Conditions: Attention Deficit/Hyperactivity Disorder ADHD
Keywords: Attention Deficit/Hyperactivity Disorder ADHD Attention Deficit Disorder ADD Magnesium
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: no

Brief summary:
This study is a 12-week, open-label pilot study to test the effects of MMFS-201-301 on cognition and function in adults with ADHD. Subjects may enter the trial on a stable dose of medication for ADHD, and MMFS-201-301 will be given. Subjects who do not enter on a stable dose of ADHD medication will receive MMFS-201-301 alone.

Detailed description:

Arms:
arm 1: Subjects received open label L-Threonic acid Magnesium salt for 12 weeks. Subjects took MMFS202 (6-hour release) and MMFS302 (12-hour release) by mouth each day, up to three times a day.

Interventions: intervention 1: L-Threonic Acid Magnesium Salt (L-TAMS)
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
 
MMFS202 and MMFS302 use in ADHD: 
An Open-label Pilot Study of Cognitive and Functional Effects 
 
 
 
 
Craig B.H. Surman, MD 
Massachusetts General Hospital 
Clinical and Research Program in Adult ADHD and Pediatric Psychopharmacology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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I. 
BACKGROUND AND SIGNIFICANCE 
There is need to improve management of Attention Deficit Hyperactivity Disorder: 
Attention-deficit hyperactivity disorder (ADHD) is a neurobiological disorder associated with high 
levels of impairment in adulthood1-4, and is estimated to affect up to 5% of adults worldwide 5-7.  While 
currently approved pharmacotherapies for adults with ADHD are often effective, there are limits to their clinical 
utility. Stimulants are the mainstay of treatment for adults with ADHD due to larger effects than nonstimulants 
on ADHD8-11. Two decades of study by our research team and others, including controlled studies of stimulant 
medications and open studies of tricyclic, monoamine oxidase inhibitor, and atypical antidepressants, reveal that 
20-50% of adults with ADHD are considered pharmacologic nonresponders12-14. Moreover, adults who are 
considered responders clinically often show a 50% or less reduction in the core symptoms of ADHD13. In 
addition to residual ADHD symptom burden, pharmacologically treated patients also have residual burden in 
other cognitive capacities such as executive function challenges. For example, In a recent study of robust open 
label dosing with the amphetamine lisdexamfetamine, 40% of adults with ADHD were considered to have 
unresolved and clinically significant impairment in essential elements of behavioral executive control15 
Therefore there is significant clinical need for interventions that support the self-regulatory challenges that are 
not managed by current pharmacotherapies.  
Investigation into the neurobiological basis of ADHD has identified that a circuit involving prefrontal, 
subcortical and parietal regions is implicated in the pathological basis of ADHD.16-20 Delay in cortical 
maturation of cortex might impair executive functions, resulting in the poor working memory, attention, and 
response inhibition in ADHD children.21 
Magnesium (Mg) is involved in a wide range of biochemical reactions. Preclinical work demonstrates 
that L-Threonic acid Magnesium salt (L-TAMS) administration is associated with neurobiological and 
neurofunctional effects in the following ways: 1) Elevation of brain Mg lead to increase in synapse density and 
plasticity in PFC and hippocampus in young and old rats22, 23; 2) Elevation of brain Mg leads to enhancement of 
working memory, short- and long-term memory in rats 23, and 3) Elevation of brain Mg leads to enhance fear 
memory extinction and reduction of anxiety in rats.22 
There have been two published studies of L-threonate in animals, which identified metabolic interaction 
with ascorbic acid (Vitamin C) but no evidence of toxicity attributable to L-threonate. One published study of 
calcium L-threonate pharmacokinetics (single and multiple dose) in humans, found that L-threonate was rapidly 
absorbed and metabolized with no observed adverse effects. While we are not aware of studies focusing on the 
effects or safety of magnesium L-threonate itself in humans, in 2007, the European Food Safety Authority 
reviewed a number of unpublished animal studies involving calcium L-threonate including acute toxicity, 
subchronic and chronic toxicity, genotoxicity, and reproductive and developmental toxicity studies. The 
assessment concluded that the use of calcium L-threonate at levels that would result in 2,700 mg/d of L-
threonate intake is not a safety concern. 
The European Food Safety Authority comments are based on its review effects of Calcium L-threonate 
on rats and dogs.  For reference, “NOAEL” refers to “no adverse effects level” in their comments. In discussing 
the safety of Calcium L-threonate, this opinion notes that: 
 “Calcium L-threonate has low oral acute toxicity, with no adverse effects observed at doses as high as 
40 g/kg bw in mice or 32 g/kg bw in rats. In sub-chronic studies with calcium L-threonate, the Panel identified a 
NOAEL of 4 g/kg bw/day in the rat with regard to effects on blood coagulation time and accretion of the 
thyroid gland, and of 1 g calcium L-threonate/kg bw/day in the dog with regard to hyperplasia of the thyroid 
gland. The Panel noted that the effects on blood coagulation time and the thyroid gland were reversible and that 
a mild accretion in the thyroid gland in rats was limited to males only. The Panel further noted that these effects 


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are likely to be attributed to the high dosage of calcium administered over a long period, as a high concentration 
of calcium ions can result in accelerated blood coagulation, and can influence intestinal absorption of iodine and 
reduce/suppress the secretion of thyroxin by the thyroid gland.” The panel also wrote that “Studies using 
different test systems in vitro and in vivo indicated that calcium L-threonate was not genotoxic. Although no 
carcinogenicity studies were available, the Panel considered that such studies were not needed given that L-
threonate is an endogenous compound in the body and that calcium L-threonate did not show any genotoxic 
potential. Reproductive and developmental toxicity studies in mice indicated that calcium L-threonate in doses 
up to 6 g/kg bw/day has no adverse effect on the fertility and the developing fetus, and did not cause maternal 
toxicity.” 
The agency further notes in their statement that  “the margin of safety between the estimated human 
exposure to L-threonate and the amount of L-threonate equivalent to the NOAELs for calcium L-threonate, as 
demonstrated in sub-chronic toxicity studies in dogs and rats, is 39 – 19 for the dog and 155-77 for the rat. The 
Panel considers this margin of safety to be sufficiently large given that threonate is an endogenous compound in 
the body, and that the NOAELs in the dog and rat studies were identified for effects attributable not to L-
threonate but to the calcium dosages.”42 
 
Role of Magnesium in ADHD and ADHD management: 
Magnesium deficiency, like Vitamin D deficiency, is common, and has been studied among individuals 
with ADHD. Kozielec and Starobrat-Hermelin (1997) found magnesium deficiency in 95 per cent of children 
with ADHD across three sources examined, most frequently in hair (77.6 per cent), in red blood cells (58.6 per 
cent) and in blood serum (33.6 per cent). 24 However, a recent study by another group did not find lower serum 
Mg in children with ADHD. This could be due to poor resolution of serum Mg for evaluation of body. 26  
Studies have also explored magnesium supplementation in children with ADHD.  Another study by 
Starobrat-Hermelin and Kozielec (1997) recruited 50 hyperactive children, aged 7-12 years, who fulfilled DSM-
IV criteria for ADHD, with recognized deficiency of magnesium in the blood (blood serum and red blood cells), 
and in hair using atomic absorption spectroscopy. Some of the participants had disruptive behavior disorders. 
Over six months, subjects took magnesium preparations in a dose of about 200 mg/day. Participants received 
either standard treatment, or standard treatment with a magnesium preparation. For the subgroup of children 
that did not have other mental disorders coexisting with hyperactivity, there was an increase in the magnesium 
content in hair and a decrease of hyperactivity, both of which were significant relative to baseline. These 
changes were also greater than those seen in the control group that was not treated with magnesium. 27 
A more recent open-label study evaluated the effects of 100 mg of a combined Mg(2+)/vitamin B6 
regimen on the behavior of 52 “hyperexcitable” children under the age of 15 and their families. Thirty of the 52 
hyperactive children had lower than expected erythrocyte Mg values. Combined Mg(2+)/vitamin B6 intake for 
3 to 24 weeks restored expected erythrocyte Mg values, and variables of hyperexcitability were reduced after 1 
to 6 months treatment. 28 
An open-label study conducted by Mousain-Bosc and colleagues followed erythrocyte Mg and 
symptoms of hyperactivity, hyperemotivity, aggressiveness, and lack of attention at school in 40 children with 
clinical symptoms of ADHD during a magnesium-vitamin B6 (Mg-B6) regimen (6 mg/kg/d Mg, 0.6 mg/kg/d 
vit-B6) over at least 8 weeks. Children from the ADHD group showed significantly lower erythrocyte Mg 
values than control children (n = 36). Over the study, measures of hyperactivity, hyperemotivity/aggressiveness, 
and attention in school improved, while there was also a significant increase in erythrocyte Mg values. When 
the Mg-B6 treatment was stopped, ADHD symptoms reappeared within a few weeks, and erythrocyte Mg 
values decreased. 29 


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Rationale for Magnesium L-Threonate as a support for ADHD and related cognitive deficits: 
 
Preclinical studies suggest that L-Threonic acid Magnesium salt can modulate rat brain function.  
Slutsky, et al (2010) demonstrated that oral delivery of L-Threonic acid Magnesium salt to rats achieves 
significantly higher levels than the control feed, whereas magnesium chloride, magnesium orotate, or 
magnesium gluconate did not. This report also demonstrated increases in synaptic density in hippocampal 
regions, and reversed task impairment in Alzheimer’s-model rodents.  Therefore, L-Threonic acid Magnesium 
salt could be expected to have central nervous system effects in human subjects, including potentially 
alleviation of ADHD symptoms. 23 
The risk profile of magnesium supplementation is favorable relative to that of pharmaceuticals currently 
available under FDA indication for Attention Deficit Hyperactivity Disorder. In a rat model, magnesium 
chloride at an intake of up to 2.5% of food resulted in no significant toxic effects. 30 In addition, acute and 
chronic supplementation for hypomagnesemia has been well tolerated with a favorable safety profile. 31, 32  
Magnesium supplements, including L-Threonic acid Magnesium salt, are widely purchased and 
consumed. The most common side effect of magnesium supplementation may be diarrheic effects.  
Neurocentria, the makers of the study agent MMFS202 6-hour release and MMFS302 12-hour release, has 
communicated that in preliminary studies they have not found significant side-effects with 2 g/day of L-
Threonic acid Magnesium salt.33 Some subjects reported sleepiness, but it subsided after a few days. There were 
also some reports of vivid dreams and restlessness. 34 
Conventional therapies for ADHD are thought to work in part through reuptake blockade and/or 
increased release of the catecholamines dopamine and norepinephrine. 13 L-Threonic acid Magnesium salt, 
therefore, offers a novel mechanism of modulating cognitive function. If effective and well tolerated, it could 
offer a novel modality for support of ADHD or related cognitive deficits.  
Because L-Threonic acid Magnesium salt could have positive effects on ADHD symptoms, it has not yet 
been evaluated in adults with ADHD, and is expected to be well tolerated, we propose to conduct an open-label 
pilot study enrolling 15 adults with ADHD to receive L-Threonic acid Magnesium salt. The study is designed to 
evaluate tolerability and feasibility of the protocol, and guide development of future more definitive double-
blind study of the selected outcomes.  
Subjects with moderate levels of ADHD will be enrolled, including individuals on no current treatment 
and those receiving current pharmacotherapy for ADHD.  Six weeks is a typical interval over which stimulant 
effect on ADHD may be seen, and we will extend observation to 12 weeks to measure L-Threonic acid 
Magnesium salt effects that might occur during a reasonable time frame for clinical intervention. 
 
II. 
SPECIFIC AIMS 
Aim 1:  Assess the safety of the effects of L-Threonic acid Magnesium salt on cognitive functioning when 
administered to adults with ADHD. 
Hypothesis 1: L-Threonic acid Magnesium salt will be well tolerated in adults.  
Aim 2: Assess effect of L-Threonic acid Magnesium salt on attention, behavioral control and cognition. 
Hypothesis 2: Compared to pre-administration baseline, administration L-Threonic acid Magnesium salt will 
yield a significant reduction of (2a) attention and behavioral ADHD traits (as measured by the AISRS) and 2b) 
ratings of clinical global improvement, (2c) symptoms of executive dysfunction (as measured by BRIEF-A 
subscales). 


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Hypothesis 3: Compared to pre-administration baseline, performance on individual neuropsychological tests 
will improve (as measured by a) elements of the Cambridge Neuropsychological Test Automated Battery, and 
b) tests used to estimate IQ, and c) higher correlation between performance on neuropsychological tasks. 
We also will explore whether baseline red blood cell magnesium level, deficits on BRIEF or 
neuropsychological tests predict improvements on AISRS or BRIEF measures.   
These supplements are not known to diagnose, cure, mitigate, treat or prevent ADHD. 
III. SUBJECT SELECTION 
We plan to recruit until we enroll 15 male or female subjects between the ages of 18-55 in the study. We 
will recruit subjects from the pool of existing adult subjects and new referrals to the Pediatric 
Psychopharmacology and Adult ADHD Program at the MGH. No pediatric subjects will be recruited for this 
study. If a potential subject's clinician ascertains that the patient has an interest in study participation, the 
clinician will offer him/her contact information for the study coordinator. The patient can then contact the study 
coordinator independently for more information on the study. If a subject is enrolled from among an 
investigator’s own patients through the aforementioned referral process, the process of informed consent must 
be completed by a physician colleague who is on the approved study staff and whom the potential subject has 
not seen for clinical care. Under no circumstances will a physician investigator complete informed consent with 
his or her own patient. All subjects that enter the study will undergo standard screening and diagnostic 
procedures. Clinical records are not scanned in order to recruit subjects. Subjects who have completed a 
previous medication trial in our program may be eligible to participate in this study. Other medical records on a 
subject will not be used at any point, unless explicit written permission is provided by the subject. 
The majority of subjects referred to our program first participate in our general screening protocol 
entitled, “Screening Protocol for Adults with Attention Deficit Hyperactivity Disorder” (Protocol # 2002-P-
001856).  This protocol includes a phone screen and clinical interviews tailored to identifying subjects eligible 
for research in our program. After participating in this screening protocol, subjects are triaged to specific studies 
based upon eligibility requirements (i.e. age, prior medication efficacy or tolerability).  
 
Study Entry Criteria 
Inclusion Criteria: 
1. Male or female adults ages 18-55 years of age. 
2. A diagnosis of childhood-onset ADHD, meeting the DSM-V criteria for ADHD in adulthood, including at 
least 5 current symptoms of inattentive or impulsive-hyperactive traits, and childhood onset by age 12, 
defined as two symptoms of inattentive or of impulsive/hyperactive traits by the age of 12. 
3. A score of 20 or more on the Adult ADHD Investigator Symptom Report Scale (AISRS), and, for those 
individuals stably treated with stimulants, a CGI-ADHD severity score of no greater than 4 (“moderately 
ill”). 
i. Subjects on a stable dose of stimulant medication must be treated on the same dose for at 
least 1 month prior to study entry. 
 
 
 


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Exclusion Criteria: 
1. A history of intolerance to magnesium supplementation, or the ingredients in MMFS202 (6-hour release) 
AND MMFS302 (12-hour release). 
2. Pregnant or nursing females. 
3. A known unstable medical illness including hepatic, renal, gastroenterological, respiratory, cardiovascular 
(including hypertension ≥ 140/90 mmHg at screening), endocrinologic (e.g. thyroid), neurologic (e.g. 
seizure), immunologic, hematologic, or psychiatric (other than ADHD) disorder. Individuals with kidney 
dysfunction will be excluded, as dysfunctional kidneys may have difficulty clearing the magnesium from 
the body (which can result in dangerously high magnesium levels). Individuals with heart block will be 
excluded from the study.  
4. Any medical condition that the Principal Investigator (PI) believes will be exacerbated by study 
participation. 
5. A history of cancer (except localized skin cancer without metastases or in situ cervical cancer) within 5 
years prior to screening.  
6. A known history of narrow-angle glaucoma. 
7. Current (within 3 months) DSM-V criteria for abuse or dependence with any psychoactive substance other 
than nicotine. 
8. IQ<80 (based on the Wechsler Abbreviated Scale of Intelligence-II Full Scale IQ calculation) 
9. Multiple adverse drug reactions. 
10. Any other concomitant medication with primarily central nervous system activity as specified in 
Concomitant Medication portion of the protocol. 
11. Current use of MAO Inhibitor or use within the past two weeks. 
12. Current use of antibiotics, as the study agent may reduce the absorption of antibiotics.  
13. Subjects may not take any of the following substances for at least 7 days prior to baseline and throughout 
the study:  
a. Calcium channel blockers including: 
i.  Felodipine (Plendil®) 
ii. Amlodipine besylate (Norvasc®).  
b. Any psychoactive medications including: 
i. Antipsychotics 
ii. Anxiolytics 
iii. Antidepressants  
c. Any medications known to interact with magnesium including:  
i. Potassium-sparing diuretics such as Amiloride (Midamor), Spironolactone (Aldactone®), 
and triamterene (Dyrenium®), as they may increase magnesium levels;  
ii.  Loop and thiazide diuretics such as Furosemide (Lasix®) and Hydrodiuril (Microzide ®, 
Esidrix®, Hydrodiuril®) as they may decrease magnesium levels;  


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iii. Muscle relaxants such as Carisoprodol (Soma®), Pipecuronium (Arduan®), Orphenadrine 
(Banflex®, Disipal®, Norflex ®), Cyclobenzaprine (Flexeril®, Fexmid®, Amrix ®), 
Gallamine (Flaxedil®), Atracurium (Tracrium®), Pancuronium (Pavulon®), and 
Succinylcholine (Anectine ®, Quelicin®);  
iv. Penicillamine (Cuprimine®, Depen ®) 
v. Corticosteroids (Prednisone or Deltasone®)  
vi. Magnesium containing antacids including Maalox®, Mylanta®, Milk of Magnesia, Tums® 
and Rolaids  
d. Supplemental magnesium or any magnesium-containing products  
e. All dietary or herbal supplements or products including those purported to improve memory, 
improve sleep, or decrease stress.  
Any subject found to be taking these substances during the study will be evaluated by the PI for ongoing 
eligibility. 
14. Investigator and his/her immediate family; defined as the investigator’s spouse, parent, child, grandparent, 
or grandchild. 
There will be two categories of individuals presenting with ADHD that will participate in the study: (1) 
those that have residual ADHD symptoms despite benefit from well-tolerated standard of care ADHD 
pharmacotherapy (stimulant medication or Atomoxetine); and (2) those that are not on medication for ADHD. 
Because the study is a pilot study, we will recruit a sample of subjects, and have not specified a ratio of 
participants in these two groups to be enrolled. 
No individual will be removed from an effective and stable treatment regimen for the purposes of 
participating in the study. Individuals who enter the study on medication for ADHD must be on an effective, 
well tolerated, and stable dose of a prescription indicated by the FDA for ADHD for at least one month prior to 
entry.  Efficacy and tolerability will be determined by the study clinician, and subjects must have a Clinical 
Global Impression-ADHD severity rating of no greater than 4 (“moderately ill”), because a score greater than 4 
indicates that their ADHD symptoms are unlikely to be effectively treated by their current medication regimen.   
 
IV. SUBJECT ENROLLMENT 
Informed consent will be obtained prior to the performance of any protocol procedures and prior to 
administration of study drug. The informed consent document will be used to explain in simple terms the risks 
and benefits of study participation to the subject. The nature of the study will be fully explained to the subject 
by a board-certified physician who is either the primary investigator or a co-investigator. The subject will be 
encouraged to ask questions pertaining to their participation in the study and the subject may take as much time 
as they feel is necessary to consider his/her participation in the study as well as consult with family members or 
their physicians.  Participation in this study is voluntary and the subjects may withdraw from the study at any 
time. The IRB-approved informed consent documents will be signed and dated by the subject and the physician 
obtaining consent.  
 
 
 


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V. STUDY PROCEDURES 
We will conduct a 12-week open label pilot clinical trial exploring the cognitive effects and tolerability 
of L-Threonic acid Magnesium salt in adults with ADHD. We will recruit up to 25 subjects, and enrollment will 
stop once 15 subjects are expected to complete the study.  
After providing study information and obtaining IRB approved informed consent, participants will 
undergo a comprehensive assessment including a psychiatric assessment reviewing current and lifetime DSM-V 
Axis I conditions, medical history including history of any cardiac symptoms or abnormalities reported on 
routine clinical exams, and a neuropsychological evaluation which will include confirmation of an IQ greater 
than 80 (which can be completed at the screening or baseline visit for scheduling flexibility). If a subject has 
never had a cardiac physical exam a clinician will conduct one. The information obtained at this visit will be 
reviewed to assure that all inclusion and exclusion criteria are met prior to receiving study agent at the baseline 
visit. Subjects who do not meet all the criteria for enrollment after these assessments will be discontinued. 
We anticipate that subjects may enter this trial following completion of withdrawal from other protocols 
in our office, and that there may be procedural overlap. So as to not burden subjects with redundant time 
commitments, we will use the following diagnostic data previously collected:  If a subject has completed an 
evaluation with one of the study clinicians within the previous year prior to entrance into this study, they will 
not be asked to repeat any overlapping diagnostic procedures; if a subject has completed a neuropsychological 
evaluation within the last 3 months they will not have to repeat this. With subjects’ permission, we will use the 
diagnostic data that had been previously collected. However, the study clinician will review the interval time 
period to assess for clinically significant medical or psychiatric history, to ensure that the subject meets 
appropriate study entrance criteria.   
Medication Washout: 
If clinically appropriate, any subjects taking medication exclusionary to the study must be tapered off 
this medication prior to baseline visit for the length of 5 half-lives of the medication, corresponding to 95% of 
the agent leaving the participant’s system), plus several days to assess the participant off medication. 
Discontinuation or taper off of a current medication will be recommended only for subjects with inadequate 
response to a current treatment. Subjects will not enter the study if it would require tapering a medication that is 
optimally and comfortably managing a clinical concern.  Medication tapers will be monitored by the study 
clinician in agreement with the research subject and in consultation with the prescribing physician. The 
prescribing physician will be contacted to discuss feasibility and correctness of removing a subject from current 
medications and will be asked to monitor the subject’s response to the medication change. If the prescribing 
physician does not find medication discontinuation appropriate or if they do not agree to monitor the subject’s 
response to stopping medications, then the subject will not be enrolled. No subject will be removed from a 
stable and effective treatment regimen for the purposes of participating in the study. 
Participants who fulfill the inclusion and exclusion criteria will participate for 12 weeks, or until withdrawing or 
terminating participation. 
Safety Assessments: 
Vital signs (blood pressure, pulse, weight) will be measured at every in-office visit. Height will be 
measured at baseline and at the end of the study. A urine drug screen will be performed at screening, week 6, 
and week 12. If the participant is found to have taken an illicit drug, he/she will have a discussion with the 
doctor to determine if he/she can be in the study. Subjects will be discontinued if there is suspicion of ongoing 
substance use. For safety purposes, an EKG will be conducted during screening and at the endpoint of the study. 
Females who are able to have children will also have a urine pregnancy test at screening, week 6, and week 12. 


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If a participant has a positive pregnancy test she will not be able to take part in the study. Female subjects of 
childbearing potential must agree to use a medically acceptable form of birth control (such as male for female 
condoms with or without spermicidal agent, diaphragm or cervical cap with spermicide, medically prescribed 
IUD, hormonal contraceptives like birth control pills, or abstinence) while they are receiving study agent and 
for 1 month after the last dose of study agent. In the event that a subject becomes pregnant, we will ask the 
subject’s permission to obtain information about the outcome of the pregnancy and the condition of the 
newborn. Those subjects who terminate study participation before the completion of the study will be asked to 
complete all tasks scheduled to take place on the final study visit at the time of study discontinuation. 
We will draw blood samples at the screening visit and at study endpoint to determine erythrocyte (red 
blood cell or RBC) levels of magnesium and calcium. Samples will be analyzed by LabCorp through services 
provided by the Harvard Clinical and Translational Science Center. Each sample volume will be approximately 
3 teaspoons, for a total of 6 teaspoons drawn over the entire study. 
All efforts will be made to protect subject privacy, and samples will be labeled with codenames and 
medical record numbers. The sponsor will not have access to information that identifies participants’ samples. 
Results from laboratory testing (i.e. laboratory values) may become a part of the subjects’ MGH medical 
records, however no information regarding participation in the study will become a part of the medical record. 
Subject Visits: 
Subjects will be evaluated in the office at baseline (week 0), and weeks 3, 6, 9 and 12. Subjects will be 
contacted by phone each week between these visits (weeks 1, 2, 4, 5, 7, 8, 10, and 11 by a member of the study 
staff who will inquire about study drug adherence. The phone visit at Week 1 will be conducted by a study 
clinician, who will collect Adverse Events. The clinician’s assessment of adverse events will inform the 
decision to alter the dosing instructions and timing, if necessary.  Subsequent phone calls will be conducted by a 
study research assistant to assess medication compliance. At any time, contact can occur by phone or in person 
as needed with a clinician or research assistant, based on the judgment of the clinician, or by needs of the 
subjects as they arise. Study clinicians are also available to subjects 24 hours each day by pager. At each office 
visit, assessments of safety and efficacy will be obtained by administering measures of efficacy (CGI, GAF, 
AISRS), tolerability (adverse events), and safety (vital signs). At weeks 0, 6, and 12, the clinician will 
additionally assess for adverse events specifically related to any discontinued medications for the purpose of 
enrollment. CGI, GAF, and adverse events will not be collected at screening. Neuropsychological assessments 
will be repeated at week 6 and study endpoint, excluding the WASI-II, which will be repeated only at study 
endpoint. 
Assessments and Instruments: 
During the study, the following, assessments and instruments will be used:  
Demographic/Background Interview: 
• A brief demographic interview to obtain information used to calculate socioeconomic status and 
information about head injury and traumatic experiences. This will take place during the Screening 
Visit, after subjects have signed consent. 
Brief neuropsychological measures (at screening or baseline, depending on scheduling flexibility, unless 
otherwise noted): 
• Wechsler Abbreviated Scale of Intelligence- II (WASI-II) Vocabulary and Matrix: to calculate verbal 
performance, and full-scale IQ. This will be used to ensure that subjects have an IQ greater than 80, and 
will be repeated at study endpoint to assess change in performance.  


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• The Delis-Kaplan Executive Function System Trail-making subtest, which measures flexibility of 
thinking on a visual-motor sequencing task (conducted at screening or baseline, Week 6, and Week 12). 
Cambridge Neuropsychological Test Automated Battery (CANTAB) (at screening or baseline, week 6 and 
week 12): CANTAB is a computer-based system designed to look at frontal lobe (executive functioning). Select 
subtests will include the following:  
• Spatial Working Memory (SWM), tests comprehension, learning and reversal.  
• Stockings of Cambridge (SOC), assesses spatial planning and motor control.  
• Intra-Extra Dimensional Set Shifting (IED), tests rule acquisition and attentional set shifting.  
• Reaction Time (RTI), measures speed of response. 
• Rapid Visual Information Processing (RVP), tests sustained visual attention.  
• Affective Go/No-go (AGN) assesses information-processing biases for positive and negative stimuli.  
• Verbal Recognition Memory (VRM), assesses immediate free recall, and immediate and delayed 
recognition memory 
• Cambridge Gambling task (CGT), to assess decision-making and risk-taking behavior. 
Clinician rated assessments (rated at each in-office study visit, unless otherwise noted): 
• Global Assessment of Functioning (GAF) scale. The GAF will assess global functioning using a scale 
from 1 (worst) to 100 (best). This will be collected at all study visits, excluding the screening visit. 
• Clinical Global Impressions (CGI) scale for ADHD. The CGI is a measure of illness severity, 
improvement, and efficacy of treatment.  
• Adult ADHD Investigator Symptom Rating Scale (AISRS). Each of the individual symptoms of ADHD 
is rated 0 to 3 on a scale of severity. 
• Adverse Experiences (collected at all visits excluding the screening and baseline visits) and 
Concomitant Medications. 
Subject rated scales (all scales rated at baseline, week 6, and week 12 or drop visit, unless otherwise noted): 
• The 18-item ADHD Self Report Rating Scale (ASRS) to evaluate frequency of ADHD symptoms on a 
scale of 0 to 4.  
• The 86-item Behavior Rating Inventory of Executive Function – Adult Form (BRIEF-A) to assess levels 
of executive function deficits. 36 This will be collected at baseline and at Week 12. 
• The Adult Self-Report Form (ASR) to measure a wide range of psychiatric syndromes (i.e., depressive 
problems, anxiety problems, antisocial personality problems) in adults. The ASR provides dimensional 
scale scores for each syndrome that are age- and gender-normed. 37 
• The 16-itm Quality of Life Enjoyment & Satisfaction Questionnaire (Q-LES-Q) to measure overall 
satisfaction across different aspects of daily life. 38 
• The 25-item Endicott Work Productivity Scale (EWPS) to measure behaviors and feelings likely to 
reduce productivity and efficiency in work activities. 39 
 


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Data Collection: 
 
Self-report and clinician-rated measures will be collected using DatStat Illume™, a platform for electronic 
data capture that streamlines data collection and management, and ensures data integrity, resulting in improved 
data quality. The DatStat™ software allows researchers to design and implement study surveys for collecting, 
storing, retrieving, and manipulating data electronically. Participants and/or research staff enter survey 
responses into electronic assessment forms, and the responses are then transmitted securely via encrypted 
connection and stored in a secured database. This electronic data capture obviates the need for subsequent data 
entry by staff, thus minimizing human error. Efforts will be made to have all surveys completed in-office, but if 
needed participants may complete them from home. 
 
Survey respondents will log in to the secure data-collection system at the study site, on a desktop 
computer provided by MGH staff, or from home, using a personal computer with Internet access. All responses 
will be transmitted to and stored in a secure database via an encrypted connection. This electronic data capture 
system obviates the need for the physical transportation of paper source data as well as the entry of paper source 
data by staff, thus minimizing human error. All data collected via DatStat™ are immediately available for 
analysis by a statistical package.  
All collected data are stored automatically and securely on a Microsoft SQL Server, accessed over an 
industry standard SSL 128 bit RSA encrypted connection during data transfers. Data is routinely backed up 
locally onto a redundancy server and stored in a separate database. Individual computers designated for data 
capture do not store participants’ identifying information nor study data. All collected data will be 
systematically checked by the Project Coordinator.   
In the event that the electronic data capture system is unavailable during a study visit (due to technical 
issues), rating scales will be collected on paper and then entered into the program manually once the system 
becomes available.  
The DatStat Illume™ and Discovery™ Electronic Data Capture Platform has been approved for use at 
Massachusetts General Hospital by Partners Health Care System Research Computing, Enterprise Research 
Infrastructure and Services (ERIS) Department. The data collection, transmission, and storage methods are 
secure and in compliance with Partners policies and procedures. In addition, it is in compliance with the HIPPA 
HITECH ACT because data is hosted and stored internally (PHS IS Data Center) and managed by Partners 
Employees. 
For quality control purposes, clinician-administered measures completed during the visits may be audio 
taped, with subjects’ permission. These recordings will be used to monitor quality control and inter-rater 
reliability in this study by the PI. Each digital audio file will be coded with subject initials and number to 
maintain confidentiality. These files will be de-identified and stored on a password-protected, encrypted 
computer within the Partners firewall, and will be accessed only by the appropriate study staff. 
Study Completion: 
Upon completion of the study, participants can choose to pursue follow-up care, as possible, at our 
MGH practice or continue treatment with their primary care physician. Study clinicians may also offer 
psychiatric referrals to treaters in their communities. All subjects will be offered two free follow-up visits in the 
clinic. 
ADHD Pharmacotherapy: 
If a subject enters the study on pharmacotherapy for ADHD, they will be maintained on this agent 
during the study by a study clinician, and will receive L-Threonic acid Magnesium salt in addition.  With 


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written permission of the subject, prior to beginning the study, subjects’ treaters will be contacted by mail 
(followed by a phone call) before the study clinician initiates treatment.  
Subjects who are not on pharmacotherapy for ADHD as they enter the study will take only L-Threonic 
acid Magnesium salt during the study. No individual will be removed from an effective and stable treatment 
regimen for the purposes of participating in the study.  
Those subjects who are treated for ADHD prior to their enrollment in the study will continue to be 
responsible for the cost of their medication, as they will be instructed to take this medication as usual. The study 
drug will be provided at no cost to study participants. 
Study Agent and Dosing: 
L-Threonic acid Magnesium salt will be provided as MMFS202 (6-hour release) and MMFS302 (12-hour 
release). Neurocentria, the makers of MMFS202 (6-hour release) and MMFS302 (12-hour release), will provide 
a detailed Certificate of Analysis attesting to the contents of the product. 
Neurocentria has provided the following list of ingredients for MMFS202 (6-hour release) and MMFS302 (12-
hour release): 
• Active ingredients: Magtein ® (L-Threonic acid Magnesium salt). L-Threonic acid Magnesium salt is a 
magnesium salt of L-Threonic acid, having a molecular formula of Mg(C4H7O5)2. MMFS202 will 
release the active ingredient at a constant rate over 6 hours. MMFS302 will release the active ingredient 
over a 12 hour period. 
• Inactive ingredients: polyvinyl pyrolidone, microcrystalline cellulose, silicon dioxide, talc, and magnesium 
stearate 
Both MMFS202 (6-hour release) and MMFS302 (12-hour release) will be provided in 0.5-gram tablets. 
Participants will be instructed to take one tablet of MMFS302 (12-hour release) in the morning and one tablet of 
MMFS202 (6-hour release) in the evening for one week 2 hours before bedtime. After one week, if well 
tolerated subjects will start a regimen of two tablets of MMFS302 (12-hour release) in the morning and two of 
MMFS202 (6-hour release) in the evening.  Therefore, subjects will take up to 2 grams per day of L-Threonic 
acid Magnesium salt during the course of the study. However, study agent dosing will be flexible. If individual 
subjects display patterns of adverse effects or drug effects that suggest an alternative dosing schedule would be 
preferred, this will be allowed, including dose reduction to only one of either MMFS202 (6-hour release) or 
MMFS302 (12-hour release). The study clinician can increase or decrease the dose based on tolerability and 
reinstate higher doses after a decrease if tolerability increases. No subject will take more than two MMFS202 
(6-hour release) or more than two MMFS302 (12-hour release) 0.5-gram tablets a day, and subjects will be 
instructed not to take more than two tablets at a time or to take more than four tablets in a day total. Subjects 
will be encouraged to spread out the daily dose into at least two doses several hours apart.  
This approach to dosing will allow us the flexibility to maintain subject comfort and convenience during study 
participation. 
The active ingredient in MMFS202 (6-hour release) and MMFS302 (12-hour release), L-Threonic acid 
Magnesium salt has been granted GRAS status by the FDA. Neurocentria produces MMFS202 (6-hour release) 
and MMFS302 (12-hour release) using good manufacturing practices.  
Study clinicians, or research assistants under the supervision of a study clinician, will be responsible for 
dispensing MMFS302 (12-hour release) and MMFS202 (6-hour release) at our research office. The MGH 
Clinical Trials Pharmacy will receive and label and distribute the product for dispensing during the study. 


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Study clinicians, in cooperation with the subject and the subject’s treater, may develop a plan for continued 
MMF302 (12-hour release) and MMF202 (6-hour release) treatment after the completion of the study, if 
appropriate. At each visit, measures of safety and effectiveness will be administered and subjects will be 
evaluated for response and side effects to the treatment. To assess and increase adherence to dosing of the agent, 
the study agent and any concurrent ADHD medication treatment will be returned and counted at office visits. 
Concomitant Medications / Treatments: 
A detailed past and present treatment history will be taken as part of initial screening. Concomitant 
medications with primarily central nervous system activity, other than ADHD pharmacotherapy as noted above, 
are not allowed in this study. No subject will be tapered from medication that is useful to him or her.  Non-
pharmacological treatments such as individual, family or group therapy will be allowed if they were in place 
before the patient joined the study.  Any such therapy regimen must remain the same throughout the study.  If a 
subject is asked to stop a medication with central nervous system activity for participation in the study, 
sufficient time will pass off the medication prior to baseline visit, based on the pharmacokinetics of the agent, to 
ensure that it has been eliminated from the patient’s system.  
Subjects will be instructed not to take any medications or supplements that contain any forms of 
magnesium compounds to avoid unsafe levels of magnesium. All new medications and supplements started 
during the study will be reviewed by the PI, and subjects may be dropped from study participation, but their 
data will be retained in the safety and intent-to-treat analyses with PI discretion. 
In addition, any subject found to be taking medication listed as exclusionary during the course of the 
study or the seven days prior to baseline will be evaluated by the PI for ongoing eligibility. 
Study Discontinuation Criteria 
 Subjects who: 1) develop intolerable AE(s) despite dose adjustments; 2) have (a) clinically relevant 
serious AE(s) as determined by the investigator; 3) have worsening ADHD symptoms (much worse or very 
much worse as rated on CGI-Improvement at two consecutive visits); or 4) have emergent adverse mental 
health state including psychosis, suicidality, substance use, or worsening mood and/or anxiety; 5) are non-
adherent to study procedures or withdraw from the study; 6) intend to be or become pregnant will no longer 
continue in the study. If study participation is discontinued due to safety reasons, participants will receive two 
follow-up visits, giving adequate time for appropriate psychiatric referrals to treaters in their communities.  
Subjects found to be taking substances listed as exclusionary during the course of the study may be 
discontinued based on PI evaluation of their eligibility.  
VI. 
BIOSTATISTICAL ANALYSIS 
As this is a single-arm, open study designed to evaluate the effectiveness and safety/tolerability of L-
Threonic acid Magnesium salt, formal power analyses are not warranted.  
 
Data processing and management will follow procedures developed by the investigators and used in 
ongoing studies.  15 subjects will receive L-Threonic acid Magnesium salt. Changes in outcome ratings within 
and between study groups will be tested. All analyses will be intention to treat (ITT), utilizing.  
Our exploratory hypotheses are as follows.  Our primary test of Hypothesis 1 will be review of the 
occurrence of moderate or severe adverse events. Hypothesis 2 will be tested by evaluating whether over the 
course of L-Threonic acid Magnesium salt administration the following are seen: a) at least a 25% reduction in 
ADHD as rated by the AISRS total score; b) CGI of much or very much improved, c) reduced symptoms of 
executive dysfunction (defined by a 0.5 standard deviation improvement on BRIEF-A self-report total or 
subscale scores).  Hypothesis 3 predicts that there will be measurable improvement in cognitive function, as 


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measured by a) statistically significant improvement on CANTAB tasks, and b) improvement in performance 
on the WASI matrix, used to estimate IQ, and c) increased correlation between performance on domains of 
function. 
For ADHD AISRS, BRIEF, and CANTAB evaluations, we will compare pre-treatment and study visit 
values of measures using paired t-tests, via an intention-to-treat analysis with the last observation carried 
forward (LOCF) for subjects who did not complete the full study. Alpha will be set at 0.05 for all comparisons. 
We will also explore descriptively whether baseline erythrocyte magnesium level, or deficits in BRIEF 
or CANTAB ratings as measured against norms predict improvement on AISRS or BRIEF ratings.  
 
VII. 
RISKS AND DISCOMFORTS 
All efforts are made to minimize risks to subjects. Consistent with good clinical practice, safety will be 
monitored by the Principal Investigator, and will reflect the oversight of co-investigator study clinicians. 
Adverse events will be recorded and reported according to institutional policies. Risks of the study agent have 
been incorporated into the exclusionary criteria for this proposal. 
Study clinician evaluation and subject questionnaires: 
Some questions may make subjects feel uncomfortable. Subjects may refuse to answer any question they 
wish. In the event that a participant reports risk of harm to himself or herself, or to another person, study 
clinicians will assess the level of risk, and take appropriate actions, including disposition of an immediate 
referral to a local Psychiatric Emergency Room.  
Study Agents –MMF202 (6-hour release) and MMF303 (12-hour release):  
The active ingredient in MMF202 (6-hour release) and MMF303 (12-hour release) is L-Threonic acid 
Magnesium salt, is considered a dietary supplement that the manufacturer has self-certified as fulfilling the US 
Food and Drug Administration criteria for agents that are Generally Regarded as Safe. There are few risks to 
taking L-Threonic acid Magnesium salt orally. Magnesium is known to cause gastrointestinal discomfort, 
nausea, vomiting, or diarrhea. Although occurrences are rare, very large amounts of magnesium might cause 
hypermagnesemia with symptoms including thirst, hypotension, drowsiness, confusion, loss of tendon reflexes, 
muscle weakness, respiratory depression, cardiac arrhythmias, coma, cardiac arrest, and death. There have been 
only two reports of death from hypermagnesemia that we found record of. 43 The dose prescribed to subjects as 
part of this study will unlikely lead to hypermagnesemia, as extremely high doses of magnesium are required to 
produce this effect. 
ADHD Pharmacotherapies: 
Some individuals will enter the study taking medication for ADHD and continue in the study on this 
medication.  Only subjects taking FDA approved agents for treatment of ADHD in adults (stimulants-class 
medication or Atomoxetine) will be enrolled.  The risks to these subjects are not expected to change with the 
addition of L-Threonic acid Magnesium salt to their treatment regimen. 
 
Commonly observed side effects associated with the use of these FDA-approved stimulants include 
insomnia, decreased appetite, dry mouth, headache, or increased pulse.  Other less common side effects include 
irritability, stomach pain, onset of tics, or mood changes. Stimulants have also been associated with more rare, 
but serious, adverse effects such as sudden death, stroke, and heart attack in adults with a history of heart 
disease.    


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Side effects of Atomoxetine are similar to those of stimulants, but notably include fatigue, nausea, 
increase in heart rate, increase in blood pressure, sexual side effects, agitation or changes in mood.  The label 
for Atomoxetine carries warnings about rare reports of liver failure and of suicidal ideation. Subjects receiving 
ADHD pharmacotherapy prior to trial entry will continue their regimen as usual, with treatment managed by the 
study clinicians.  
Washout: 
 
During the washout period, if the subject stops taking his/her medications, his/her symptoms might get 
worse. Medication washout will be monitored by the study clinician in agreement with the research subject and 
in consultation with the prescribing physician. No subject will be removed from a stable and effective treatment 
regimen for the purposes of participating in the study. All medications that are discontinued for the purpose of 
enrollment will be thoroughly documented, and the PI will regularly evaluate the subject’s status off the drug 
and document any subsequent adverse events. This will be done at Week 0, 6, and 12, although all adverse 
events will be documented throughout the study, including any relation to medication washout. If the 
investigator determines that it would be beneficial to the subject to resume their previous medication, they will 
be withdrawn form the study and referred for clinical care. 
 
Confidentiality: 
 
All research-related records initiated as a result of a subject’s participation in this study that reveal the 
subject’s identity will remain confidential except as may be required by law. Results of urine drug or pregnancy 
testing will not become part of the subject’s medical record. The result of the magnesium and calcium blood test 
may be be entered in the subject’s hospital medical record, as Medical Record Numbers may be used by the 
laboratory to identify samples. This will be explained in the Consent Form so that all subjects are made aware 
of this. 
Information regarding communication with subject’s other treater(s) will be explained explicitly in the 
Consent Form. Should a subject be opposed to study staff communicating with subject’s treaters, he/she may 
refuse consent to participate in the study. Data obtained from this study will not identify the subjects 
individually. Subjects will be assigned code-names and ID numbers.  Data obtained from our studies may be 
published, but no subjects will be identified individually in these publications. Original research-related records 
may be reviewed by the Partners Human Research Committee, and regulatory authorities, for the purpose of 
verifying clinical trial procedures and/or data. Information may be held and processed on a computer.  Access to 
these computerized records will be password protected and restricted to study staff. Subjects will only be 
contacted regarding future studies if they indicate that they are interested in being contacted by initialing in the 
specific section of the consent form. 
VIII. POTENTIAL BENEFITS 
There may be no direct benefit to subjects participating in this study. Potential benefits to the 
participants include education about ADHD, a trial of a supplement that could be continued after the study, and 
the opportunity to contribute to medical science and thus help others with similar difficulties.  
 
IX. 
DATA AND SAFETY MONITORING 
At each study visit, the interviewing clinician will evaluate the appropriateness of a subject’s continued 
participation based on presence and severity of adverse events. The study Principle Investigator will review all 
adverse events that have occurred across all subjects of the study at least monthly to determine if there are 


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concerning trends in participants’ experience that would require discontinuation of study participation or 
modification of the protocol. The Principal Investigator will confirm that all adverse events are correctly entered 
into the adverse event log by the coordinator and will be available to answer any questions that the coordinators 
may have concerning adverse events and notifying the IRB of all serious adverse events and adverse events in 
accordance with the guidelines outlined on the Partners Human Research Committee web site.   
The Principal Investigator will meet regularly with study staff to address procedural issues and the study 
coordinator will audit each subject’s data within 48 hours of each study visit. Furthermore, all data will be 
audited by the study statistician on a regular basis to ensure the progress of the study and confirm that all 
necessary data is being collected and can be transitioned to the statistical package smoothly. Co-investigators 
are actively involved in the monitoring and quality assurance of these trials. Periodic quality assurance audits 
will insure accuracy and completeness of all subject documents, IRB files and correspondence, and the 
informed consent documentation. 
 
 
VIII.  Visual Timeline of Key Study Elements 
 
Screen 
Baseline 
(Week 0) 
Week 1 
Week 2 
Week 3 
 
Week 4 
Week 5 
Week 6 
 
Week 7 
Week 8 
Week 9 
Week 10 
Week 11 
Week 12 
(Drop) 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
Procedures 
Blood 
Pressure 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Pulse 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Weight 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
RBC Mg and 
Calcium 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine Drug 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Urine 
Pregnancy 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Drug 
accountability 
 
Xb 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Drug 
Dispensing 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Phone Contact 
 
 
Xc 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
Assessments 
Demographic 
Interview 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
WASI-II 
Xd 
Xd 
 
 
 
 
 
 
 
 
 
 
 
X 
D-KEFS 
Trails 
Xd 
Xd 
 
 
 
 
 
X 
 
 
 
 
 
X 


Study Protocol: MMFS202 and MMFS302 use in ADHD 
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CANTAB 
Xd 
Xd 
 
 
 
 
 
X 
 
 
 
 
 
X 
Clinician 
Evaluation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinician Rated Scales 
AISRS 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
CGIs 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
GAF 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Adverse 
Events 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Concomitant 
Medications 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Subject Rated Scales 
BRIEF-A 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
ASRS 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
ASR 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Q-LES-Q 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
EWPS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Phone calls to evaluate adherence to study agent dosing and to protocol will occur on weeks 1, 2, 4, 5, 7, 8, 
10, and 11. The Week 1 Phone Call will be conducted by a study clinician, who will assess adverse events, 
and determine if any alterations in study agent dosing are necessary. Phone calls during weeks 2, 4, 5, 7, 10, 
and 11 will be conducted by a research assistant, who will assess medication compliance. 
(a) Eligibility will be confirmed at baseline. 
(b) Drug accountability will take place at Week 0 only for subjects entering the trial on 
treatment for ADHD. 
(c) Phone contact at Week 1 will be conducted by the study clinician, who will assess 
adverse events. Thereafter, contact will be made by a research assistant. 
(d) Can be completed at either screening or baseline visit 
 
 
 
 
 
 
 
 
 
 
 
 


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