Healing takes energy. Energy requires thiamine. Modern foods, lifestyles, medications and chemical exposures threaten thiamine status in a large percentage of the population. Modern thiamine deficiency does not look like classic thiamine deficiency, and thus, goes largely unrecognized by the medical community. Modern thiamine deficiency does not originate from starvation, but rather, from a state of being well fed and sometimes over-fed. As a result, many of the symptoms are incongruent with current textbook definitions. This presentation discusses the chemistry and symptomology of modern thiamine deficiency.

1. Thiamine and the energy to
heal
CHANDLER MARRS, PHD

2. Introduction
 Thiamine Deficiency Disease, Dysautonomia,
and High Calorie Malnutrition
 Synopsis: Hiding in Plain Sight: Modern Thiamine
Deficiency
 Research analysis and case stories
 HormonesMatter.com
 Discussion – patient driven
 Understanding Mitochondrial Nutrients – FB
 Fun - powerlifting
 Oldladieslift.com/Oldladieslift - FB

3. Objectives
 To provide a framework for understanding and recognizing modern
thiamine deficiency
 Well fed but malnourished adults – walking sick
 Basic thiamine chemistry
 Role in food metabolism
 Role in mitochondrial function and OXPHOS
 Metabolic patterns associated with insufficient thiamine
 Overview of symptoms across time
 Treatment options
 Resources for more information

4. Premise
THIAMINE IS THE
MISSING PIECE TO MANY
MODERN ILLNESSES

5. WHY
THIAMINE?
 Thiamine is required for ATP/energy
synthesis
 Rate-limiting for effective macronutrient
metabolism and mitochondrial
energetics - OXPHOS
 Thiamine is required for
mitochondrial oxidation and cellular
oxygenation
 Insufficient thiamine -> hypoxia
 No energy, no oxygenation, no life
 And lots of ill-health along the way
 One of the main drivers of chronic illness
 An important component of acute illness
Life requires
energy.
Energy requires
thiamine.

6. What is thiamine?
 Vitamin B1 (thiamin, thiamine) found in
 Lean pork, poultry and other meats, wheat germ, liver and other organ meats, eggs,
fish, beans, peas, nuts, whole grains, garlic
 Processed foods (enrichment/fortification)
 Antagonized by
 High carbohydrate/sugar diets, coffee, tea, alcohol, tobacco, polyphenol supplements
 Many (all) pharmaceutical, environmental, and industrial chemicals
 Critical for
 Metabolism, mitochondrial energy production, protein expression, and general
function, and array of CNS/PNS functions – life itself

7. Basic kinetics
 Humans and animals must consume
 Plants and microbes synthesize
 Gut microbes synthesize ~2% of total
thiamine – used mainly by colonocytes
 Substrate/micronutrient availability
determine microbial balance
 Deficiency ↑ pathogenic species (better
with salvage pathways) ↓ more helpful
species
 Short half life: 1-12 hours
 Limited storage: 2-3 weeks after
complete cessation
 Complete cessation is rare in west. Intake
and need wax and wane.
 Absorbed mainly in intestine
 Passive diffusion at higher
concentrations
 Via transporters at low concentrations
 At least 7 transporters (see ‘Hiding’
paper) discovered so far.
 Transporter activity is susceptible to
 Genetic defects that are quite common
 Environmental regulation – meds and
other substances block transporters

8. Once absorbed
 Free thiamine is phosphorylated into
thiamine pyrophosphate (TPP) also called
thiamine diphosphate (ThDP)
 Mg2+ and ATP dependent
 TPP = ~90% of circulating thiamine
 Phosphates removed or added to form
thiamine monophosphate (TMP), thiamine
triphosphate (TTP)
 Microbial thiamine: adenosine thiamine
diphosphate (AThDP) Defects in TPK linked to Huntington’s
disease, possibly other neurodegenerative
disease processes.

9. From food to ATP
MITOCHONDRIA ARE KEY
AND THIAMINE IS RATE-
LIMITING

10. We believe
It doesn’t matter what we eat, so long as there is sufficient intake,
we get ATP.

11. BARRING ‘RARE’
GENETIC
DEFECTS OR
FRANK
STARVATION
All of this
happens
automatically

12. “The presumption is that all calories are created equally
e.g. that calories are calories and no matter the origins of
those calories, the end result will be ATP. Indeed, from the
mitochondrial perspective, each fuel, no matter its origins,
will be broken down to its carbon skeleton and through a
series of reactions, the final output will be ATP. In that sense,
the fuel source makes little difference: the net result will be
ATP.”
Graphic: Lonsdale & Marrs, Thiamine Deficiency
Disease, Dysautonomia, and High Calorie Malnutrition.

13. “However, and this is a big however, what this perspective
fails to recognize, is to get from fats, proteins and
carbohydrates to ATP, there is an entire
factory of enzymatic reactions that absolutely require non-
caloric nutrients - vitamins and minerals – to function
properly.”
Graphic: Lonsdale & Marrs, Thiamine Deficiency
Disease, Dysautonomia, and High Calorie Malnutrition.

14. In reality
 Enzymes require nutrient cofactors to perform
metabolic tasks.
 When appropriate nutrient co-factors are present in
sufficient concentrations for the enzymes to operate fully,
the food we eat is successfully metabolized into end-
products that are useful for all manner of processes and
cellular energy is produced.
 Even in the case of genetic aberrations that limit enzyme
function endogenously, there is evidence that nutrient
manipulation can overcome inadequate enzyme activity.
 Pyruvate dehydrogenase deficiencies, Parkinson’s, and
Huntington’s, for example.
Graphic: Elliot Overton, https://www.hormonesmatter.com/beyond-
deficiency-thiamine-metabolic-stimulant/

15. With Co-factor deficiency
 When nutrient co-factors are in short-supply, resources are
reallocated.
 Metabolism shifts directions, it takes a right turn when it should move left or vice versa.
 Different enzymes are activated and metabolism eventually reaches a dead-end but not
before potentially toxic, unused, waste products build up. Dirtier burn.
 As toxins build up, other systems become disrupted, inflammatory and immune responses
are activated, demanding ever more energy to resolve.
 This is the energy spiral that induces and maintains many of the
illnesses we see today.

16. What the body needs to make energy
Macronutrients
with adequate
micronutrients
to power
enzyme
machinery.
Graphic: Lonsdale & Marrs, Thiamine Deficiency
Disease, Dysautonomia, and High Calorie Malnutrition.
Absent
micronutrients, it
doesn’t matter
how many
calories one
ingests, the
wheel will not
spin (or it will
spin backwards).

17. When it comes to energy
 Per glucose molecule
 Glycolysis: 2-4 units
 TCA/Krebs/Citric acid cycle:
1-2 units
 OXPHOS: 30-38 units
 Per fat molecule
 OXPHOS: >100 units
 Protein
 Substrates for the synthesis of
other proteins
 Glucose via liver gluconeogenesis (-
4)
 Glutamine > a-KGDH > 24 units of
ATP
 Used primarily in quickly replicating
immune cells and cancer > reverse spin
of TCA
 Pyruvate to citric acid cycle or
converted to lactate
90-95% of ATP produced via mitochondrial OXPHOS
El Bacha, T., M. R. M. P. Luz, and A. Da Poian. "Dynamic adaptation of nutrient utilization in
humans." Nat Educ 3, no. 8 (2010).

18. When it comes OXPHOS
 Can’t get into the mitochondria
without thiamine.
 All roads are blocked
 We don’t metabolize foods well
 Even glycolysis is challenged
Combs Jr, G.F. and McClung, J.P., 2016. The vitamins: fundamental aspects in nutrition and health. Academic press.
Thiamine is king

19. When we lose thiamine, we lose ATP
Imagine this happening in vivo in different tissues/organs. What
havoc would this initiate? What disease processes might evolve?

20. When OXPHOS is blocked
“OxPhos defects trigger mtDNA
instability and cell-autonomous stress
responses associated with the
hypersecretory phenotype,
recapitulating findings in plasma of
patients with elevated metabokine and
cell-free mitochondrial DNA (cf-mtDNA)
levels. These responses are linked to the
upregulation of multiple energy-
dependent transcriptional programs,
including the integrated stress response
(ISR).” –Jan 2023
Fig. 9: Conceptual model including potential sources of hypermetabolism in cells and patients with mitochondrial diseases.
From: OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases
It costs the cell more to do less
Leads to chronic illness

21. Understanding
thiamine –
dependent
enzymes
JUST A BIT OF
CHEMISTRY

22. Transketolase
 Transketolase (TKT)
 Located in the cytosol
 Connects pentose phosphate pathway (PPP) to
glycolytic and oxidative pathways
 Determines energy spent on ribose for
DNA/RNA and NADPH for steroid, myelin and
antioxidants (glutathione, thioredoxin) versus
what is shunted towards glycolysis
 TKT↓ TD and long list of other disease processes
 TKT activity among the more accurate tests of TD
 ↑ in tumor cells – an energy siphon
 But ↓ in the human
http://thiamine.dnr.cornell.edu/Thiamine_biochemistry.html
Mitochondrion

23. Thiamine dictates fatty metabolism
 a-oxidation of fatty acids begins in the
peroxisome
 Larger FAs are broken into smaller ones
 2-hydroxyacyl-CoA lyase (HACL1) – the enzyme
responsible, is thiamine dependent
 Impaired a-oxidation leads to
 ↓ Acetyl-CoA for mitochondria> ↓OXPHOS >↓ATP
 Particularly problematic for the heart
 High phytanic acid/sphingolipid foods (beef, lamb,
dairy, eggs) cannot be metabolized fully
 May account for some food intolerances; later stage
symptoms - visual field restriction, peripheral
neuropathies, ataxia
Dhir, S., Tarasenko, M., Napoli, E. and Giulivi, C., 2019. Neurological, psychiatric, and biochemical
aspects of thiamine deficiency in children and adults. Frontiers in psychiatry, p.207.

24. In the mitochondria
 Pyruvate dehydrogenase complex (PDC)
 Governs entry into the TCA/Krebs/Citric acid cycle
 Pyruvate to Acetyl-CoA
 a-ketoglutarate dehydrogenase (a-KGDH)
 Metabolic flux through the TCA, direction and
speed of spin
 Generates NADH>electrons for ETC
 Produces and is susceptible to ROS
 Branched chain keto acid dehydrogenase
(BCKAD/BCKADH)
 Dictates BCAA catabolism
 Influences fatty acid metabolism - > increase in
inflammatory diacylglycerol and ceramides
(hallmarks of metabolic syndrome)
Dhir, S., Tarasenko, M., Napoli, E. and Giulivi, C., 2019. Neurological, psychiatric, and biochemical
aspects of thiamine deficiency in children and adults. Frontiers in psychiatry, p.207.
↓ ALZ &
Parkinson’s
Lactate

25. Insufficient thiamine > metabolic
dysfunction
 Blocked TKT and PDC > impaired
glucose metabolism
 Shifts to polyol/sorbitol, hexosamine,
diacylglycerol/PKC, AGEs
 Micro-vascular damage associated with
hyperglycemia
 Aging
 Increased lactate/poor lactate recycling
capacity
 Pyruvate cannot enter the TCA
 Fatigue, exercise intolerance and a
laundry list of other symptoms
 When severe lactic acidosis
Mechanism of Development of Atherosclerosis and Cardiovascular Disease in
Diabetes Mellitus, September 2017 Journal of Atherosclerosis and Thrombosis
25(1); DOI: 10.5551/jat.RV17014; LicenseCC BY-NC-SA 4.0

26. Even marginally insufficient thiamine
wreaks havoc
Oxalosis and thiamine
 Low TKT = low NADPH
 ↓NADPH > ↓ glutathione
 ↓ glutathione > poor detox of glyoxal and
methylglyoxal ↑ carcinogenic protein adducts
 ↓pyridoxal kinase (PK) activity
 PK converts inactive B6 (pyridoxine 5-phosphate)
into active (pyridoxal 5-phosphate - P5P)
 ↓ P5P prevents glyoxylate from being converted
back into glycine, leading to high oxalates
Shangari, N., Depeint, F., Furrer, R., Bruce, W.R. and O’Brien, P.J., 2005. The effects of partial thiamin deficiency
and oxidative stress (ie, glyoxal and methylglyoxal) on the levels of α-oxoaldehyde plasma protein adducts in
Fischer 344 rats. FEBS letters, 579(25), pp.5596-5602.

27. But wait, there’s
more
INSUFFICIENT THIAMINE
INDUCES HYPOXIA
NO OBSTRUCTION
NEEDED

28. Thiamine Deficiency Induces Hypoxia
 TD downregulates PDC and impairs oxidation and oxygenation
 Oxidation: ability to utilize O2 in the mitochondria and efficiently
produce ATP
 Oxygenation: ability to traffic oxygen (↓arterial O2
saturation/↑venous) – ATP dependent function
 Think ‘air hunger’ or the ‘happy hypoxic/hypoxemic’ – at least
initially.

29. ↓ PDC stabilizes HIF1a proteins
 HIF1a > signals 100s of genes to
 Increase angiogenesis, erythropoiesis, and glycolysis - Warburg
 HIFs feedback and degrade PDC further
 Upregulates pyruvate dehydrogenase kinases – energy spiral
 HIFs are stabilized with any hypoxic condition – universal
response
 Unlike obstructive or exertional, there is plenty of O2, but it
cannot be used or trafficked effectively – pseudo-hypoxia
 Partly local – cell/mitochondria
 Partly neural – brainstem hypoxia > dysautonomic function
Watts, M.E., Pocock, R. and Claudianos, C., 2018. Brain energy and
oxygen metabolism: emerging role in normal function and disease.
Frontiers in molecular neuroscience, 11, p.216.

30. Another reason SAD is bad
 Heavy in seed oils
 Upregulates pyruvate dehydrogenase kinases (PDKs)
– inactivate PDC
 PDKs upregulated in tumor environment
 Stabilize HIF1a
 Heavy in HFCS
 Uses more ATP than it produces
 Low in nutrition
 Relative to the caloric, toxicant load

31. And yet more hits to the PDC
 Magnesium is required to activate/
phosphorylate thiamine
 ~50% of population is deficient
 Riboflavin and alpha-lipoic acid required for
subunits of PDC
 Heavy Metals
 Arsenic, mercury block ALA, impairs the PDC, induces
HIFs and impairs mitochondrial respiration
 Symptoms similar to TD and respond to increased
thiamine
 Thiamine chelates heavy metals Graphic: Elliot Overton, from: https://www.hormonesmatter.com/why-
thiamine-supplementation-requires-magnesium/

32. Just how important is the PDC?
In response to severe stress, the PDC translocates to the cell nucleus.

33. If thiamine is that
important
WHY DON’T WE
MONITOR IT?

34. When we think of thiamine deficiency
 We only think of late stage, frank deficiency in
specific populations with purely neuro symptoms
 Beriberi or Wernicke’s encephalopathy in chronic
alcoholics
 Ataxia, nystagmus, confusion/memory loss
 We miss the earlier symptoms in this and other
populations
 And we mostly miss Wernicke’s too
 80% of alcohol related Wernicke’s missed 1
 58% of pediatric Wernicke’s missed2
 Unknown % of hyperemesis gravidarum Wernicke’s missed
 Only 16% cases exhibit classic triad1
1. J Neurol Neurosurg Psychiatry. 1986 Apr;49(4):341-5.; 2. Pediatr Neurol. 1999 Apr;20(4):289-94.

35. Lonsdale & Marrs, 2017. Thiamine Deficiency Disease, Dysautonomia and High Calorie Malnutrition

36. We fail to recognize
 More subtle, metabolic disturbances
 Hyperglycemia and dyslipidemia cascades
 Vague, non-specific symptoms that correspond to a long list of disease processes – but at root
reflect poor energy capacity
 That develops slowly across time and is non-linear
 Food is abundant, obesity reigns
 Symptoms wax and wane before reaching critical point – just like thiamine intake and the
stressors that demand increased thiamine
 Brain lesions don’t happen overnight
 Or that there is even a problem
 We solved nutrient deficiency, didn’t we?

37. THIAMINE
DEFICIENCY
WAS SOLVED
 Fortification/enrichment eradicated
thiamine deficiency in the west
 Intake of processed foods provides
sufficient thiamine (RDA 1.1 – 1.4mg)
 Food intake surveys – only 5% of the
population consumes insufficient
thiamine
 Average American consumes 4X (NIH)
Right?

38. EVERY
PUBLISHED
STUDY
“A severe depletion is not commonly seen,
except in cases of inadequate nutrition
and/or alcoholism.”
“Cardiac beriberi, or heart failure due to
thiamine deficiency, is considered rare in the
developed world.”
“Thiamine deficiency is rare in developed
countries and is most commonly associated
with chronic alcoholism. The other
predisposing conditions include chronic
dietary deprivation and impaired absorption
or intake of dietary nutrients.”
“Nowadays, in the developed world, it is
relatively rare.”
Suggests TD is
rare and limited
to certain
populations or
conditions

39. IF WE DIG A
LITTLE
DEEPER
 Without processed foods
 Over 40% of population does not consume
enough thiamine (or other nutrients)
 If we look at the research
 A large portion of the population is either
frankly or functionally deficient
 Frank deficiency – lab confirmed
 We rarely measure – so how would we know?
 And there problems with the labs – see Hiding
 Functional deficiency – problems with thiamine
or OXPHOS machinery; magnesium deficiency;
high consumption/exposure to anti-thiamine
factors e.g. modern foods and medications;
chronic or severe illness that demands much
higher intake of thiamine
It’s not rare at
all

40. Especially with hyperglycemia
 ‘Healthy’ individuals see a reduction in
thiamine beginning at 55% carb intake
 Standard American Diet > 55% carbs
 Type 1 and 2 diabetics are frequently
deficient in thiamine
 ~75% lower thiamine than controls
 98% diabetics were deficient
 ~10% of population is diabetic (NIH)
Hyperglycemia increases demand
“…prevalence of low plasma thiamine
(<70 nmol/L [[23]]) was 98% in the
diabetes group with microalbuminuria
and 100% in the diabetes group without
microalbuminuria and in the control
group.”

41. Just how common is thiamine deficiency?
 15-29% of obese patients pre-
bariatric surgery, higher post
surgery (~49%)
 No data on those not seeking surgery
 20-50% of community dwelling
elderly, 45% of elderly patients in
acute care
 30% psychiatric patients
 20% ER patients (random sample)
 10% ICU patients upon admission (small,
prospective study)
 20% after 3 days
 70% if septic
 Up to 91% congestive heart failure
patients
 38% pregnant women
 47-63% hyperemesis (likely more, not often
measured until WE is present)
Quite common, it appears.

42. WHY THE
DISCREPANCY?
 We assume it is was solved, so we
don’t look for it
 We look at intake only and ignore
basic kinetics and dynamics
 Absorption/transport
 Metabolism (activation)
 Utilization
 We disregard the myriad of anti-
thiamine factors or that increased
energetic demands require increased
intake – e.g. illness

43. Many roads to thiamine deficiency
 Increased dietary demand
 Low thiamine relative to sugar intake or toxicant
load
 Poor absorption
 Dysbiosis, dysmotility disorders, leaky gut
 Dietary deactivation/inactivation
 Alcohol, tobacco, coffee, tea, other common
foods
 Mg2+ deficiency
 Genetic factors
 SNPs in transporters or enzymes
 Medications & environmental
chemicals
 Block thiamine transporters,
degrade the molecule,
increase excretion, or just
damage mitochondria
(requiring more)
Two most common: diet and
medications

44. Common medications that deplete
thiamine
 Metformin [167]
 92 million prescriptions in 2020 (Statista)
 Psychiatric medications [168]
 13% of adults (CDC)
 Metronidazole [169], trimethoprim [170] and other antibiotics
 NSAIDs, acetaminophen, and aspirin [172]
 Proton pump inhibitors [173]
 Diuretics [174]
 Chemotherapeutic drugs [175] Marrs, C. and Lonsdale, D., 2021. Hiding in Plain Sight: Modern Thiamine
Deficiency. Cells, 10(10), p.2595.

45. A key mechanism
“Overall, our comprehensive study was
able to identify 146 inhibitors of ThTR-2,
most of which were not previously
known .”

46. Environmental threats to mitochondrial
function
“However, although many of these chemicals cause effects other than
mitochondrial toxicity, the importance of the mitochondrial effects is in
some cases supported by the fact that there is overlap in the
pathologies observed after exposures and mitochondrial diseases.”

47. What does all of this mean?
 Thiamine sufficiency is more than just intake
 All sorts of threats to thiamine stability
 Deficiency is more common than recognized
 Lots of folks are walking around with inadequate thiamine
 Impairs metabolism of food into energy
 Derails the metabolism of fatty acids, proteins and
carbohydrates (metabolic syndrome)
 Diminishes mitochondrial function and oxidative capacity >
forces the switch to glycolysis
 Increases hypoxia molecules
 Drives inflammation, among other things
It doesn’t look
like we think it
does.

48. “There is often something sinister about familiar concepts. The
more familiar or ‘natural’ they appear, the less we wonder what
they mean; but because they are widespread and well-known, we
tend to act as if we know what we mean when we use them.”
Devisch, I. and Murray, S.J., 2009. ‘We hold these truths to be self‐evident’: deconstructing
‘evidence‐based’medical practice. Journal of evaluation in clinical practice, 15(6), pp.950-954.

49. Identifying
modern thiamine
deficiency
ITS ALL ABOUT
ENERGY – OR LACK
THEREOF

50. What does TD look like?
 Depends upon severity and chronicity of the deficiency
 Classical descriptions depict later stage deficiency
 By the time we get to white matter lesions TD has been chronic and/or severe
 TD is a long process with ↑morbidity/↓ mortality
 Frequently begins in the gut
 With caloric sufficiency/excess, one may live with TD for years before presenting classical
symptoms, and may not present with classical symptoms at all
 Symptoms may also wax and wane in parallel with periods of thiamine
deficiency/sufficiency

51. A series of studies in the 1930-1940s
Looked at TD across time in a female inpatient population. There were 3 studies in total,
two with four women each and one with 11 women maintained on a diet of .15mg of
thiamine per day for 147 days, .45mg of thiamine for 88 days, and 11 women at ~.15 – .2mg
thiamine per day plus 1mg of thiamine given intermittently for up to 196 days, respectively.
(RDA is 1.2mg)
In the third study, where additional thiamine was provided, when averaged, the total
thiamine consumed was ~.175mg per 1000 calories of food or .35mg for a 2000 calorie per
day diet. Also, in this study, 5 of the 11 women were maintained on the diet for an
undisclosed period before resuming a normal diet, while the remaining 6 were kept on the
diet for as long as 196 days. This is approximately 30% of the recommended daily allowance
needed to stave off deficiency symptoms and syndromes.
https://www.hormonesmatter.com/are-thiamine-deficiency-symptoms-too-narrowly-focused/

52. Case notes on two women
First few weeks: emotional instability, irritability, moodiness, anxiety, agitation, depression, reduced activity, and numerous, often
vague, somatic complaints. Weakness and anorexia begin to present.
30 days: anorexia, weight loss, epigastric distress, increasing weakness, periodic vomiting
50 days: nausea and vomiting after meals, progressive weakness from low energy to bedridden, sometimes constipation
70 days: constant nausea, severe weakness, apathy, confusion, numbness, and tingling in extremities
90 days: inability to read or focus, aberrant to absent sensory recognition, tender calves, inability to stand from squatting position,
hypoactive Achilles tendon reflex, nausea progresses to regular vomiting after meals
110 days: appetite fails, apathy, vagueness and confusion, low blood pressure and heart rate at rest, rapid increase upon ordinary
exertion, aberrant and absent sensory perceptions, aberrant and reduced reflexes, reduced flexion of ankles and knees, ataxia, inability
to stand on toes.
120 days: impaired pain perception on legs, loss of patellar and Achilles reflex, weakness in abduction, adduction, and flexion of thighs,
weakness in the legs with limited ability to extend legs with quadriceps, inability to stand or walk without support, ankle and knee
clonus absent, Babinski response absent.
How many of your patients present with some of these symptoms?

53. Outcome
One of these two subjects developed severe neurological defects at 120 days and so the experiment was
stopped. The researchers noted that appetite had completely failed and remarked that ‘inanition seemed
imminent’.
They also remarked that with 60-80mg of thiamine given orally and parenterally many, but not all, of the
deficits resolved.
Appetite returned and strength was regained within the first week, and within 30 days, the less severely ill
of the two women was mostly recovered.
At 60 days, one of the women was fully recovered.
For the other women, recovery was incomplete, even after 120 days of treatment. Of note, it was the
younger and more active woman who suffered the most serious neurological deficits and who was unable to
fully recover.

54. Insights
.45mg of thiamine for 88 days
“We nevertheless are impressed by the degree of debility induced by the isolated withdrawal of thiamine. Fatigue,
lassitude, and loss of interest in food developed early and increased progressively as the period of deficiency extended,
to the point of intolerance for food. So great was this intolerance that uncontrollable vomiting, even after tube feeding
and parenteral injection of solutions of sodium chloride and dextrose, automatically brought the observations to a
close.”
“The time of development of symptoms and the time of development of severe symptoms differed among the subjects
and seemed to be related to physical activity. The subjects who were more active showed symptoms earlier and were
more seriously affected later than others who from the beginning were less energetic.”

55. WHAT THESE
STUDIES TELL
US
 Even with severe dietary restriction of
thiamine
 When calories/nutrients maintained, early (and
even late) TD symptoms are non-specific
 Food intolerance, dysbiosis and dysmotility are
signs of TD
 More active people affected more quickly and
seriously
 Hyperglycemia, obesity, sedentary behavior likely
masks TD
 Symptoms may wax and wane relative to changes
in thiamine
 When women given extra thiamine after periods of
deficiency, recovered, at least temporarily
 Recovery takes time

56. On the wax and wane of symptoms
Marrs, C. and Lonsdale, D., 2021. Hiding in Plain Sight: Modern Thiamine Deficiency. Cells, 10(10), p.2595.

57. Thresholds and tipping points
 Time course of cerebral TD relative WE in
rodents (ataxia, loss of righting, rigid
body arching)
 2.5 wks: weight loss, progressive anorexia,
hair loss and drowsiness
 4.5 wks: rapid progression of symptoms and
decline of health over next 5 days with
incoordination with walking, impairment of
the righting reflex, reluctance to walk,
walking backwards in circles, imbalance, rigid
posturing and eventually a total loss of
righting activity and severe drowsiness
 Neuro symptoms became apparent when cerebral
thiamine concentrations reached 20% of normal.
 Have to lose 80% of cerebral thiamine before WE
symptoms become noticeable
 Recovery began when concentrations climb to 26% of
normal.

58. HOW LONG
DOES IT TAKE
TO LOSE 80%
OF CEREBRAL
THIAMINE AND
INDUCE WE IN
HUMANS?
 With severe and consistent dietary restriction –
weeks to months
 But with modern diet, thiamine intake varies across time –
it may be years before WE symptoms manifest
 Poor intake/poor absorption plus excess elimination
 Hyperemesis gravidarum: 2-3 weeks (not often tested
until 6-8 weeks, if then, after serious brain damage has
begun)
 Non-pregnant, severe vomiting/diarrhea: 2-3 weeks
depending upon other variables
 Poor intake with hyper-metabolism of severe
illness/injury
 ICU – a few days
Does the time frame really matter? If thiamine ↑ATP and ATP is needed for
everything, shouldn’t we be providing support well before it reaches this point?

59. What does early TD look like
 Mitochondrial in nature – mitochondria fuel everything – wide variety of symptoms
 High energy organ systems impacted most dramatically
 Nervous system
 Cardiovascular system
 Gastrointestinal
 Musculature
 Metabolic changes locally <> systemically
 Recall the cell culture study where the heart cells ceased functioning after ~10 days
Everything and nothing

60. Some symptoms
• Fatigue, exercise intolerance, decreased wakefulness (orexin/hypocretin
neurons)
• Cyclic vomiting , gastroparesis, and pseudo bowel obstructions
• Myalgia, myopathy, neuropathy
• Migraines, seizures, syncope
• Ataxia and tremors
• Hormone disorders
• Depression, mania, anxiety, psychosis
• Cognitive impairment
• Diabetes, metabolic, inflammatory and immune dysfunction

61. Biochemistry for Medics:
http://www.slideshare.net/n
amarta28/thiamin
More
symptoms

62. General autonomic instability
 Inadequate energy supply
to the ANS > inconsistent
regulation.
 Too much, too little, too
soon, too late, too long, too
short
 Inability to adapt to stress of
any kind
 Dysautonomia
 Even more oddball
symptoms

63. When to consider thiamine
 If the patient has a long list of medically
unexplained symptoms that don’t quite fit
any diagnosis, it’s probably related to poor
mitochondrial function and insufficient
thiamine.
 If the history suggest repeat illnesses, poor
healing, diet issues, chronic medication use –
it’s probably related to thiamine.
 Metabolic syndrome
 Persistent fatigue
 If the patient has been vomiting or has severe
diarrhea, or a severely restricted diet due to
food intolerances, they would benefit from
thiamine
 Pregnancy and especially hyperemesis
 Severe illness or injury demanding increased
energy to heal, they would likely benefit from
thiamine
 And any of the conditions listed earlier that
have a high rate of thiamine deficiency
Rules of thumb
In other words, much of the population would
benefit from extra thiamine.

64. “Thiamine deficiency impacts on the most basic survival mechanisms:
oxygenation and oxidation. Both oxygenation of the blood and its delivery to
the tissues for the process of cellular oxidation are dependent on thiamine. Its
deficiency, particularly by its effects on the functions of the limbic system and
brainstem, places the ANS front and center. Both endogenous and exogenous
signals from the brain to body organs become chaotic, leading to a vast array
of symptoms.”
Lonsdale & Marrs, Thiamine Deficiency Disease,
Dysautonomia, and High Calorie Malnutrition.

65. Neurological
 Antonio Costantini’s work with
Parkinson’s and dystonia patients
 Research link
 YouTube video library of patients
before and after
 Using thiamine in Alzheimer’s
 Dozens of articles
 Clinical trial underway
 Huntington’s disease
 Thiamine/biotin transporter to
SLC19A3
 TPK (enzyme that converts free
thiamine to TPP)
Brain thiamine deficiency without apparent nutritional
deficiency
“Thiamine/biotin treatment of R6/1 HD mice to compensate for TPK1
dysregulation restores OL maturation and rescues neuronal pathology. Our
insights into HD OL pathology spans multiple brain regions and link OL
maturation deficits to abnormal thiamine metabolism.”

66. How to test
 Labs – See Hiding article or book for details
 In the office: watch and listen
 Too many symptoms, serious, unexplainable decline in health, marked by persistent fatigue
 Subtle and not so subtle changes in gait, stability, muscle tone, speech, decrements cognitive
or affective acuity or stability
 Asymmetrical pulse pressure, postural hyper- or hypotension, general tachycardia (early stage),
bradycardia (later stage)
 Other irregularities in autonomic function
 In the hospital or acute setting
 History and severity of illness > ↑ energy demand ↑ need for thiamine
 If not deficient on admission, likely to become deficient during stay

67. How to treat: option 1
Hard and fast
 High dose, IV, IM - theory is to kick start
downregulated enzymes
 Warranted in acute care, with WE, severe
neurological symptoms, and where oral intake
and/or absorption is problematic
 Dependent upon case and clinical experience
 Refeeding responses are real and difficult to
navigate
 Need to manage electrolytes and cofactors esp.
those with wet beriberi, affecting the heart
 The patient may get worse before getting
better – articles on HM
 IV multivitamin/mineral useful
Dosing ranges
 Guidelines vary significantly
 IV 100-500 mg 1-3X per day for several days to
week followed by oral at a range of doses
 Many patients need IV support for months,
followed by high dose oral intake indefinitely
 IM – Parkinson’s 100mg 2X per week for
months followed by 1000-3000mg (thiamine
HCL) orally indefinitely – per Costantini’s work.

68. How to treat: option 2
Low and slow
 Start at a low dose and gradually increase
over time in stair step fashion
 Allows the body to reregulate over time
 When IV/IM and regular clinical oversight
are not available
 ‘Refeeding’ still problematic and can last
for weeks to months
 The patient may get worse before getting
better
 Difficult with prolonged GI symptoms
Dosing
 Dosing varies significantly
 Starting dose: from micro-doses, fractions of a
mg to 100s of mgs even grams
 How long the patient has to stay at each dose
before increasing varies
 What co-factors and electrolyte support is
needed varies
 Need a good multi plus good electrolyte
support
 What formulation of thiamine the patient can
handle and respond to varies too

69. Oral thiamine supplements
 Thiamine mononitrate
 In cheap OTC vitamins – not recommended
 Thiamine HCL (various brands)
 Requires a transporter, lower potency, requires much higher dose
 At high doses works well with Parkinson’s, CFS; easier to titrate up than TTFD or benfotiamine
 Thiamine tetrahydrofurfuryl disulfide (TTFD) - Thiamax, Allithiamine, Lipothiamine
 Chemically modified to cross cell barrier, doesn’t require a transporter, higher potency, requires lower dose
than HCL
 Works for a variety conditions, may be too potent for some to begin with, sometimes problematic for those
with sulfur problems, low glutathione and/or high food sensitivities
 Benfotiamine
 Chemically modified to cross cell barrier, doesn’t require a transporter (different mechanism than TTFD),
higher potency, requires lower dose than HCL
 Works well for hyperglycemia, seems to be tolerated better by those with GI issues, by children with
neurodevelopmental disorders (tastes better than TTFD and can be hidden in foods more easily)
Which works best
for the patient is
highly individual.
For info on chemistry of
the different supplements
see: Elliot Overton’s video.

70. Cofactors and electrolytes
 As thiamine comes on board, it will unmask other deficiencies – usually
other B vitamins and/or mineral deficiencies
 Magnesium needed for thiamine activation
 Potassium will be drawn into the cell more readily – increase intake
 Calcium reregulation frequently requires additional Ca2+ , will see this with heart
related symptoms, and elevated ‘anxiety’ type symptoms
 Cal/Mg - 2/1 supplement typically counters this. See articles on HM.
 Low phosphate diets need to be improved or hypophosphatemia
 Sodium may need to increased (with POTS, migraine esp.)

71. Health requires
energy
ENERGY REQUIRES
THIAMINE