The Promise & Pitfalls of Intravenous Micronutrient Therapy:

From Practice to Theory, & Back Again

David Katz, David Katz, MD, MPH, FACPM, FACPMD, MPH, FACPM, FACP

Yale Prevention Research CenterYale Prevention Research CenterYale University School of MedicineYale University School of Medicine

ACAM ACAM Dallas, TXDallas, TX

5-4-065-4-06

www.davidkatzmd.comwww.davidkatzmd.com

History of Myers’ Cocktail(shaken, not stirred)

Treatment pioneered by John Myers – a physician from Baltimore

Myers did not leave any published or print material on the composition of the IV treatment

It appears that he used a combination of magnesium chloride, calcium gluconate, thiamine, vitamin B6, vitamin B12, calcium pantothenate, vitamin B complex, vitamin C, and dilute hydrochloric acid

Current formulations have been modified to by Dr. Alan Gaby who took over care of Dr Myers’ patients after his death in 1984

Popular brew-Popular brew-

Members from a wide range of national medical Members from a wide range of national medical associations report use of IVMT, including:associations report use of IVMT, including:• The American College for Advancement in Medicine The American College for Advancement in Medicine

(ACAM)(ACAM)• The American Association of Naturopathic Physicians The American Association of Naturopathic Physicians

(AANP)(AANP)• The American Holistic Medical Association (AHMA)The American Holistic Medical Association (AHMA)• The American Academy of Pain Management (AAPM)The American Academy of Pain Management (AAPM)• The Great Lakes College of Clinical Medicine (GLCCM) The Great Lakes College of Clinical Medicine (GLCCM)

andand• International Society of Orthomolecular Medicine (ISOM)International Society of Orthomolecular Medicine (ISOM)

The Myers’ Cocktail

Myers’ Cocktail Composition-Myers’ Cocktail Composition-

Magnesium chloride hexahydrate (20%)Magnesium chloride hexahydrate (20%) 5 ml5 ml Calcium gluconate (10%)Calcium gluconate (10%) 3 ml3 ml Hydroxocobalamin (1,000 mcg/ml)Hydroxocobalamin (1,000 mcg/ml) 1 ml1 ml Pyridoxine hydrochloride (100 mg/ml)Pyridoxine hydrochloride (100 mg/ml) 1 ml1 ml Dexpanthenol (250 mg/ml)Dexpanthenol (250 mg/ml) 1 ml1 ml B-complex 100*B-complex 100* 1 ml1 ml Vitamin C (500 mg/ml)Vitamin C (500 mg/ml) 5 ml 5 ml Sterile WaterSterile Water 20 ml20 ml

B-Complex 100 contains the following per each ml:B-Complex 100 contains the following per each ml:

Thiamine HClThiamine HCl 100mg100mg RiboflavinRiboflavin 2mg2mg Pyridoxine HClPyridoxine HCl 2mg2mg PanthenolPanthenol 2mg2mg NiacinamideNiacinamide 100mg100mg Benxyl AlcolholBenxyl Alcolhol 2% 2%

Composition, cont.

Theories, at least in theory-

Higher Serum Concentrations

IV administration of nutrients achieves serum concentrations much higher than those achieved by oral or IM administration

E.g. Highest serum dose achieved after oral administration of pharmacological dose of vitamin C is 9.2mg/dL. IV administration of 50 g/day of vitamin C resulted in a mean peak plasma level of 80 mg/dL

Pharmacological Effects of Nutrients

Various nutrients may exert pharmacological effects only in concentrations achieved through IV administration

Eg. Antiviral effect of Vitamin C demonstrated at a concentration of 10-15 mg/dL – a level achieved through IV therapy only

Correcting Intracellular Nutrient Deficits

Higher intracellular nutrient concentration necessary in some cases to maintain proper cellular function

E.g. Magnesium concentration 10 times higher in myocardial cells as compared to extra-cellular concentrations

in certain disease conditions cell membrane capacity to maintain high concentrations may be compromised

IV administration of Mg may lead to a significant though

transient increase in Mg levels

Therapeutic Applications of IVMTTherapeutic Applications of IVMT

IVMT has been effective in treatingIVMT has been effective in treating

----- ----- AsthmaAsthma

----- M----- Migrainesigraines

----- Fatigue (including chronic fatigue ----- Fatigue (including chronic fatigue syndrome)syndrome)

----- Fibromyalgia----- Fibromyalgia

----- Acute muscle spasm----- Acute muscle spasm

---- Upper respiratory tract infections---- Upper respiratory tract infections

----- Chronic sinusitis----- Chronic sinusitis

----- Seasonal allergic rhinitis----- Seasonal allergic rhinitis

----- Cardiovascular disease ----- Cardiovascular disease

AsthmaAsthma

IV magnesium can abort acute asthma attacksIV magnesium can abort acute asthma attacks

1.1. Skobeloff EM, Spivey WH, McNamara RM, Greenspon L. Intravenous magnesium sulfate for the Skobeloff EM, Spivey WH, McNamara RM, Greenspon L. Intravenous magnesium sulfate for the treatment of acute asthma in the emergency department. JAMA 1989;262:1210-1213.treatment of acute asthma in the emergency department. JAMA 1989;262:1210-1213.

2.2. Bloch H, Silverman R, Mancherje N, et al. Intravenous magnesium sulfate as an adjunct in the Bloch H, Silverman R, Mancherje N, et al. Intravenous magnesium sulfate as an adjunct in the treatment of acute asthma. Chest 1995;107:1576-1581.treatment of acute asthma. Chest 1995;107:1576-1581.

3.3. Ciarallo L, Brousseau D, Reinert S. Higher-dose intravenous magnesium therapy for children with Ciarallo L, Brousseau D, Reinert S. Higher-dose intravenous magnesium therapy for children with moderate to severe acute asthma. Arch Pediatr Adolesc Med 2000;154:979-983.moderate to severe acute asthma. Arch Pediatr Adolesc Med 2000;154:979-983.

4.4. Ciarallo L, Sauer AH, Shannon MW. Intravenous magnesium therapy for moderate to severe pediatric Ciarallo L, Sauer AH, Shannon MW. Intravenous magnesium therapy for moderate to severe pediatric asthma: results of a randomized, placebo-controlled trial. J Pediatr 1996;129:809-814.asthma: results of a randomized, placebo-controlled trial. J Pediatr 1996;129:809-814.

5.5. Rowe BH, Bretzlaff JA, Bourdon C, et al. Intravenous magnesium sulfate treatment for acute asthma in Rowe BH, Bretzlaff JA, Bourdon C, et al. Intravenous magnesium sulfate treatment for acute asthma in the emergency department: a systematic review of the literature. Ann Emerg Med 2000;36:181-190.the emergency department: a systematic review of the literature. Ann Emerg Med 2000;36:181-190.

MigraineMigraine

Beneficial effect of IVMT in treatment of migraine has been demonstrated in some clinical trials

1. Mauskop A, Altura BT, Cracco RQ, Altura BM. Intravenous magnesium sulphate relieves migraine attacks in patients with low serum ionized magnesium levels: a pilot study. Clin Sci 1995;89:633-636.

2. (29.) Demirkaya S, Vural O, Dora B, Topcuoglu MA. Efficacy of intravenous magnesium sulfate in the treatment of acute migraine attacks. Headache 2001;41: 171-177.

3. (30.) Mauskop A, Altura BT, Cracco RQ, Altura BM. Intravenous magnesium sulfate relieves cluster headaches in patients with low serum ionized magnesium levels. Headache 1995;35:597-600.

Fatigue

Duration of benefit from few days to few monthsDuration of benefit from few days to few months

1. Manuel y Keenoy B, Moorkens G, Vertommen J, et al. Magnesium status and parameters of the oxidant-antioxidant balance in patients with chronic fatigue: effects of supplementation with magnesium. J Am Coll Nutr 2000;19:374-382

2. Howard JM, Davies S, Hunnisett A. Magnesium and chronic fatigue syndrome. Lancet 1992;340:426.

3. Howard JM, Davies S, Hunnisett A. Magnesium and chronic fatigue syndrome. Lancet 1992;340:426.

4. Clague JE, Edwards RH, Jackson MJ. Intravenous magnesium loading in chronic fatigue syndrome. Lancet 1992;340:124-125

5. Ellis FR, Nasser S. A pilot study of vitamin B12 in the treatment of tiredness. Br J Nutr 1973;30:277-283.

What is Fibromyalgia (FMS)?

Clinical syndrome of unknown etiology and Clinical syndrome of unknown etiology and pathogenesispathogenesis

Characterized by musculoskeletal pain, non Characterized by musculoskeletal pain, non restorative sleep and fatigue, psychiatric, neurological restorative sleep and fatigue, psychiatric, neurological and other symptomsand other symptoms

Epidemiology

3.7 million persons ages 18 older or 2% of the 3.7 million persons ages 18 older or 2% of the population affected in USpopulation affected in US

0.5 -5% of the population affected worldwide0.5 -5% of the population affected worldwide

4-7 times more common in adult women than men; 4-7 times more common in adult women than men; highest prevalence in women 50-60 years of agehighest prevalence in women 50-60 years of age• Ethnic, genetic, social and cultural factors may influence Ethnic, genetic, social and cultural factors may influence

FMS predispositionFMS predisposition

Pathophysiology Considered-

4 theories of pathophysiology have emerged: 4 theories of pathophysiology have emerged:

Neurogenic (Central Nervous System)Neurogenic (Central Nervous System)

--- --- generalized pain

--- increase in CSF substance P

--- decrease in serum and CSF

serotonin

--- increased central sensitization

Pathophysiology, cont.

Muscle PathologyMuscle Pathology

--- decreased oxygen tension and blood flow

--- abnormal muscle biopsies

--- weakness

Pathophysiology, cont.

PsychopathologyPsychopathology

--- --- anxiety, depression

Immune-mediated diseaseImmune-mediated disease

--- --- triggered bytriggered by other infections, such as Lyme diseaseother infections, such as Lyme disease

Clinical Presentation

Pain (musculoskeletal tenderness) Lightheadedness, dizziness, syncope Fatigue Chronic insomnia; sleep disturbance Cognitive deficits/short-term memory loss Depression/anxiety Numbness, dysesthesia in hands and feet

Diagnosis

Based on the 1990 ACRclassification guidelines: 1 historical feature + 1 physical finding

Historical feature = widespread (axial) pain of 3 months or more

Physical finding = pain in at least 3 of the 4 body segments + a finding of at least 11 tender points on digital palpation of 18 designated tender points

Treatment

Patient Education

--- reading materials, videos, support groups

Physical Exercise

--- low-grade (muscle stretches, aerobic conditioning)

Pharmacologic Therapies

--- tricyclic antidepressants, NSAIDS, topical capsaicin, opioids*

*Drug therapies have been used with varying degrees of success in

treating fibromyalgia

Treatment, cont.

Complementary TreatmentsComplementary Treatments

--- Mind body interventions--- Mind body interventions

--- Homeopathy--- Homeopathy

--- Acupuncture--- Acupuncture

--- Nutriceuticals--- Nutriceuticals

Practice seeking theoryPractice seeking theory(cart, seeking horse…)(cart, seeking horse…)

Myers’ cocktail has been a popular Myers’ cocktail has been a popular “alternative” treatment for decades“alternative” treatment for decades

No trials for FMS have been publishedNo trials for FMS have been published The anecdotal support is strongThe anecdotal support is strong

Necessity is the mother of…Necessity is the mother of…

investigation.investigation.

Current treatments do not adequately address Current treatments do not adequately address FMS symptoms in most patientsFMS symptoms in most patients

The apparent promise of the Myers’ Cocktail The apparent promise of the Myers’ Cocktail (IVMT) called out for testing(IVMT) called out for testing

Tribulations, prior to Trial-Tribulations, prior to Trial-

Lack of theoretical rationaleLack of theoretical rationale• Empirical evidence onlyEmpirical evidence only

Toxicity concernsToxicity concerns Need for IND statusNeed for IND status

First RCT of IVMT for FMS(the alphabet gets a workout!)

Study DesignStudy Design

--- Randomized, double blind, placebo controlled trial--- Randomized, double blind, placebo controlled trial

Inclusion criteriaInclusion criteria

--- Musculoskeletal pain for 3 months--- Musculoskeletal pain for 3 months

--- Pain in 11 of 18 tender point sites on digital palpation--- Pain in 11 of 18 tender point sites on digital palpation

MethodsMethods

40 subjects randomized to treatment or control group40 subjects randomized to treatment or control group

Treatment Treatment 8 weekly treatments performed at one week intervals8 weekly treatments performed at one week intervals

Control Control Placebo / IV saline infusionPlacebo / IV saline infusion

Assessments Fibromyalgia Impact Questionnaire (FIQ), Beck Depression Index (BDI),

Visual Analog Scale (VAS) and Health Status Questionnaire (HSQ 2.0)

Evaluation

Primary outcome: The Tender Point Index (TPI) Primary outcome: The Tender Point Index (TPI)

• The severity of pain, assessed by an algometer with a force of 4 Kg, The severity of pain, assessed by an algometer with a force of 4 Kg, determined by a scoring system ranging from 0 (no reported tenderness) to 4+ determined by a scoring system ranging from 0 (no reported tenderness) to 4+ (severe pain). The TPI is the composite of scores at 18 tender point sites.(severe pain). The TPI is the composite of scores at 18 tender point sites.

At At baseline (following 2-week run-in period) One-week post intervention period 3-months following the intervention

Results are now pending; trial is nearing completion

From Practice, to Theory-

Theoretical PathwayTheoretical Pathway

Predisposing Factor HLA Susceptibility OR Precipitating Factors (Predisposing Factor HLA Susceptibility OR Precipitating Factors (Trauma/Medical illness) --- Autoimmune Disorder: Formation of autoantibodies to surface proteins on myocytes or

endothelial cells

--- Deficiency in Nitric Oxide Production OR Impaired Release of, or Response to, Nitric Oxide --- Vasomotor Dysregulation --- Muscle Hypoperfusion ---Impaired intracellular energetics--- Induction of Pain

Katz DL et al. The Pain of Fibromyalgia Syndrome is due to Muscle Hypoperfusion Katz DL et al. The Pain of Fibromyalgia Syndrome is due to Muscle Hypoperfusion Induced by Regional Vasomotor Dysregulation. Medical Hypotheses: In pressInduced by Regional Vasomotor Dysregulation. Medical Hypotheses: In press

And Theory to Practice: Arginine

Precursor to NO production Vasodilatory influence Ameliorates endothelial function

Also: Promotes production of growth hormone. FM patients have an

abnormal sleep pattern involving stages 3 and 4 of non REM sleep.  As GH is secreted predominantly during stages 3 and 4 of non-REM sleep, it was originally hypothesized that FM patients

may have impaired GH secretion

Other Nutriceuticals

Guai Guai Theory: FMS may be caused by an excess of Theory: FMS may be caused by an excess of intracellular phosphate, and possibly oxalic acid, intracellular phosphate, and possibly oxalic acid, which build up in the cells and depress the formation which build up in the cells and depress the formation of energy (ATP) in the cell's mitochondria. Based on of energy (ATP) in the cell's mitochondria. Based on biochemical results, guai intake results in elimination biochemical results, guai intake results in elimination of excess phosphate and calcium from the systemof excess phosphate and calcium from the system

Dose – Determined by individual responseDose – Determined by individual response 300 mgm to 3,600 mgm/day 300 mgm to 3,600 mgm/day

Other nutriceuticals, cont.Other nutriceuticals, cont.

Vitamin B3 and B6 Vitamin B3 and B6

Theory: FMS patients may be deficient in serotonin Theory: FMS patients may be deficient in serotonin because the tryptophan obtained from food because the tryptophan obtained from food metabolizes into kynurenin rather than to tryptophan metabolizes into kynurenin rather than to tryptophan and 5-htp. For this reason, 5-htp is likely to be more and 5-htp. For this reason, 5-htp is likely to be more efficient than L-tryptophan in boosting serotonin.efficient than L-tryptophan in boosting serotonin.

A combination of Vitamin B3 and B6 plus tryptophan A combination of Vitamin B3 and B6 plus tryptophan and magnesium addresses serotonin deficiency.and magnesium addresses serotonin deficiency.

Other nutriceuticals, cont.Other nutriceuticals, cont.

Zinc and calcium supplementsZinc and calcium supplements• Improves sleep patternsImproves sleep patterns

B Complex plus Vitamin C• Improvement of overall nutritional status

Antioxidants• Theory: Inflammatory response creates damage to tissues. Antioxidants

minimize the damage.• Natural carotenoids (carotenes, lycopenes and others), vitamin A

(retinol), bioflavonoids like rutin, hesperidin, quercetin, catechin and the proanthocyanidins (grape seed extract, pine bark extract or pycnogenols)

Other nutriceuticals, cont.Other nutriceuticals, cont.

Malic acid• Theory: FMS is the result of local hypoxia to the muscles.

Patients with fibromyalgia have low muscle-tissue oxygen pressure in affected muscles. Muscle biopsies from affected areas showed muscle tissue glycolysis is inhibited, reducing ATP synthesis. This stimulates the process of gluconeogenesis, which results in muscle tissue breakdown and mitochondrial damage.

• Malic acid reverses hypoxia induced inhibition of glycolysis and energy production, possibly improving energy production in fibromyalgia, and reversing the negative effect of the relative hypoxia

Conclusions

The needs of FMS patients are not fully met at presentThe needs of FMS patients are not fully met at present

CAM / Nutriceuticals show promiseCAM / Nutriceuticals show promise

Promising results from practice must be tested in trialsPromising results from practice must be tested in trials

Practice may inform theory; theory may then serve to advance Practice may inform theory; theory may then serve to advance practice practice

If a causal pathway for FMS can be established, we can better If a causal pathway for FMS can be established, we can better direct our efforts at breaking the linksdirect our efforts at breaking the links

Conclusions, cont.Conclusions, cont.

IVMT appears promising for treatment of FMS IVMT appears promising for treatment of FMS sysmptoms; trial results will be available soonsysmptoms; trial results will be available soon

Larger trial is planned for follow-up, to include Larger trial is planned for follow-up, to include assessment of mechanismassessment of mechanism

Use of IVMT/Myers’ Cocktail is justified at Use of IVMT/Myers’ Cocktail is justified at present, although still over the line of evidencepresent, although still over the line of evidence

Future efforts will need to move further Future efforts will need to move further ‘upstream’‘upstream’

Conclusions, cont.Conclusions, cont.

If promise of IVMT for fibromyalgia is If promise of IVMT for fibromyalgia is realized, a similar approach to other conditions realized, a similar approach to other conditions will be warranted:will be warranted:• Delineation of theoretical causal pathwaysDelineation of theoretical causal pathways• Controlled testing of interventionsControlled testing of interventions

• Evidence, not conviction, will best advance the Evidence, not conviction, will best advance the causecause

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Thank you.Thank you.

David L. Katz, MD, MPH, FACPM, FACPDavid L. Katz, MD, MPH, FACPM, FACPDirector, Yale Prevention Research CenterDirector, Yale Prevention Research Center

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