Author's personal copy

Drugs & Therapy Perspectives

https://doi.org/10.1007/s40267-019-00623-x

REVIEW ARTICLE

A critical review of pyritinol

Alok Singh1   · Vinay Purohit2

© Springer Nature Switzerland AG 2019

Abstract
Pyritinol (pyrithioxine) is a combination of two molecules of vitamin B ­ 6 (pyridoxine) with disulfide linkage. Its pharma-
cokinetic profile mimics that of its parent compound. Because it crosses the blood–brain barrier, its major clinical utility
is in brain-related disorders. Pyritinol regulates signalling pathways of various neurotransmitters including acetylcholine,
γ-aminobutyric acid, N-methyl-d-aspartate, etc. Pyritinol has also been shown to act as an antioxidant and anti-inflammatory
agent, and also reduces plasma viscosity. It is indicated in paediatric populations to treat learning disabilities, developmental
dysphasia, postnatal hypoxia and other cognitive disorders. In adults, it is indicated for improving cognition and memory,
Alzheimer’s disease, multi-infarct dementia and rheumatoid arthritis. It has also been investigated in many other clinical
conditions, but results are inconclusive. The positive results of many animal studies have not been replicated into consistent
clinical success. This review aims to discuss potential uses of pyritinol and its future prospects.

Introduction Pharmacology of pyritinol

Pyritinol ­(Encephabol®) is a semi-synthetic molecule syn-
thesized by combining two molecules of pyridoxine with
disulfide linkage, which is also known as pyridoxine disul-
phide or pyrithioxine. It was first manufactured in 1961 by
Merck Laboratories; since then it has been prescribed as
a nootropic agent for cognitive disorders and learning dis-
abilities in children. In the US, it has been used as a dietary
supplement. It is approved for impaired brain function in
dementia syndromes, treatment of sequelae of cranio-cer-
ebral trauma, Alzheimer’s disease (AD) and alcohol with-
drawal in adults, and developmental disorders of the brain in
infants and children, in various European countries including
Austria, Germany, France, Italy, Portugal and Greece [1].
In France, pyritinol is approved to treat rheumatoid arthritis
[1]. It was approved in India by the Drug Controller General
of India as a cerebral stimulant in 1965. It is available as an
over-the-counter product in many countries.
* Alok Singh
draloksingh@aiimsraipur.edu.in
Vinay Purohit
vinaytgbp@gmail.com
1
Department of Pharmacology, All India Institute of Medical
Sciences, Raipur, Chhattisgarh, India
2
Procter and Gamble, Mumbai, Maharashtra, India
As pyritinol is a derivative of pyridoxine, its pharmacoki-
netic profile is similar to  that of the parent compound.
Pyritinol is rapidly absorbed after enteral administration.
Maximum radioactivity concentration is reached 30–60 min
after oral administration of 100 mg of 14Cpyritinol HCl–H2O.
The plasma elimination half-life of total radioactivity is
2.5 h (range 2–8 h). The metabolites are eliminated in the
form of their conjugates via the kidney. Total urine excre-
tion amounted to 72.4–74.2% of the total dose within 24 h
of oral or intravenous administration. Pyritinol crosses the
blood–brain barrier, accessing various parts of the brain,
especially the cortex. No accumulation of the substance is
observed after repeated oral administration. Toxic concen-
trations were not reached, even in the presence of impaired
renal function.
Pyridoxine, the parent molecule of pyritinol, has diverse
physiological functions and is involved in numerous bio-
chemical reactions (e.g. decarboxylation, transamination,
etc.) by serving as coenzyme. Likewise, pyritinol has a vari-
ety of different actions on various organ systems.
The CNS is the primary system in which pyritinol exerts
observable pharmacological effects. A number of animal
studies have shown effects on different neurotransmitters.
Pyritinol facilitates the recovery of cortical cholinergic
deficit due to nucleus basalis lesions. It increases the activ-
ity of choline acetyltransferase, which leads to increased

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accumulation of choline into cholinergic neurons [2]. Pyri-
tinol metabolites also increase the cortical release of acetyl-
choline [3]. In aged rats, pyritinol increased choline uptake
in striatal synaptosome, where choline uptake is reduced
due to ageing, which may be a mechanism responsible for
beneficial effects of pyritinol on cognitive disorders [4].
Acetylcholine is thought to be the primary neurotransmitter
responsible for cognition and memory; as the level of ace-
tylcholine is increased by pyritinol, this explains the role of
pyritinol as a cognition enhancer.
Pyritinol has a supportive role in restoration of age-related
brain deficits. When administered for a longer time in aged
mice, it restored the reduced density of N-methyl-d-aspartate
(NMDA), which is a primary excitatory neurotransmitter
[5]. Pyritinol inhibits the binding of γ-aminobutyric acid
(GABA) to GABA receptors in the cerebral cortex, dien-
cephalon, striatum, cerebellum and spinal cord by reducing
their affinity without altering the number of receptors [6]. As
GABA is the primary inhibitory neurotransmitter, decreased
affinity of GABA indicates diminished activity of GABA,
which is possibly responsible for the activating effect of
pyritinol. Pyritinol also inhibits glutamate decarboxylase,
which converts glutamate into GABA, in turn decreasing
GABA activity and promoting activation of the CNS, lead-
ing to increased activity of neurons in the limbic system and
reticular formation. In addition, pyritinol increases glucose
metabolism by a poorly understood mechanism.
Pyritinol acts as an antioxidant and also improves cer-
ebral circulation [7]. Animal studies have shown the poten-
tial of pyritinol to improve cognition and prevent and
manage learning disabilities. In an animal model of postnatal
hypoxia, pyritinol had preventive and therapeutic effects on
learning deficits [4]. It improved learning and retention in
an animal model, with beneficial effects observed in poor
learners but not good learners [8]. Furthermore, pyritinol
may also be useful in learning and memory deficits due to
malnutrition and environmental deprivation [9].
In addition to enhancing cognition, pyritinol has been
shown to prevent acute ethanol intoxication [10] and may be
a treatment option in the management of alcoholic hango-
vers. It also has antioxidant and immunostimulant proper-
ties [11]. These animal studies point towards the potential
usefulness of pyritinol in a variety of clinical conditions.
Clinical considerations
Although the therapeutic potential of pyritinol was shown in
animal studies, the same could not be translated into clini-
cal practice. The results of clinical studies of pyritinol are
supportive (Table 1), but the studies were not of an adequate
standard. Pyritinol is used in both adult and paediatric popu-
lations, primarily for cognitive disorders and learning dis-
abilities. The use of pyritinol in other indications remains
debatable.
Clinical studies in paediatric populations
Developmental dysphasia is defined as a specific dysfunction
in the development of speech and language expression and/

Table 1  Clinical trials of pyritinol in paediatric and adult populations

Study Diagnosis/indication (no. of pts) Pyritinol regimen Rand- Improvement
omized with pyritinol
trial

 Paediatric populations
 Zavadenko et al. [13] Developmental dysphasia (40) 12–15 mg/kg Yes Yes
 Zavadenko and Kozlova [14] Developmental dysphasia (120) Not available No Yes
 Nair et al. [15] Post-asphyxia encephalopathy (108) 20–100 mg from postnatal day 8–6 months Yes No
 Zykov and Begasheva [16] Cognitive disturbances in tics and Age 5–7 years: 200–300 mg/day No Yes
Tourette syndrome (83) Age > 7 years: 600 mg/day
 Zenkov and Zenkova [17] Cognitive disorders in epilepsy (24) 600 and 300–400 mg/day No Yes
 Adult populations
 Hindmarch et al. [18] Healthy (12) 600 or 1200 mg/day No Yes
 Fischhof et al. [21] SDAT and MID (156) 200 mg three times daily Yes Yes
 Knezevic [22] SDAT (26) Not available Yes Yes
 Herrmann et al. [23] Organic mental disorder (120) 200 mg three times daily Yes Yes
 Alkuraishy et al. [2] Cerebrovascular disorder (30) 100 mg daily Yes Yes
 Khan et al. [25] Prevention of alcohol hangover (17) 1200 mg (three divided doses) No Yes
 Lemmel [27] Rheumatoid arthritis (78) 600 mg/day No Yes

MID multi-infarct dementia, pts patients, SDAT senile dementia of the Alzheimer’s type
 Author's personal copy
or reception, in the absence of other causal disabilities [12].
Its aetiology is multi-factorial and may involve a variety of
neurotransmitters (i.e. acetylcholine, glutamine and dopa-
mine). As established by animal studies, pyritinol boosts the
level of these neurotransmitters and improves glucose utili-
zation, which may be responsible for its beneficial effects in
developmental dysphasia.
Pyritinol has been investigated in the treatment of devel-
opmental dysphasia (Table 1) [13]. Although results were
encouraging, trials with larger sample sizes are required to
establish its efficacy in this indication. In the study, 40 chil-
dren aged 3–5 years with developmental dysphasia were ran-
domized into two equal groups: group 1 received pyritinol
suspension at a daily dosage of 200–250 mg or 12–15 mg/
kg for 2 months; group 2 constituted the control group. The
group receiving pyritinol showed significant improvement
of expressive and impressive speech, and speech attention.
After treatment, parents reported a decrease in motor distur-
bances and psychosomatic disorders, and improved attention
and emotional states in the children [13].
In a study in 120 children aged 3–4 years (Table 1) [14],
children were randomized in groups of 30 to receive cer-
ebrolysin, hopantenic acid, pyritinol, or no drug therapy for
2 months. Using a standard questionnaire, the three groups
receiving active treatment achieved highly significant
(p < 0.001) improvements on the expressive language scale,
as well as the receptive language and attention to speech
scales, relative to the control group, who did not show any
improvements. Repeated administration of a nootropic agent
was recommended together with speech therapy [14].
A study in 108 full-term babies with post-asphyxial
encephalopathy randomized patients to receive liquid pyri-
tinol 20–100 mg (1–5 mL) or placebo from postnatal day
8 to the end of 6 months (Table 1) [15]. At 1 year of age,
there were no statistically significant between-group dif-
ferences in Mean Mental Development Index and Psycho-
motor Development Index scores on the Bayley Scales of
Infant Development [15]. These results were disappointing
and pyritinol was not found to be useful in treatment post-
asphyxial encephalopathy in neonates.
In a study of cognitive disturbance associated with move-
ment disorders (Table 1) [16], 83 patients received pyritinol
(200–300 mg/day if aged 5–7 years, and 600 mg if aged > 7
years) for 6 weeks. Pyritinol significantly improved memory,
attention and praxis function after 6 weeks of treatment [16].
Pyritinol has shown benefits in the treatment of cogni-
tive disorders. In a study in 24 paediatric patients with epi-
lepsy (Table 1) [17], patients aged < 12 years received pyri-
tinol 300–400 mg/day, and those aged > 12 years received
600 mg/day. Statistically significant improvements in global
self-rating of cognitive function, speed of reading, decrease
of errors as well as learning of content were seen after the
end of treatment. Improvements in cognitive traits correlated
significantly with improvements in computed EEG param-
eters [17].
Overall, the results of paediatric studies varied, with stud-
ies showing favourable results having smaller sample sizes,
which may lead to erroneous conclusions. Well-designed
clinical studies are needed to establish valid conclusions on
the benefits of pyritinol in paediatric patients.
Clinical studies in adult populations
Pyritinol was also investigated as a treatment to enhance
memory and to improve cognitive disturbance, circulatory
disturbance and rheumatoid arthritis. In a randomized, dou-
ble-blind, crossover study in 12 normal healthy volunteers
(Table 1), relative to placebo, pyritinol 600 or 1200 mg/day
for 3 days significantly improved psychomotor function, as
shown by the results of critical flicker fusion and choice
reaction time tests [18].
AD is a neurodegenerative disorder characterized by
irreversible cognitive deterioration associated with loss of
cholinergic neurons in the basal forebrain [19]. Hippocam-
pus and cortical areas receive cholinergic input from basal
forebrain nuclei [20]. Drugs enhancing cholinergic transmis-
sion are used to manage AD.
Pyritinol increases cholinergic transmission and was
superior to placebo in patients with mild to moderate demen-
tia of both degenerative and vascular aetiology (Table 1)
[21]. In a study in 156 patients with senile dementia of the
Alzheimer type (SDAT) or multi-infarct dementia, patients
received pyritinol 200 mg three times daily or placebo for
12 weeks [21]. The therapeutic efficacy of pyritinol was
clearly demonstrated, as it was statistically significantly
superior to placebo with regard to all three target variables
(i.e. Clinical Global Impression [CGI], Short Cognitive Per-
formance Test [SKT] and the factor ‘cognitive disturbances’
on the Sandoz Clinical Assessment Geriatric [SCAG] scale).
EEG mapping demonstrated improvement in vigilance [21].
Another cross-over trial of pyritinol versus placebo was
conducted with 26 patients (Table 1) [22]. Psychiatric and
neurological examination, psychometric testing and meas-
urement of the regional cerebral blood flow (rCBF) at rest
and during mental activation were used to assess treatment
effects. Pyritinol was associated with a significant improve-
ment in cognitive performance. Regional cerebral blood flow
data showed that treatment with pyritinol normalized the
pattern of blood flow increase during activation [22].
Pyritinol 200 mg (coated tablets) three times daily was
evaluated in the treatment of organic mental disorder in 120
geriatric patients using SCAG, CGI and SKT to assess the
condition and recovery of patients (Table 1) [23]. Statisti-
cally significant results were found in favour of pyritinol
over placebo in both the levels of clinical symptomatology
 Author's personal copy
and performance, especially with regard to the superiority of
pyritinol in the ‘social behaviour’ domain of the SCAG [23].
In a recent study in patients with cerebrovascular dis-
orders aged 50–65 years, three groups of 10 patients each
received vinpocetine 10 mg once daily, pyritinol 100 mg
once daily or both drugs simultaneously for 2  weeks
(Table 1) [2]. The third group showed significant improve-
ment in blood rheological parameters, which may improve
blood flow in the CNS [2].
Pyritinol may be useful in reducing hangover symptoms
after alcohol consumption. Alcohol hangover is charac-
terized by headache, diarrhoea, anorexia, tremulousness,
fatigue and nausea [24]. Prophylactic pyritinol reduced the
number of hangover symptoms by ≈ 50% in a double-blind,
cross-over study (Table 1) [25], in which 17 men and women
attended a social function and were asked to consume alco-
holic beverages until intoxicated. Participants received either
pyritinol 1200 mg in three divided doses (i.e. 400 mg at the
beginning of the function, 3 h later and at the end of the
function) or placebo, with crossover to the alternate regi-
men at a second function. The severity of alcoholic hangover
was assessed with 20 parameters rated between 1 and 10.
Mean symptom scores were significantly better (lower) with
pyritinol than with placebo (3.2 ± 2.8 vs 6.8 ± 3.8; p ≤ 0.01)
[24, 25]. Few studies are available in this area, opening up a
potential area of research.
Probably due to its immunostimulant and antioxidant
properties, pyritinol has been evaluated in the treatment of
rheumatoid arthritis, which is an immune-mediated systemic
disease of multifactorial aetiology primarily affecting the
joints [26]. Patients with rheumatoid arthritis received pyri-
tinol 600 mg/day or auranofin (gold preparation) 6 mg/day
for 1 year. Severity and recovery were assessed using the
Ritchie index, joint swelling index, rating scales for pain
and general well-being, functional index, morning stiffness
and ESR [27]. The response rate with pyritinol was supe-
rior to that with auranofin, with the drugs having similar
adverse effect profiles [27]. The viscosity-reducing property
of pyritinol may be helpful in ameliorating the symptoms of
rheumatoid arthritis [2].
Pyritinol at usual dosages is well tolerated. General
adverse effects include gastrointestinal problems, insomnia
and agitation. Severe cholestatic hepatitis has been reported
in six patients receiving pyritinol [1].
Conclusion
Current evidence from animal studies on therapeutic appli-
cations of pyritinol are convincing, but clinical data are
limited, mixed, contradictory or inconclusive. Some of the
results of clinical studies were found to be impressive, while
others could not establish significant clinical efficacy. The
overall usefulness of pyritinol in various CNS disorders, as
a supplement or adjuvant treatment, needs to be established
through high-quality multicentre randomized controlled
clinical trials, with a sufficient sample size. Considering
its regulatory status as a supplement in some countries and
relatively excellent safety profile, pyritinol can be considered
as an adjuvant to any standard therapy for CNS conditions,
such as developmental dysphasia and selected cognitive dis-
orders where current therapeutic options are limited.
Compliance with ethical standards 
Conflict of interest  Authors declare no conflicts of interest relevant to
this article.
Funding  No funding received from any source.
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