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VITAMIN B6 AND MAGNESIUM ON
NEUROBEHAVIORAL STATUS OF AUTISM
SPECTRUM DISORDER: A RANDOMIZED, DOUBLE-
BLIND, PLACEBO CONTROLLED STUDY
FARHANA KHAN1, MD SAYEDUR RAHMAN2, SHAHEEN AKHTER3, ABDUL BASIT IBNE MOMEN4, SHEIKH
GOLAM RAIHAN5
Abstract
Background: Autism Spectrum Disorder (ASD) is a neurobehavioral disorder for which till date, no
pharmacological treatment has been proven effective. Some studies on complementary alternative
medicines have shown neurobehavioral improvements among children diagnosed with ASD, notably
with the administration of a combination of Vitamin B6 and Magnesium.
Methods: This trial was designed to observe the effectiveness of a combination of Vitamin B6 and
Magnesium in children with ASD with hyperactivity. One of the primary aim was to investigate any
improvement among the six domains of ASD: general observation, cognition, emotion, social behavior,
communication, and sensory deficits. Patients attending the outpatient department of the Institute of
Pediatric Neurodisorder and Autism (IPNA), Bangabandhu Sheikh Mujib Medical University, diagnosed
as ASD, were selected for this trial on meeting the selection criteria diagnosed by DSM 5 (Diagnostic
and Statistical manual of Mental disorders) and ADCL (Autism Diagnostic CheckList). Then the patients
were randomly assigned into intervention group (Vitamin B6 and Magnesium) or placebo group. The
intervention group received tablets of Vitamin B6 and Magnesium daily, for 3 months, where the
dosage was pre-determined by age of the subjects. Patients aged 2-3 years received 50mg Magnesium
and 25mg Vitamin B6 daily, aged 4-8 years received 100mg Magnesium and 50mg Vitamin B6 daily,
and patients aged 9-12 years were given 200mg Magnesium and 100mg Vitamin B6 daily. The
placebo group received similar looking oral placebo tablets for the duration as the intervention group.
After 3 months, each patient was assessed once again using ADCL tool by a psychologist.
Results: Seventy (70) patients were enrolled for this study over a period of seven months. Among
them fifty (50) met all criteria to be eligible for analysis. Therefore, intention to treat (ITT) was seventy
(70) and per protocol treatment was fifty (50). Of these patients, twenty-seven (27) received Vitamin
B6 and Magnesium and twenty-three (23) received placebo. The improvement observed in the proportion
of patients in the intervention group (81%) was significantly (pd”0.05) higher compared to placebo
(47%) group. This study revealed an overall improvement in the symptoms of autism along with
improvements in specific domains e.g., Emotion (pd”0.01) and Cognition (pd” 0.05).
Conclusion: Despite the small population size, this study demonstrated neurobehavioural improvement
among children with ASD with hyperactivity and irritability. Consequently, this can be expected that
future studies conducted on a larger scale might help to establish the beneficial role of Vitamin B6
and Magnesium as a complementary treatment for autism with hyperactivity and irritability.
Received: 21 November, 2020 Accepted: 25 December,2020
DOI: https://doi.org/10.3329/bjm.v32i1.51089
1. Senior Lecturer, Department of Pharmacology, Ad-Din Women’s Medical College
2. Professor and Chairman, Department of Pharmacology, BSMMU
3. Director, Institute of Pediatric Neurodisorder and Autism, BSMMU
4. Registrar, Department of Medicine, Bangladesh Medical College
5. Medical Officer, Department of Blood Transfusion, Bangladesh Medical College
Address of Correspondence: Dr. Farhana Khan, 9/B Eastern Housing Apartment Shiddheshwari, 104,
Baramagbazar, Dhaka-1217, Email: farhanakhan488 @gmail.com
Bangladesh J Medicine 2021; 32 : 12-18
Introduction
Autism Spectrum Disorder (ASD) is a lifelong
neurobehavioral disorder which is not curable. There
is no specific treatment for autism. There are some
guidelines for treating ASD, such as NICE guidelines(1),
recommendations by American Academy of Child &
Adolescent psychiatry(2)and Indian Clinical Practice
guideline for autism(3). All of these guidelines do not
advocate a specific protocol for treating autism.
The Food and Drug Administration (FDA) has approved
Risperidone and Aripiprazole for the treatment
hyperactivity and irritability present in ASD
patients(4)(5). Combinations of medicines, parent
teacher training as well as other interventions are more
fruitful for behavioral issues and for proper functioning.
For many years the target has been switched to notice
the relations between metabolic and nutritional
disturbances and developmental disorders, for example
attention deficit hyperactive disorder or intellectual
disorder or learning disorder(6).
There are some studies on vitamins and minerals
showing mixed results, such as those with-Vitamin A
(7), Vitamin B(8), Vitamin C(9), Vitamin D(10), Folinic
Acid(11), Zinc(12), Among these studies vitamin B6 and
magnesium given by parents to ASD children have been
observed to produce improvement for about 30
years(13)(14)(15).
Although a lot of researches have been conducted for
treatment of ASD; the treatment options are still
lacking. There exists behavioral therapies but
unfortunately pharmacological interventions are
inadequate. Studies have observed that the children
with ASD do show some improvement with
supplementation of Vitamin B6 and Magnesium in
many areas like language, eye contact and behavior.
So this study is being conducted to investigate the
benefits of using Magnesium and Vitamin B6 in patients
of ASD with hyperactivity and irritability.
Methods
Trial design
The trial was a single site, randomized, double-blind,
placebo controlled trial to evaluate the effect of vitamin
B6 and Magnesium on the neurobehavioral status of
ASD conducted on the out patients in a tertiary level
hospital in Bangladesh. According to the eligibility
criteria patients were enrolled in the study with
informed written consent given by their parents. After
that each patient was then randomly provided with a
medicine or placebo with prescription. Patients in the
intervention arm received Magnesium and Vitamin B6
tablets and control arm received placebo for three
months starting after the day of initial assessment.
Patients
The patients were eligible to be included in the study
if they were a newly diagnosed patient of ASD, Children
between 2 to 12 years diagnosed & confirmed by DSM
5, Children between 2 to 12 years grading done by
ADCL, have Co-morbid neurological disorder like
hyperactivity and irritability. Excluding criteria
included patient having history of epilepsy and parents
unwilling to give informed consent.
Randomization was done by online graph pad software
by using computer. The software automatically
generated two distinct sets of random numbers after
giving necessary inputs (sample size, sets of number).
The online graph pad calculator equally distributed
the patients into two comparable groups. The
randomization was conducted by a competent third
person, a researcher who has no relationship with this
research. Immediately after randomization, random
numbers of the two sets were assigned as patient code
number. One set was designated as intervention group
and another set was placebo group. Then the set of
code numbers that belongs to the intervention group
were written as patient ID numbers on the packages
contained Magnesium and Vitamin B6 tablets. On the
other hand, the set belonged to the placebo group were
designated as patient ID numbers on the packages
contained placebo. The participants, caregiver and the
outcome assessor who require being blind for such
study, were effectively blinded.
Treatment
In the intervention arm Magnesium tablets were given
to the patients in following dose: 50 mg for ages 2-3
years, 100 mg for ages 4-8 years and 200 mg for ages
9-12 years for three months. Vitamin B6 tablets were
given to the patients in following dose: 25 mg for ages
2-3 years, 50 mg for ages 4-8 years and 100 mg for
ages 9-12 years for three months.In the other arm
patient received oral placebo in the same manner,
schedule and time frame. Patients in both arm received
Risperidone for hyperactivity and irritability.
Outcome
The outcome was any improvement in the six domains
of general observation, cognition, emotion, social,
communication and sensory deficiency evaluated at
90 days of initial therapy by a psychologist using ADCL
tool who was completely unaware about the study.
Statistical analysis
Appropriate statistical test (Unpaired t-test) and Chi –
squared test were done in this study for drawing an
appropriate conclusion.
Unpaired t-test was done to compare the age
distribution between the placebo and intervention
Vitamin B6 and Magnesium on Neurobehavioral Status of Autism Spectrum Disorder BJM Vol. 32 No. 1
13
groups, and comparison of score of DSM-5 between
placebo and intervention group both before and after
the intervention and comparison of neurobehavioral
improvement between patients receiving placebo and
intervention assessed by ADCL
Chi – square (x2) test was done to compare the sex
distribution between the placebo and intervention
group, to see the distribution of mild, moderate and
severe cases in the placebo and intervention group.
Result
Characteristics of the patients
From January 2019 to July 2019, 70 patients were
recruited based upon eligibility criteria as has been
designated for the study. Of which thirty five (35)
patients received intervention and thirty five (35)
received placebo. Twenty (20) patients were dropped
out during the research due to denial to take
medication (n=5), unable to travel (n=10), non-
compliance (n=5). For these patients, determination
of end point was not possible and therefore they were
excluded per-protocol analysis. At the end of the
research a total of 50 patients were assessed and
evaluated.
the mean age and SD of the patients in the intervention
were 3.68 ± 1.24 years. In the placebo group, out of
twenty three (23) patients, fourteen (14) were males
and nine (9) were females. While in the intervention
group seventeen (17) were males and ten (10) were
females.In the placebo group out of twenty three (23)
patients, three (3) patients (13.04%) had mild, eight
(8) patients (34.78%) had low moderate, eleven patients
(47.83%) had high moderate and one (1) patient
(4.35%) had severe ASD when assessed with ADCL
tool during initial assessment. While in the intervention
group out of twenty seven (27) patients, three (6)
patients (22.22%) had mild, seven (7) patients (25.93%)
had low moderate, twelve patients (44.44%) had high
moderate and two (2) patients (7.41%) had severe ASD
when assessed with ADCL tool during initial
assessment. The distribution of severity between the
placebo and intervention group was statistically
insignificant (p = 0.20).
Table 1
Variables PlaceboaInterventionbP value
n=50 23 27
Age in years 3.85 ± 0.99 3.68 ± 1.24 0.58 x
(Mean ± SD)
Male 14 17 0.88 y
Female 910
Distribution according to severity
Mild 3 (13.04%) 6 (22.22%) 0.20 z
Low Moderate 8 (34.78%) 7 (25.93%)
High Moderate 11 (47.83%) 12 (44.44%)
Severe 1 (4.35%) 2 (7.41%)
a Placebo patients received placebo tablets
b Intervention patients received Magnesium and
Vitamin B6 tablets
x Unpaired t-test was done. P e” 0.05 = statistically
insignificant
y Chi – square (x2) test was done. P ≥0.05 = statistically
insignificant
zChi – square (x2) test was done. P ≥0.05 = statistically
insignificant
Outcome
Assessment after 90 days showed (Table II) that in the
placebo group out of twenty three (23) patients, two
(2) patients (8.69%) had mild, eleven (11) patients
(47.83%) had low moderate, nine patients (39.13%)
had high moderate and one (1) patient (4.35%) had
severe ASD when assessed with ADCL tool during final
Table 1: There was no significant difference in age (p =
0.58), gender (p = 0.88), age of mother and father (p =
0.96, 0.85). In the placebo group the mean age and
SD of the patients were 3.85 ± 0.99 years. Whereas,
Vitamin B6 and Magnesium on Neurobehavioral Status of Autism Spectrum Disorder BJM Vol. 32 No. 1
14
assessment. While the in the intervention group out
of twenty seven (27) patients, thirteen (13) patients
(48.15%) had mild, twelve (12) patients (44.44%) had
low moderate, two patients (7.41%) had high moderate
and zero (0) patients (0%) had severe ASD when
assessed with ADCL tool during the final assessment.
The distribution of severity between the placebo and
intervention group was statistically significant (p d”
0.01).
Table-II
Comparison of Distribution of Patients According to
Severity Assessed by ADCL in the Placebo and
Intervention Group at Final Assessment
PlaceboaInterventionbP value
Mild 2 (8.69%) 13 (48.15%) ≤0.01 z
Low Moderate 11 (47.83%) 12 (44.44%)
High Moderate 9 (39.13%) 2 (7.41%)
Severe 1 (4.35%) 0 (0%)
a Placebo patients received placebo tablets
b Intervention patients received Magnesium and
Vitamin B6 tablets
zChi – square (x2) test was done. P d” 0.05 = statistically
significant
* ADCL (Autism Diagnostic Check List)
Forty three (43%) percent of the patients in the placebo
group (Table 3) improved with ADCL assessment when
the initial and final assessment were compared. While
in the intervention group eighty one (81%) percent of
the patients improved with ADCL assessment when
the initial and final assessment were compared.
Table 3
PlaceboaInterventionb
Overall 43.48%(10/23) 81.48%(22/27)
a Placebo patients received placebo tablets
b Intervention patients received Magnesium and
Vitamin B6 tablets
The mean score and SD (Table 4) in the placebo and
intervention group in overall score was 2.61 ± 19.1
and 17.44 ± 19.70 respectively. In general observation
score was 2.87 ± 5.55 and 4.41 ± 6.30 respectively. In
cognition score was -1 ± 3.12 and 1.56 ± 3.92
respectively. In emotion score was 1.48 ± 3.91 and
5.07 ± 4.73 respectively. In social score was 0.48 ±
4.12 and 0.78 ± 3.39 respectively. In communication
score was -0.17 ± 5.97 and 2.37 ± 5.68 respectively.
In sensory deficiency score was -0.78 ± 7.38 and 3.04
± 6.12 respectively. The improvement when comparing
the placebo group and intervention group in overall
score was statistically significant (p d” 0.01). The
improvement when comparing the placebo group and
intervention group in general observation score was
statistically insignificant (p = 0.36). The improvement
when comparing the placebo group and intervention
group in cognition score was statistically significant
(p = 0.01). The improvement when comparing the
placebo group and intervention group in emotion score
was statistically significant (p d” 0.01). The
improvement when comparing the placebo group and
intervention group in social score was statistically
insignificant (p = 0.78). The improvement when
comparing the placebo group and intervention group
in communication score was statistically insignificant
(p = 0.13). The improvement when comparing the
placebo group and intervention group in sensory
deficiency score was statistically insignificant (p = 0.06).
Table-IV
Comparison of Neurobehavioral Improvement Between Patients Receiving Placebo and Intervention Assessed by
ADCL
Improvement (Mean ± SD)
Placebo a Intervention b P - value
Overall 2.61 ± 19.1 17.44 ± 19.70 d” 0.01
General observation 2.87 ± 5.55 4.41 ± 6.30 0.36
Cognition -1 ± 3.12 1.56 ± 3.92 d” 0.05
Emotion 1.48 ± 3.91 5.07 ± 4.73 d” 0.01
Social 0.48 ± 4.12 0.78 ± 3.39 0.78
Communication -0.17 ± 5.97 2.37 ± 5.68 0.13
Sensory Deficiency -0.78 ± 7.38 3.04 ± 6.12 0.06
a Placebo patients received placebo tablets
b Intervention patients received Magnesium and Vitamin B6 tablets
Unpaired t-test was done. P d” 0.05 = statistically significant, P e” 0.05 = statistically insignificant.
Vitamin B6 and Magnesium on Neurobehavioral Status of Autism Spectrum Disorder BJM Vol. 32 No. 1
15
Discussion:
Autism spectrum disorder has been in existence for a
long time and even though several guidelines do exist
for its treatment, there are however no recommendable
drugs to treat it due to their tendencies to show
inconsistent results. One combination is the use of
Vitamin B6 and Magnesium to observe the effectiveness
in the neurobehavioral improvement in autism.
Rimland16 found significant improvement with the use
of high doses of pyridoxine, however high doses of
pyridoxine showed side effects which could be negated
by co-administering Magnesium. In another study,
patients were divided into three groups, and were given
only Magnesium, Vitamin B6 and Vitamin B6-
Magnesium combination respectively15, the patients
in the group who got the combination of both showed
the most improvement.
This study was done to find if there were any
improvements though the use of Vitamin B6 and
Magnesium combination. The study showed that
patients in the intervention group (81%) showed
improvement compared to the placebo study (43%),
where another study reflects that twenty out of thirty
three patients showed improvements (60%)17. A 2007
survey found improvements in 47% of patients(18).
According to LeLord(19) 34% patients showed
improvements out of 44 patients.
Our current study found an overall improvement in
the symptoms of autism along with improvements in
specific domains.20 found a global improvement in
children when magnesium was used along with
decreased autistic and behaviors and other signs. This
study found improvement mainly in two domains in
autistic children, emotion and cognition. Emotion
domain has many attributes such as hyperactivity,
aggressiveness, emotional lability, stress. The possible
explanation may be Magnesium inhibits the excitatory
channel glutamate N—methyl—D—aspartate
(NMDA)21 and reduces hyperactivity- a part of
emotional domain.Integral to cognition are memory and
learning, which are affected by environment and diet.
In ratsit had been seen that memory- both short and
long term, ability to learn and working memory are
somehow enhanced by using magnesium or
magnesium related compound.Mg increases pre-
synaptic releases that suggest that Mg in brain
enhances both short term and long term synaptic
facilitation and long-term potentiation and improves
learning and other memory functions.22
According to Cochrane database of systemic reviews
done in 2005 of Combined Vitamin B6-Magnesium
treatment in autism spectrum disorder, only three
studies could be regarded as valid as the others were
plagued with many methodological flaws. Tolbert23
found that there was no significant difference between
placebo and intervention, also Findling24 found no
improvement. The possible explanation could be that
one of these studies were conducted with Magnesium
oxide, which is poorly absorbed from the intestine
which fails to dissolve in water. Compared to the oxide
form, magnesium citrate, glycinate, malate and
threonate dissolve into water far better in absorption,
tolerability, and other health benefits. In our study we
have used Magnesium glycenate, which is absorbed
quite easily from the intestine and may show some
promising effects. Kuriyama25 also did not find any
significant difference, but he concluded that his study
should not be used as a recommendation due to the
short duration of study period and the limited number
of patients it was conducted on.
Mousain-Bosc17 found that when Vitamin B6 and
Magnesium were stopped, the previous symptoms
reappeared in the patients. So further studies should
be designed to look into the effects of discontinuation
of the medication on the patients suffering from ASD.
This study almost half of the autistic children showed
an intra-erythrocyte Mg depletion. Erythrocyte-
Magnesium (Erc-Mg) level can be considered as a
representative of some intracellular Mg2+, any decrease
in Erc-Mg without a change in serum Mg concentration
could be the result of an alteration of Mg2+ transport
through the plasma membrane. Genes involved in
primary inherited hypomagnesaemia has been
identified on the basis that TRPM receptors are involved
in Mg homeostasis 26,27. The Mg channels on the cell
membranes belongs to the family of TRPM
proteins28,29. So further studies should be done to look
into the genetic background of autism.
Moreover, this study has not utilized the maximum
tolerable dose of vitamin B6. Thereupon dose escalation
should be considered in further studies as Vitamin B6
is water soluble and non-toxic.
Many studies were done to look into the effects of the
combination in patients of ASD. We found a positive
relationship between the combination and ASD with
hyperactivity in improving the overall status of autism
plus cognition and emotion aspects of ASD. But we
cannot recommend it due to the small number of
patients and study period. So we hope that in the future
a larger well designed study will be conducted to further
establish the role of Vitamin B6–Magnesium in the
management of patients with autism spectrum disorder
with hyperactivity and irritability.
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