speaking, vocalizing six different words
tient would chatter and play, rather than kick and jump. during a session. The progress continued with daily treat-
Treatment reduced the night-time stimming by about ment of 4.7 grams of oral MSM and .25 grams of DMSO.
90%, and daytime stimming by about 80%. Even upon The patient attempted to speak more than thirty times
discontinuation of MSM/DMSO administration stimming 45 per day and added several words to his vocabulary.
behavior, though slightly increased as compared to dur- Throughout treatment, his vocabulary and communica-
ing treatment, was reduced compared to pre-treatment tive skills increased. The patient gained a vocabulary of
behavior. Thus, in several embodiments MSM, either over 200 words, and demonstrated the ability to read post
alone or in combination with DMSO, reduces the inci- treatment. As above, these gains are maintained, even
dence of stimming behavior associated with autism. In 50 after cessation or reduction of the MSM/DMSO treat-
some embodiments, the combination of MSM with DMSO ment. As discussed above, the methods and composi-
further reduces the incidence of stimming. In some em- tions disclosed herein are used as a chronic treatment
bodiments, the combination of MSM and DMSO is par- for an autism phenotype, and/or for counteracting one or
ticularly advantageous because higher concentrations of more symptoms associated therewith. In some embodi-
DMSO can be used (to achieve greater therapeutic ef- 55 ments, chronic treatment is not necessary, as the positive
fects) and the typical side effects of DMSO (odor, gas- therapeutic effects persist beyond the period of admin-
trointestinal effects among others) are counteracted by istration.
the MSM. In some embodiments, the methods and com- [0084] Hyperactive Gag Reflex: Prior to DMSO/MSM

10
 19 EP 2 552 200 B1 20

treatment, the patient struggled with a hyperactive gag er, in some embodiments, one or more of the symptoms
reflex, which manifested itself up to five times daily. At discussed herein may be improved in the absence of one
times, the reflex was so severe that the patient would or more of the other symptoms (e.g., an autistic child may
vomit when witnessing someone eating, even when ob- exhibit improved toilet-training in response to MSM/DM-
serving a stranger eating an ice cream cone across a 5 SO without a coordinate improvement in communica-
shopping center. After a few months of treatment, his tion).
hyperactive gag reflex diminished dramatically. Even af-
ter cessation of therapy, the reduction in hyperactive gag
reflex was maintained. Thus, while in some embodi- Claims
ments, the methods and compositions disclosed herein 10
are used as a chronic treatment for an autism phenotype, 1. A formulation for use in the treatment of a broad au-
and/or for counteracting one or more symptoms associ- tism phenotype disorder, wherein the formulation
ated therewith, in some embodiments, chronic treatment comprises:
is not necessary, as the positive therapeutic effects per-
sist beyond the period of administration. 15 dimethylsulfoxide (DMSO); and
[0085] Constipation: The patient has struggled with methylsulfonylmethane (MSM),
constipation since he was a baby. This has been so se- wherein said formulation is suitable for admin-
vere, that he has developed a chronic anal fissure. Treat- istration to a subject having a broad autism phe-
ment with 90% DMSO vastly improved constipation. Im- notype disorder,
provement in constipation was also achieved with the 20 wherein said DMSO is present in an amount
dosage of 4.7 grams of MSM and .25 grams DMSO, with ranging from about 0.01 g to about 10 g, and
softer stool and more regular bowel movements. Upon wherein said MSM is present in an amount rang-
cessation of treatment with MSM/DMSO, the patient be- ing from about 1 g to about 50 g.
gan having difficulties with constipation. Thus in some
embodiments, while other symptoms of autism can be 25 2. The formulation for use according to Claim 1, where-
treated on non-chronic basis (e.g., the therapeutic effects in MSM reduces one or more undesired side effects
extend beyond the period of administration), mainte- of said DMSO, wherein said undesired side effects
nance doses of MSM and/or DMSO are used to maintain comprise gastrointestinal effects and/or tissue irrita-
the positive effects on constipation. Depending on the tion, or wherein said broad autism phenotype disor-
patient, MSM and/or DMSO may be administered in re- 30 der is autism.
sponse to distinct periods of constipation (e.g., non-
chronic, but episodic maintenance doses). In other em- 3. The formulation for use according to Claim 1, where-
bodiments, a long-term maintenance dose is adminis- in said MSM is combined with said DMSO resulting
tered (e.g., for those patients having severe constipation in a solid formulation at room temperature, or where-
issues). 35 in said MSM reduces odor associated with said DM-
[0086] While normally developing children are often SO, thereby enhancing subject compliance in taking
fully toilet-trained by the age 2-4, many autistic children the formulation.
are not toilet-trained until the age of 8 years old. Even in
such trained autistic children, accidents may be frequent. 4. The formulation for use according to any one of the
In some cases, the delay of toilet-training is autistic chil- 40 preceding claims, wherein said formulation further
dren is due to autistic children often feeling no pleasure comprises one or more of a serotonin reuptake in-
from making their parents and teachers happy, thus hibitor, urea, risperidone, a sulfur binding agent, or
causing the conventional methods that rely on a sense a nutrient that reduces one or more side effects as-
of pride for success with toilet training to fail. However, sociated with the components of said formulation.
despite the patient’s parents placing minimal focus on 45
the issue of toilet-training or pushing the patient to com- 5. The formulation for use according to any of one of
plete training, after treatment with MSM/DMSO, the pa- the preceding claims, where said formulation is suit-
tient was fully toilet-trained by age 5. Thus, in some em- able for the treatment of or improvement in one or
bodiments, the methods and compositions disclosed more of a hyperactive gag reflex, anti-social behav-
herein are useful for the treatment of a wide variety of 50 ior, language skills in a developmentally delayed
symptoms of an autism phenotype. Moreover, in some subject, stimming and/or repetitive behavior, social
embodiments, therapy with MSM/DMSO improves cer- interaction in a subject, or the ability of a subject to
tain underlying behavioral issues present in autistic chil- focus the subject’s attention.
dren (e.g., the psychological barriers that make toilet
training difficult). In some embodiments, such improve- 55 6. The formulation for use according to any of one of
ments may be accounted for by improvements in other the preceding claims, wherein said formulation is
symptoms discussed above (e.g., toilet training is im- configured to administer said DMSO and said MSM
proved as a result of improved communication). Howev- individually.

11
 21 EP 2 552 200 B1 22

7. The formulation for use according to any of claims, tism phenotype disorder, wherein the formulation
1-5 wherein said formulation is configured to admin- comprises:
ister said DMSO and said MSM in combination.
dimethylsulfoxide (DMSO); and
8. The formulation for use according to any of one of 5 methylsulfonylmethane (MSM),
Claims 1 and 3-7, wherein said MSM reduces odor wherein said formulation is suitable for admin-
associated with said DMSO or reduces one or more istration to a subject having a broad autism phe-
undesired side effects caused by said DMSO. notype disorder.

9. The formulation for use according to Claim 8, where- 10

in said side effects comprise gastrointestinal effects Patentansprüche
and/or tissue irritation.
1. Formulierung für die Verwendung bei der Behand-
10. The formulation for use according to any one of the lung einer breiten Autismus-Phänotyp-Störung, wo-
preceding claims, wherein said DMSO is present in 15 rin die Formulierung Folgendes umfasst:
an amount ranging from about 0.01 g to about 5 g,
and wherein said MSM is present in an amount rang- Dimethylsulfoxid (DMSO); und
ing from about 1 g to about 5 g. Methylsulfonylmethan (MSM),
worin die genannte Formulierung für die Verab-
11. The formulation for use according to any one of 20 reichung an ein Subjekt mit einer breiten Autis-
Claims 1-10, wherein said DMSO is present in an mus-Phänotyp-Störung geeignet ist,
amount ranging from about 0.005 to about 0.1 g/kg worin das genannte DMSO in einer Menge im
of said subject’s body weight and said MSM is Bereich von etwa 0,01 g bis etwa 10 g vorliegt,
present in an amount ranging from about 0.1 to about und
0.8 g/kg of said subject’s body weight. 25 worin das genannte MSM in einer Menge im Be-
reich von etwa 1 g bis etwa 50 g vorliegt.
12. The formulation for use according to any one of
Claims 1-10, wherein said DMSO is present in a con- 2. Formulierung für die Verwendung nach Anspruch 1,
centration of about 0.1%-3% and said MSM is worin MSM eine oder mehrere unerwünschte Ne-
present in a concentration of about 10%-25% of the 30 benwirkungen des genannten DMSO verringert, wo-
total volume of the formulation. rin die genannten unerwünschten Nebenwirkungen
Wirkungen auf den Magen-Dram-Trakt und/oder
13. The formulation for use according to any one of Gewebereizung umfassen oder worin die genannte
Claims 1-10, wherein the ratio of MSM to said DMSO breite Autismus-Phänotyp-Störung Autismus ist.
is between about 20:1 to 500:1. 35
3. Formulierung für die Verwendung nach Anspruch 1,
14. The formulation for use according to any one of the worin das genannte MSM mit dem genannten DMSO
preceding claims, wherein said formulation is con- kombiniert ist, was zu einer festen Formulierung bei
figured for administration between 1 and 4 times dai- Raumtemperatur führt, oder worin das genannte
ly. 40 MSM den Geruch reduziert, der mit dem genannten
DMSO assoziiert wird, wodurch die Compliance des
15. The formulation for use according to any one of the Subjekts zur Einnahme der Formulierung verbessert
preceding claims, wherein said formulation is in a wird.
solid form and wherein administration of said solid
formulation results in timed release of said DMSO 45 4. Formulierung für die Verwendung nach einem der
and said MSM. vorstehenden Ansprüche, worin die genannte For-
mulierung weiter eines oder mehrere der Folgenden
16. An oral formulation for use in the treatment of a broad umfasst: einen Serotonin-Wiederaufnahme-Hem-
autism phenotype disorder, wherein the formulation mer, Harnstoff, Risperidon, ein Schwefelbindendes
comprises: 50 Mittel oder einen Nährstoff, der eine oder mehrere
Nebenwirkungen, die mit den Komponenten der ge-
dimethylsulfoxide (DMSO); and nannten Formulierung assoziiert werden, verringert.
methylsulfonylmethane (MSM),
wherein said formulation is suitable for admin- 5. Formulierung für die Verwendung nach einem der
istration to a subject having a broad autism phe- 55 vorstehenden Ansprüche, worin die genannte For-
notype disorder. mulierung für die Behandlung oder Verbesserung
von einem oder mehreren der Folgenden geeignet
17. A formulation for use in the treatment of a broad au- ist: einem hyperaktiven Würgreflex, antisozialem

12
 23 EP 2 552 200 B1 24

Verhalten, Sprachfähigkeiten bei einem entwick- täglich konfiguriert ist.

lungsverzögerten Subjekt, Stimming und/oder repe-
titivem Verhalten, sozialer Interaktion bei einem 15. Formulierung für die Verwendung nach einem der
Subjekt oder der Fähigkeit eines Subjekts, die Auf- vorstehenden Ansprüche, worin die genannte For-
merksamkeit des Subjekts zu fokussieren. 5 mulierung in einer festen Form vorliegt und worin die
Verabreichung der genannten festen Formulierung
6. Formulierung für die Verwendung nach einem der zu einer zeitversetzten Freisetzung des genannten
vorstehenden Ansprüche, worin die genannte For- DMSO und des genannten MSM führt.
mulierung zur einzelnen Verabreichung des genann-
ten DMSO und des genannten MSM konfiguriert ist. 10 16. Orale Formulierung für die Verwendung bei der Be-
handlung einer breiten Autismus-Phänotyp-Stö-
7. Formulierung für die Verwendung nach einem der rung, worin die Formulierung Folgendes umfasst:
Ansprüche 1-5, worin die genannte Formulierung zur
kombinierten Verabreichung des genannten DMSO Dimethylsulfoxid (DMSO); und
und des genannten MSM konfiguriert ist. 15 Methylsulfonylmethan (MSM),
worin die genannte Formulierung für die Verab-
8. Formulierung für die Verwendung nach einem der reichung an ein Subjekt mit einer breiten Autis-
Ansprüche 1 und 3-7, worin das genannte MSM den mus-Phänotyp-Störung geeignet ist.
Geruch reduziert, der mit dem genannten DMSO as-
soziiert wird, oder eine oder mehrere unerwünschte 20 17. Formulierung für die Verwendung bei der Behand-
Nebenwirkungen, die durch das genannte DMSO lung einer breiten Autismus-Phänotyp-Störung, wo-
verursacht werden, verringert. rin die Formulierung Folgendes umfasst:

9. Formulierung für die Verwendung nach Anspruch 8, Dimethylsulfoxid (DMSO); und

worin die genannten Nebenwirkungen Wirkungen 25 Methylsulfonylmethan (MSM),
auf den Magen-Dram-Trakt und/oder Geweberei- worin die genannte Formulierung für die Verab-
zung umfassen. reichung an ein Subjekt mit einer breiten Autis-
mus-Phänotyp-Störung geeignet ist.
10. Formulierung für die Verwendung nach einem der
vorstehenden Ansprüche, worin das genannte DM- 30
SO in einer Menge im Bereich von etwa 0,01 g bis Revendications
etwa 5 g vorliegt und worin das genannte MSM in
einer Menge im Bereich von etwa 1 g bis etwa 5 g 1. Formulation pour une utilisation dans le traitement
vorliegt. de troubles caractéristiques d’un phénotype élargi
35 de l’autisme, la formulation comprenant :
11. Formulierung für die Verwendung nach einem der
Ansprüche 1-10, worin das genannte DMSO in einer du diméthylsulfoxyde (DMSO) ; et
Menge im Bereich von etwa 0,005 bis etwa 0,1 g/kg du méthylsulfonylméthane (MSM),
des Körpergewichts des genannten Subjekts vor- ladite formulation se prêtant à une administra-
liegt und das genannte MSM in einer Menge im Be- 40 tion chez un sujet ayant des troubles caractéris-
reich von etwa 0,1 bis etwa 0,8 g/kg des Körperge- tiques d’un phénotype élargi de l’autisme,
wichts des genannten Subjekts vorliegt. dans laquelle ledit DMSO est présent à une
quantité qui va d’environ 0,01 g à environ 10 g et
12. Formulierung für die Verwendung nach einem der dans laquelle ledit MSM est présent à une quan-
Ansprüche 1-10, worin das genannte DMSO in einer 45 tité qui va d’environ 1 g à environ 50 g.
Konzentration von etwa 0,1 %-3 % vorliegt und das
genannte MSM in einer Konzentration von etwa 10 2. Formulation pour l’utilisation selon la revendication
%-25 % des Gesamtvolumens der Formulierung vor- 1, dans laquelle le MSM amoindrit un ou plusieurs
liegt. des effets secondaires indésirables dudit DMSO,
50 lesdits effets secondaires indésirables comprenant
13. Formulierung für die Verwendung nach einem der des effets gastro-intestinaux et/ou une irritation tis-
Ansprüche 1-10, worin das Verhältnis von MSM zu sulaire ou lesdits troubles caractéristiques d’un phé-
dem genannten DMSO zwischen etwa 20 : 1 bis notype élargi de l’autisme étant un autisme.
500 : 1 beträgt.
55 3. Formulation pour l’utilisation selon la revendication
14. Formulierung für die Verwendung nach einem der 1, dans laquelle ledit MSM est combiné avec ledit
vorstehenden Ansprüche, worin die genannte For- DMSO pour obtenir une formulation solide à la tem-
mulierung zur Verabreichung zwischen 1- und 4-mal pérature ambiante ou dans laquelle ledit MSM réduit

13
 25 EP 2 552 200 B1 26

l’odeur associée au dit DMSO, augmentant ainsi est présent à une concentration d’environ 0,1 %-3
l’adhésion du sujet au traitement par la formulation. % et ledit MSM est présent à une concentration d’en-
viron 10 %-25 % du volume total de la formulation.
4. Formulation pour l’utilisation selon l’une quelconque
des revendications précédentes, ladite formulation 5 13. Formulation pour l’utilisation selon l’une quelconque
comprenant en outre un ou plusieurs des ingrédients des revendications 1-10, dans laquelle le rapport en-
suivants : inhibiteur du recaptage de la sérotonine, tre le MSM et ledit DMSO est entre environ 20:1 à
urée, rispéridone, agent de fixation du soufre ou nu- 500:1.
triment qui amoindrit un ou plusieurs des effets se-
condaires liés aux composants de ladite formulation. 10 14. Formulation pour l’utilisation selon l’une quelconque
des revendications précédentes, ladite formulation
5. Formulation pour l’utilisation selon l’une quelconque étant configurée pour être administrée entre 1 et 4
des revendications précédentes, ladite formulation fois par jour.
se prêtant au traitement ou à l’amélioration d’un ou
de plusieurs des aspects suivants : hyperactivité du 15 15. Formulation pour l’utilisation selon l’une quelconque
réflexe pharyngé, comportement antisocial, compé- des revendications précédentes, ladite formulation
tences linguistiques chez un sujet qui présente un étant sous une forme solide et l’administration de
retard développemental, comportement auto-stimu- ladite formulation solide résultant en une libération
latoire et/ou répétitif, interactions sociales du sujet échelonnée dudit DMSO et dudit MSM.
ou capacité du sujet à concentrer son attention. 20
16. Formulation orale pour une utilisation dans le traite-
6. Formulation pour l’utilisation selon l’une quelconque ment de troubles caractéristiques d’un phénotype
des revendications précédentes, ladite formulation élargi de l’autisme, la formulation comprenant :
étant configurée pour administrer ledit DMSO et ledit
MSM individuellement. 25 du diméthylsulfoxyde (DMSO) ; et
du méthylsulfonylméthane (MSM),
7. Formulation pour l’utilisation selon l’une quelconque ladite formulation se prêtant à une administra-
des revendications 1-5, ladite formulation étant con- tion chez un sujet ayant des troubles caractéris-
figurée pour administrer ledit DMSO et ledit MSM en tiques d’un phénotype élargi de l’autisme.
combinaison. 30
17. Formulation pour une utilisation dans le traitement
8. Formulation pour l’utilisation selon l’une quelconque de troubles caractéristiques d’un phénotype élargi
des revendications 1 et 3-7, dans laquelle ledit MSM de l’autisme, la formulation comprenant :
réduit l’odeur associée au dit DMSO ou amoindrit un
ou plusieurs des effets indésirables causés par ledit 35 du diméthylsulfoxyde (DMSO) ; et
DMSO. du méthylsulfonylméthane (MSM),
ladite formulation se prêtant à une administra-
9. Formulation pour l’utilisation selon la revendication tion chez un sujet ayant des troubles caractéris-
8, lesdits effets secondaires comprenant des effets tiques d’un phénotype élargi de l’autisme.
gastro-intestinaux et/ou une irritation tissulaire. 40

10. Formulation pour l’utilisation selon l’une quelconque

des revendications précédentes, dans laquelle ledit
DMSO est présent à une quantité qui va d’environ
0,01 g à environ 5 g et dans laquelle ledit MSM est 45
présent à une quantité qui va d’environ 1 g à environ
5 g.

11. Formulation pour l’utilisation selon l’une quelconque

des revendications 1-10, dans laquelle ledit DMSO 50
est présent à une quantité qui va d’environ 0,005 à
environ 0,1 g/kg de poids corporel dudit sujet et dans
laquelle ledit MSM est présent à une quantité qui va
d’environ 0,1 à environ 0,8 g/kg de poids corporel
dudit sujet. 55

12. Formulation pour l’utilisation selon l’une quelconque

des revendications 1-10, dans laquelle ledit DMSO

14
 EP 2 552 200 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European
patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be
excluded and the EPO disclaims all liability in this regard.

Non-patent literature cited in the description

• ADAMS J B. Summary of Biomedical Treatments for • Dimethyl sulfoxide in the treatment of mental patients.
Autism. ARI Publication 40, 01 April 2007, 1-28 RAMÍREZ E et al. ANNALS OF THE NEW YORK
[0007] ACADEMY OF SCIENCES. 15 March 1967, 655-667
[0009]

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