“Killer Drugs & The Supplement Hall of Fame”

Louis Cady, MDCEO, Founder – Cady Wellness Institute

Newburgh, Indiana (US)Indiana School of Medicine,

Dept. of Psychiatry

Brazil, 2015

Learning objectives• Avoid killing/injuring patient with OBVIOUS

drug-drug interaction– Become aware of more subtle interactions– Identify some “fairly safe” medications for use

• Review key, basic concepts about groups of vitamins, relevance of antioxidants, specific minerals, and fish oil

• Will NOT review topics covered in other lectures here, or advanced topics on specific nutrients.

The BASICS

“Mr. Rohn, thedifference between success and failurein any endeavor is about a half-dozen things.”

-Earl Shoaff

Organization

• Drug interactions• Antioxidants• B-vitamins • Minerals• “PUFA’s”• Gingko• Neurotransmitter boosters• Nootropics (brief)

“Streaking”, or….. Better Buckle Up!!!

• Definition: Streaking is the act of taking off one's clothes and running naked through a public place. [ref: http://en.wikipedia.org/wiki/Streaking - accessed 09 02 2013]

• “In 1973, what the press called a ‘streaking epidemic’ hit Stephen F. Austin State University in Nacogdoches, TX, with streakers being seen in residence halls, at football games and at various other on-campus locations and events, including Spring graduation.”

(Harvard-Yale game, 2006)

“Drug-drug interactions” clinically relevant?!

Drug-drug interactions: chum for legal “sharks”

Two potential for interactions

1. PharmacoKINETICS – what the body does to the drug

2. PharmacoDYNAMICS – what the drug(s) do to the body.

The brain dead, almost too-obvious to mention FATAL drug interaction

• MAOI with ANYTHING that boosts serotonin or other catecholamines, e.g: nose spray, pseudoephedrine hydrochloride, SJW, ANY anti-depressant, or any of the following:– Phenylpiperidine, opioids, meperidine, tramadol,

methadone, dextromethorphan, propoxyphene – all appear to be weak SSRI’s.

• “Stealth MAOI’s”:– Linezolid (Zyvox ®) - for vancomycin resistant

Enterococcus faecium infections, & MRSA– Isoniazid (tuberculosis)– Moclobemide (reversible MAO-A inhibitor – n/a in USA)

The similarly brain-dead “UN-interaction”• 5HTP for precursor loading ALONG WITH

an SSRI, given reasonable doses, e.g.:– Escitalopram – 20 mg + 50 and then 100 mg

5HTP, going up to as much as 300 mg per day SLOWLY.

• (this is incredibly useful for antidepresssant “Poop-out”)

• The STUPID, BRAIN DEAD way to create a 5HTP interaction:– Fluoxetine 80 mg from a standing start, plus

300 mg 5HTP to wash it down with. DUMB.

“Strattera (atomoxetine)[coupled with Prozac or Paxil] has been great for our admissions.”

-Dr. William Beute, MDPine Rest Campus ClinicGrand Rapids, MIApril 21, 2004[quoted with

permission]

Cytochrome p-450 2D6 inhibition measured as % increase in “Desipramine AUC” – in vivo data

Preskhorn, Alderman, et al. Pharmacokinetics of desipramine coadministered with sertraline or fluoxetine. J. Clin Psychopharmacol 1994;14:90-98; Escitalopram package insert - note – different source of data, but same method

Critically important when combining with other Rx metabolized through 2D6

pathways

SomeSome drugs metabolized through drugs metabolized through cytochrome P-450 2D6 systemcytochrome P-450 2D6 system

ADHDADHD AmphetaminesAmphetamines atomoxetineatomoxetine

AnalgesicsAnalgesics• AcetaminophenAcetaminophen• AspirinAspirin

AntacidsAntacidsAntiarrthymicsAntiarrthymics

• Procainamide, Procainamide, • QuinidineQuinidine• EncainideEncainide• FlecainideFlecainide

AnticonvulsantAnticonvulsant• carbamazepinecarbamazepine

ANTI-PAINANTI-PAIN CODEINE!CODEINE!

BronchodilatorsBronchodilators• TheophyllineTheophylline

CardiacCardiac• Digoxin; digitalisDigoxin; digitalis

CoughCough• DextromethorphanDextromethorphan

DiureticsDiuretics• ChlorthalidoneChlorthalidone• FurosemideFurosemide• HCTZHCTZ• TriamterineTriamterine

AntibioticsAntibiotics• TMP & SMXTMP & SMX• AmpicillinAmpicillin• ErythromycinErythromycin• PenicillinPenicillin• TetracyclineTetracycline

AntidepressantsAntidepressants• TCATCA’’s & s & ““2Ps2Ps””

AntihistaminesAntihistaminesAntihypertensivesAntihypertensivesAntipsychoticsAntipsychotics

• clozapineclozapine• risperidonerisperidone• olanzapineolanzapine

Substrates TCA’s, 2 P’s,Duloxetine, atomoetine, Amphetamine(s) risperidone, clozapine, aripiprazole, DMX,

Codeine, hydrocodone, oxycodone, tramadol

(see also previous page)

Zolpidem, AlprazolamSimvastatin, atorvastatinziprasidone, lurasidone, OCA’s, Buspirone, TRAZODONE, CBZ, Odansetron,TERFENADINE, Methadone, Fentanyl, Codeine, (R )/Modafanil

Clozapine

INDUCERS Dexamethasone, Rifampin, oxycodone, hydrocodone

SJW (!!), RIFAMPIN, (R )/Modafanil Barbs, phenytoin, CBZ, rifampin, dill, topirimate, some antiretrovirals

Cigarette smoke

INHIBITORS “The 2 P’s”, Celebrex, Cimetidine, Ranitidine, Methadone, Chlorphenamarine, chlorpromazine

KETOCONAZOLE, voriconazole, “-conazoles” fluconazole, grapefruit juice, clarithromycin, ritonavir, “-mycin’s”, Dill, cimetidine, diltiazem,– especially, macrolides, Nefazodone

Theophylline, Ciprofloxacin, fluvoxamine

Mod. inhibitor Sertraline (mild), citalopram (mild)

DTZ, atazanavir, EES, fluconazole, verapamil

2D6 3A4 1A2

The “not so selective” SSRI’s; how to “Do yourself a favor.”

drug Clean?? 2nd order effects Side effects possible

Escitalopram (generic 3/2012)

Yes NOTHING (excess serotonin side effects only)

Sertraline Yes Dopamine (1/3 as potent as amphetamine)

Agitation, nervousness; improved [ ]

Citalopram Yes AntiH1 Sedation (note- FDA lowered max dose to 40mg)

Paxil NO!! Anti-Chol. NOT “NRI”

Doped up, TCA effects, neurocognitive problems, withdrawal. Sexual, Prostate sxs

Fluoxetine NO!! 5HT2C Agitation, appetite suppression

“Danger! Danger, Will Robinson!”

Side Effects & Drug Interactions: The Doc Cady “Can’t s” of the TCA’s

Pee PoopSpit

Spurt Focus Think

Stand up Stay awake

Stay thin

ANTICHOLINERGIC/ ANTIMUSCARINIC EFFECTS

Alpha-adrenergic blockade"Antihistamine" effects

Source: www.wiki.answers.com Accessed July 27, 2013

New Agents, New Mechanisms(agent) (MOA) Differentiating points

Venlafaxine (“IR” and XR)(2D6)

SSRI, NRI Nausea, GI side effects, sxl dysfunction

Duloxetine (2D6) SSRI, NRI Same. Better tolerated. For pain w/ dep.

Desvenlafaxine (various)Levomilnacipram (3A4)

SSRI, NRI Better tolerated

Trazodone XR with Contramid®

5HT2a/c BLOCKER, mild SSRI

Vilazodone (3A4) SPA, SSRI ONLY SPARI. Weaker SSRI. Targets 5HT1A. Less sexual side effects.

Bupropion (“XL” – not “SR”) (2B6)

“NDRI” Possibility of anxiety & “wound up.” Improved concentration. Push to 450 mg. (Seizure risk.)

…low levels of the antioxidant vitamins (Vitamins A, E, and C) may increase risk for several chronic diseases. Most people do not consume an optimal amount of all vitamins by diet alone.

Pending strong evidence of effectiveness from randomized trials, it appears prudent for all adults to take vitamin supplements.

“Inadequate intakes may result in chronic metabolic disruption, including mitochondrial decay.” “[They] cause DNA damage, such as chromosome breaks, in cultured human cells or in vivo.”

“triage theory

The Physicians’ Health Study II

• Take a multivitamin!

CONCLUSIONS: “Daily multivitamin supplementation modestly but significantly reduced the risk of total cancer.” [HR 0.92, 95% CI, p=0.04]

Antioxidants, in general

15,318 US adults in 3rd National Health and Nutrition Examination Follow-up study. (Different lifestyles and health risk factors were accounted for in the study)

“serum alpha-carotene concentrations were inversely associated with risk of death from all causes, CVD, cancer, and all other causes[sic].”

Epidemiology of Vascular Ageing (EVA study) Total plasma carotenoids are inversely related to mortality

(Akbaraly TN, et al Br J Nutr, Jan 2009)

• Study N=1389– Age range = 59 – 71 years– 9 years of duration with six waves of follow-up.

• Findings:– “low total plasma carotenoid level was significantly

associated with all cause mortality in men but not in women. – 2.94X higher relative risk of mortality of being in lowest

quintile compared to highest quintile. – “The present study suggests that total plasma

carotenoid levels could be a health indicator in elderly populations.”

Conclusions from another study

• “It is concluded that administration of antioxidants could reduce the incidence of brain tumors and probably other types of cancer.”

• - Shewelta SA , Sheikh, BY Curr Drug Metab. 2011 Jul;12(6):587-93. (Dept.of Biosciences & Technology, Alexandria University, Egypt.)

Lipid peroxidation, antioxidant status & survival in institutionalized elderly

• Plasma MDA predicted mortality independently of all other variables.

• B-carotene and alpha tocopherol were independently associated with survival. Huerta JM et al. Free Radical Research

2006, vol 40, no 6. pp 571-578.

Over 50% of the women in the Iowa study lived longer than the average life expectancy

38,000 White Women in Iowa

Early results showed women who used C, D, E, and Calcium had significantly lower rates of death

Meydani SN. Nutr Rev. 1993 Apr;51(4):106-9

“Recent studies have shown that supplementing the elderly with single nutrients or mixtures of vitamins and minerals at levels that exceed the Recommended Dietary Allowances (RDAs) significantly improves certain indices of the immune response.”

Multiple lines lines of evidence indicate that oxidative stress not only strongly participates in an early stage of Alzheimer's disease prior to cytopathology, but plays an important role in inducing and activating multiple cell signaling pathways that contribute to the lesion formations of toxic substances and then promotes the development of Alzheimer's disease.

Vitamins E & C Supplements Limit Oxidative Brain Cell Damage, Cognitive Dysfunction

• Head, E, Christie L. (UC Irvine). Cognitive performance, dementia and DNA/RNA oxidative damage in the oldest old.” Poster 256 Oxidative Stress and Synaptic Transmission, San Diego, 2007.

• “The two antioxidant vitamins were associated with decreased oxidative damage to brain cells in the frontal cortex. The researchers found that better cognitive performances in elderly subjects is associated with lower levels of oxidative DNA & RNA damage in the brain, and that those taking multivitamins including vitamins E or C tended to perform better on a test of global cognitive ability.”

Adult ADHD and antioxidant statusSelek S et al. Evaluation of total oxidative status in adult attention deficit hyperactivity disorder and its diagnostic implications. J. Psychiatry Research. 2012 Apr;46(4):451-5

• Blood samples obtained and total antioxidative status (TAS), total oxidative status (TOS), and Oxidative Stress Index(OSI) were determine at Harran University Biochemistry Labs.

• ADHD group: TAS, TOS, and OSI were significantly higher than controls. – Adult ADHD was able to be predicted for TOS (Total

oxidative status) over 9.8575 umol H2)2/L level with 86% positive predictive value and 100% negative predictive value.

• “In A-ADHD, oxidative balance in impaired. High antioxidant levels may be compensatory against the oxidant increase.”

“Antioxidants” & The State of the Literature 9/8/2015

• “Antioxidant” with…– ADHD - 124 citations– Alzheimer’s dz - 4,703 citations– Anxiety disorder - 491 citations– Autism - 253 citations– Bipolar disorder - 376 citations– “clinical depression” 869 citations– Fibromyalgia - 114 citations– Schizophrenia - 852 citations

Surf on over to www.pubmed.gov and investigate!

“Antioxidants” with schizophrenia – a taste of the literature

• Inflammation and schizophrenia: Alterations in cytokine levels and perturbation in antioxidative defense systems.– Al-Asmari A, Khan MW. Hum Exp Toxicol.

2013 July 8• The use of flavonoids in central nervous

system disorders. – Grosso C, et al. Curr Med Chem. 2013 Jun 25

Abnormal redox processes:•Parkinson's•Huntington’s•Alzheimer’s•Prions•Down’s syndrome•Ataxia•Multiple sclerosis,•Creutzfeldt-Jacob•ALS•Schizophrenia•Tardive dyskinesia

Kovacic P, et al. Curr. Neuropharm. 2012 Dec; 10(4):289-302

Rx:• Balanced MVI with antioxidants

–A–C–E–S elenium

• Plant based carotenoids, phytochemicals– Lutein, Zeaxanthin, Astaxanthin, etc. (Macular degeneration studies)

• Coenzyme Q10, N-acetyl cysteine (or analogs)

Antioxidant assessment

Reference (optional):www.cadywellness.com/cadywhitepaper2008.pdf

B-vitamins

What the OAT showed…. (& “take home” points)

• DANGER of prescribing “one shot” B-vitamins• B-vitamin COMPLEX recommended• SERIOUS Vitamin C deficiencies exist.

– (This increases oxidative stress)

• Other nutrients & co-factors easily identified

!!!

Low riboflavin confirmed; very low (!!) Vit C; moderate CoQ10

The Effects of high dose B vitamins on stress at work

• 3 month, double blind, placebo control, randomized study– Measured: Personality, work demands, mood, anxiety, and strain

• The vitamin B complex treated group reported significantly lower personal strain and a reduction in confusion and depressed/dejected mood after 12 weeks.

Strough C et al. The effect of 90 day administration of a high dose vitamin B-complex on work stress. Hum Psychopharmacol. 2011 Sept 8. doi 10.1002/hup.1229 (Swinburne University of Technology – Hawthorn, Victoria, Australia.)

BRAIN SHRINKAGE…

Smith AD, Smith SM, de Jager CA, Whitbread P, et al. (2010) Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial. PLoS ONE 5(9): e12244. doi:10.1371/journal.pone.0012244http://www.plosone.org/article/info:doi/10.1371/journal.pone.0012244

CONCLUSIONS: “The accelerated rate of brain atrophy in elderly with MCI can be slowed by treatment with homocysteine-lowering B-vitamins.”

OK. It slows shrinkage. But are they sharper? [deJager CA et al. Int J Geriatr Psychiatry. 2012 June;27(6):592-600]

“B-vitamins appear to slow cognitive and clinical decline in people with MCI.”

“Micronutrient supplementation has a beneficial effect on perceived stress, mild psychiatric symptoms, and aspects of mood in apparently healthy individuals. Supplements containing high doses of B vitamins may be more effective in improving mood states.”

The first groundbreaking study on use of a vitamin to treat a mental disorder (B3)

• “Treatment of schizophrenia with nicotinic acid and nicotinamide.” – Hoffer A, et al. J Clin Exp Psychopath, 18:131-158. Begun

in 1952, published in 1957• 30 schizophrenic patients• Randomized to placebo, niacinamide, or niacin +other standard

treatments (ECT, barbiturate, psychotherapy)

– TX: 1 gram three times daily for 30 days (only)– Then followed for 1 year.

• At one year: active treatment group had 80% recovery rate compared to placebo (30%)

1973 APA Hatchet Job on vitamins• 1973 APA Task Force on Megavitamin and Orthomolecular

Therapy in Psychiatry– Headed by Morris Lipton, MD – who was biased against.

• “… this Task Force considers the massive publicity which they promulgate via radio, the lay press and popular books, using catch phrases which are really misnomers like ‘megavitamin therapy’ and ‘orthomolecular treatment’ to be deplorable.”

• Consequences:– Inhibited any further exploration of nutrition/diet in schizophrenia– Raised fears of academic retaliation, professional ostracism

• (& Flawed medical studies followed – with high dose vitamins pushed to toxic levels (or used at ineffective dosages), and not in healthy combinations.)

Canadian Psychiatric Association: “Statement on Current Status of Megavitamin and

Orthomolecular Therapies, 1976”

“…recommends that physicians do not use

these treatments except in controlled clinical investigations.”

• Irritability• Apathy• Anxiety• Personality changes• Depression • Memory loss• Dementia• Subtle subclinical

cognitive impairment• Hallucinations• Violent behavior

Symptoms of B12 Deficiency

• Diminished sense of touch and pain

• Clumsiness• Weakness• Pernicious anemia• Chronic fatigue• Tremors• GI problems• Peripheral neuropathy

Mental Physical

Your brain and B12• If you are in the bottom 1/3rd for B-12 levels….

• SIX TIMES increase risk of brain volume loss (Odds ratio = 6.17, 95% CI)– Vogiatzoglou A et al. Vitamin B12 status and rate

of brain volume loss in community-dwellers. Neurology. 2008 Sep 9;71(11):826-32.

– (107 volunteers aged 61-87 years of age)

Vitamin B3 Restores Memory Loss Associated with Alzheimer’s Disease

• Green K et al. (UC Irvine) “Oral Nicotinamide Treatment Induces Ubiquitin-dependent degradation of phospho-tau and restores cognitive function in a mouse model of Alzheimer disease.” Poster 157, Nov 4 at Alzheimer’s Disease and Other Dementias: Therapies II; San Diego 2007

• B3 given to rice BRED to develop plaques and tangles. • Mice that received this had lower levels of phosphorylated

tau. • “These findings suggest that Vitamin B3… might be a safe

and effective therapy for people with Alzheimer’s disease.”

B6 – appears helpful in autism • Rimland, B et al. The effect of high doses of vitamin

B6 on autistic children: a double-blind crossover study.” Am J Psychiatry. 1978 Apr;135(4):472-5

• 16 autistic children previously doing well on B6 supplementation. – Double blind – removal of B6 supplement and

replacement with placebo or continuation of B6– “Behavior was rated as deteriorating significantly

during the B6 withdrawal.”

B6 with magnesium for ADHD• “Improvement of neurobehavioral disorders in children

supplemented with magnesium-vitamin B6. I. Attention deficit hyperactivity disorders.– Mousain-Bosc M et al. Magnesium Res. 2006 Mar;19(1):46-52

• 40 children with symptoms of ADHD dosed with 6 mg/kg/d of Magnesium and 0.6 mg/kg/d vit B6 for 8 weeks.

– Baseline – ADHD kids had significantly lower levels of RBC Mg than controls.

• TREATMENT:– Mg-B6 regimen – led to significant increase in RBC Mg values. – Hyperactivity and hyperemotivity/aggressiveness were reduced, and school

attention was improved.

• Withdrawal – when tx stopped, clinical symptoms re-appeared in a few weeks together with drop in Ribcage levels.

“B-vitamin deficiency” & The State of the Literature September 8, 2015

• “B-vitamin deficiency” with…– ADHD - 10 citations– Alzheimer’s dz - 213 citations– Anxiety disorder - 35 citations– Autism - 27 citations– Bipolar disorder - 23 citations– “clinical depression” 103 citations– Fibromyalgia - 5 citations – Schizophrenia - 62 citations

Surf on over to www.pubmed.gov and investigate!

Just a “taste” of B-vitamin deficiency with Schizophrenia

• Vitamin B12 deficiency masquerading as clozapine-resistant psychotic symptoms in schizophrenia– Raveendranathan D, et al. J Neuropsychiatry Clin

Neurosci. 2013 Spring; 25(2):E34-5.• Hyperhomocysteinemia & schizophrenia: case

control study.– Mabrouk H, et al. Encephale. 2011 Sep; 37(4):308-13.

• Folate supplementation in schizophrenia: a possible role for MTHFT genotype.– Hill M, et al. Schizophr Res. 2011 Apr; 127(1-3):41-5.

Minerals

- Selenium is one of the factors that may affect the risk of cognitive decline. In selenium deficiency the brain remains selenium replete the longest suggesting that Se plays an important role in brain functions.

- Results from this study: “Low Se status is a risk factor for cognitive decline even after taking into account vascular risk factors

Special needs - Zinc• Low Zinc- associated with low testosterone

– Per USDA, 60% of US men between 20 – 49 years of age do not get enough.

– N.B.: Do not supplement with > 50 mg daily (can interfere with Cu+ metabolism)

• Tsai, E.C., Boyko, E.J., Leonetti, D.L., & Fujimoto, W.Y. (2000). Low serum testosterone level as a predictor of increased visceral fat in Japanese-American men. International Journal of Obesity and Related Metabolic Disorders, 24, 485-491

Correlation between serum testosterone level and concentrations of copper and zinc in hair tissue

[Chang, CS et al. Biol Trace Elem Res. 2011 Dec; 144(1-3):264-71]

• 88 men 40 – 60 years of age.• Serum testosterone measured in a.m. • Copper and zinc levels quantified• “subjects with normal testosterone had a

significantly higher Zn level compared to low testosterone group (P=-.003)”

• “Normal testosterone is associated with a higher Zn level.”

North America 85%South America 76%Asia 76%Africa 74%Europe 72%Australia 55%

% Mineral depletion from the soil during the past 100 years, by continent

Source: UN Earth Summit Report 1992

Magnesium! (from white paper by Greenblatt and Heim)

• Depleted in soil • Nutrient depleted, calorie dense fast/processed food• NHANES study (2005-2006) – 2/3rds of men and women

don’t get enough. • First documented in 1921 – with 220/250 patients receiving

it benefited from it.1

• Confirmatory studies over last 50 years. 2,3,4

1. Weston PG. Magnesium as a sedative. Am J Psychiatry (1921) 22(1):637–8. 2. Jacka FN, Overland S, Stewart R, et al. Association between magnesium intake and

depression and anxiety in community-dwelling adults: the Hordaland health study. Aus New Zealand J Psych (2009) 43(1):45-52.

3. Eby, G.A. 3rd, Eby KL. Magnesium for treatment-resistant depression: A review and hypothesis. Medical Hypotheses(2010) 74(4):649-60.

4. Greenblatt, J. The Breakthrough Depression Solution. Sunrise River Press (2011)

Magnesium & The State of the Literature September 8, 2015

• Magnesium with…– ADHD - 47 citations– Alzheimer’s dz - 149 citations– Anxiety disorder - 76 citations– Autism - 60 citations– Bipolar disorder - 122 citations– “clinical depression” 180 citations– Fibromyalgia - 33 citations– Schizophrenia - 96 citations

Surf on over to www.pubmed.gov and investigate!

Do YOU Need Fish Oil?

5X reduction

• 493 schoolchildren, aged 7 – 9 years from mainstream Oxfordshire schoosl, selected for BELOW AVERAGE reading performance.

• Lower DHA levels assoc. with:– poorer reading ability– Higher levels of parent rated oppositional

behavior & emotional lability

PLoS One. 2013 Jun 24;8(6):e66697. doi: 10.1371/journal.pone.0066697. Print 2013.

• 29 schoolchildren with ADHD vs. 43 without

• Callous-unemotional (CU) traits were found to be significantly negatively related to both eicosapentaenoic acid (EPA), and total omega-3 in the ADHD group.

Prostaglandins Leukot Essent Fatty Acids. 2013 Jun;88(6):411-8.

• "Chronic deficiencies of certain minerals such as zinc, iron, magnesium and iodine and insufficient dietary intake of long-chain polyunsaturated fatty acids may have a significant impact on the development and deepening of the symptoms of ADHD in children.”

• Importance of DHA emphasized.

Konikowska K, et. al. Rocz Panstw Zakl Hig. 2012;63(2):127-34.

Top Targeted Supplements(# of citations in PubMed

September 8, 2015)• Gingko (3,516)• S-adenosyl methionine [SAMe] (8,396)• Curcumin (8,068)• SJW – Saint John’s Wort (2,390)• Panax Ginseng (5,302)• Ashwaghanda (766)

• Deplin, EnLyte (by RX) = l-methylfolate

Gingko – color commentary• 3,516 citations in PubMed as of September 8, 2015• Cognitive enhancement:

– 34 outpatients with moderate cognitive impairments tx’ed with standard extract of Ginkgo Biloba (EGb761) – 240 mg twice daily . Significant improvement in attention, memory, orientation, and visual-spatial/executive functions as well as anxiety and depression.”

• Boiko AN et al. Zh Nevrol Psikhiatr Im S S Korsakova. 2013 – “Possibilities of medical correction of moderate cognitive impairment.”

• In addition to cognitive effects:– Might be useful in patient with early diabetic nephropathy .

Zhang L et al. Evid Based Complement Alternat Med. 2013– Anti-inflammatory on osteoarthritis of knee. Chen YJ et al. J

Orthop Res. 2013 Mar 11.

EGb761 is used in most trials. Dosages: 80 – 720mg/day

Mechanisms of action: increasing cerebral blood flow, antioxidant and anti-inflammatory effects, with antiplatelet effects attributed to flavone and terpene lactones.

“Possible interactions with MAOI’s, alprazolam, haloperidol, warfarin, and nifedipine have been reported.”

Clinically relevant interactions – Gingko Curr Med Chem. 2011;18(31):4836-50. Chen, XW et al.

• Gingko may potentiate bleeding with warfarin or aspirin

• increases blood pressure when combined with thiazide diuretics

• has even led to a coma when combined with trazodone

• induced mania if taken concomitantly with phenelzine (MAOI)

New study – gingko/drug interactions may not be as bad as thought

• Gingko leaf extracts (GLE’s) known to be taken regularly by older people who are likely to use multiple other drugs.

• IN VIVO studies in humans could not replicate preclinical studies of high doses/concentrations of GLE that hinted at both inhibition and induction of metabolic enzymes and transporters.

• “At 240 mg/day, a clinically relevant interaction potential of the standardized GLE EgB 761 could not be shown.”

• Doses higher than that led to weak induction of CYP2C19 and weak inhibition of CYP3A4.”

Citation: Unger M. Pharmacokinetic drug interactions involving gingko biloba. Drug Metab Rev. 2013 Aug; 45(3):353-85.

New study – gingko/drug interactions may not be as bad as thought (conclusions)

• “THUS… the intake of the standardized GLE Egb 761, together with synthetic drugs appears to be safe as long as daily doses up to 240 mg care consumed.”

• One caveat [from CADY] : this does not review the potential for additive anticoagulant effects; it merely means that gingko appears safe with everything else BESIDES anticoagulants.

• Not for use with dual antiplatelet therapy or anti-coagulant therapy.

Citation: Unger M. Pharmacokinetic drug interactions involving gingko biloba. Drug Metab Rev. 2013 Aug; 45(3):353-85.

Gingko in Alzheimer’s diseaseIhl R. Effects of Gingko biloba extract Egb 761 ® in dementia with neuropsychiatric features: review of

recently completed randomized, controlled trials. Int J Psychiatry Clin Practice 2013 Jun 28.

• Review of four randomized, controlled trials investigating efficacy of EGb761 in elderly patients with Alzheimer’s or vascular dementia with neuropsychiatric features.

• N= 1,294 patients in this meta-analysis.• These trials compared 120 mg twice daily or 240 mg daily

of EGb 761®.– Three trials: EGb 761 vs. placebo– One trial: Egb 761 vs. placebo with donepezil as an active control

Gingko in Alzheimer’s diseaseIhl R. 2013 ibidem

• “Patients treated with Egb 761 ® showed improvements of cognitive performance and behavioural symptoms that were associated with advances in activities of daily living and a reduced burden to caregivers.” – Placebo treated patients showed only minimal improvements. – In each placebo controlled trial, Egb 761 ® was significantly

superior in all mentioned domains (p< 0.01)– Note: in actively controlled trial, Egb 761 ® and donepezil (as well

as a combo of both drugs) had similar effects.”

• CONCLUSIONS: “The review supports the efficacy of EGb 761 ® in age-related dementia with neuropsychiatric features. The drug [sic] was safe and well tolerated.”

“L-methylfolate: a Vitamin for your Monoamines”[Stahl, SM Journ Clin Psych. Vol 69:9, Sept 2008 1352-1353]

Source: Stephen M. Stahl, MD, Ph.D., Neuroscience Education Institute

Law of mass action: “load the left side”

• L-tyrosine 500 – 1000 mg twice daily – three times daily

• N-acetyl l-tyrosine- 300 – 600 mg daily to bid

• 5-HTP (w/ or w/o P5P) – 50 – 100 mg twice daily to three times daily (start at bedtime)

This technique is incredibly useful for stimulant or antidepressant “poop-out”

Nutraceutical “riffs”• Randomized double-blind,

placebo controlled, crossover

• 30 adults – ½ in each group then crossed over

• 3 ingredients in active– High potency

MVI/multimineral– Fish oil (2.8 g, w/ 860

mg EPA + 580 mg DHA)– “BDN’s” – brain-directed

nutrients

• Outcome: rCBF & MicroCog test

Amen, DG et al. Advances, Spring 2013 vol 27, no. 2, pp 24-33. (loaded with references!)

What was in the (deliberately lower dosed, synergistic)

brain enhancement supplement??• In four capsules:

– Gingko – 80 mg– Vinpocetine – 10 mg – Phosphatidylserine – 67 mg (lower cortisol)– Acetyl l-carnitine – 667 mg (elevate Ach levels)– Huperzine – 100ug

• (primary cognitive enhancer; dosages within 200 – 400 mcg considered safe)

– N-acetyl cysteine 400 mg• (as glutathione precursor)

So what the heck am I

supposed to do with this

stuff?

Louis B. Cady, M.D. www.cadywellness.com www.facebook.com/cadywellness www.tms-relief.comOffice: 812-429-0772 E-mail: lcady@cadywellness.com 4727 Rosebud Lane – Suite F ~ Interstate Office Park Newburgh, IN 47630 (USA) TWITTER FEEDS: @LouisCadyMD @TMS4depression

Once more…. Where to “get the slides” -

Syllabuswww.slideshare.net/lcadymdCady Wellness Institute app.

A few extra references follow…

Neural inflammation/oxidative stress in post-partum depression.

• Anderson G, Maes M. Journal of Neuropsychiatric Disease and Treatment. 2013;9:277-87. E pub Feb 21 Postpartum depression: psychoneuroimmunological underpinnings and treatment.

• Biological underpinnings reviewed:– Tryptophan catabolites, indoleamine 2,3, dioxygenase, serotonin, and

autoimmunity mediates immuno-inflammation and oxidative and nitrosative stress.

– It is suggested that the increased inflammatory potential, decreased endogenous anti-inflammatory compounds, together with decreased omega-3-poly-unsaturated fatty acids causes an inflammatory environment in the post-natal period.

– Melatonin recommended, as well as antidepressants and anti-inflammatories.

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Vitamins – good for delinquents? (2000)• DESIGN: stratified randomized, double-blind, placebo-

controlled trial with pretest and post-test measures of antisocial behavior on school property.

• SETTINGS AND SUBJECTS: Two "working class," primarily Hispanic elementary schools in Phoenix, Arizona. – C. ½ the school population participated: 468 students aged 6 to 12

years. • INTERVENTION: Daily vitamin-mineral supplementation at

50% of the U.S. recommended daily allowance (RDA) for 4 months versus placebo. The supplement was designed to raise vitamin-mineral intake up to the levels currently recommended by the National Academy of Sciences for children aged 6 to 11 years. Schoenthaler SJ, Bier ID. The effect of vitamin-mineral supplementation on juvenile delinquency among American schoolchildren: a randomized, double-blind placebo-controlled trial. Altern Complement Med 2000 Feb;6(1):7-17

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Results [Schoenthaler SJ, Bier ID. 2000, loc cit.]• Of the 468 students randomly assigned to active or

placebo tablets, the 80 who were disciplined at least once between September 1st and May 1st served as the research sample.

• The 40 children who received active tablets were disciplined, on average, 1 time each, a 47% lower mean rate of antisocial behavior than….

• The placebo group of 40 children, who were disciplined 1.875 times each (95% confidence interval, 29% to 65%, p < .020).

• The children who took active tablets produced lower rates of antisocial behavior in 8 types of recorded infractions: threats/fighting, vandalism, being disrespectful, disorderly conduct, defiance, obscenities, refusal to work or serve, endangering others, and nonspecified offenses.

Conclusions [Schoenthaler SJ, Bier ID. 2000, loc cit.]

• “Poor nutritional habits in children that lead to low concentrations of water-soluble vitamins in blood, impair brain function and subsequently cause violence and other serious antisocial behavior.”

• “Correction of nutrient intake, either through a well-balanced diet or low-dose vitamin-mineral supplementation, corrects the low concentrations of vitamins in blood, improves brain function and subsequently lowers institutional violence and antisocial behavior by almost half.”

PUFA’s & The State of the Literature September 8, 2015

• Polyunsaturated fatty acids with…– ADHD - 185 citations– Alzheimer’s dz - 978 citations– Anxiety disorder - 186 citations– Autism - 106 citations– Bipolar disorder - 219 citations– “clinical depression” 492 citations– Fibromyalgia - 34 citations– Schizophrenia - 485 citations

Surf on over to www.pubmed.gov and investigate!

Omega-3’s with memory• Yves Sauve, Ph.D. & colleagues –

University of Alberta– Applied Physiology, Nutrition &

Metabolism 2012• Lab models fed Omega-3 diet had

30% higher levels of DHA in hippocampus compared to controls

• Appears to support the theory that Omega 3 rich diet or dietary supplementation may protect memory.

“Antioxidants” & The State of the Literature 9/1/2013

• “Antioxidant” with…– ADHD - 91citations– Alzheimer’s dz - 1,539 citations– Anxiety disorder - 361 citations– Autism - 178 citations– Bipolar disorder - 294 citations– “clinical depression” 762 citations– Fibromyalgia - 95 citations– Schizophrenia - 736 (!!) citations

Surf on over to www.pubmed.gov and investigate!

References for previous research published on cited supplements –

two years ago

Top Targeted Supplements(# of citations in PubMed 07 27 2013)

• Gingko (3,056)• SAMe (7,713)• Curcumin (5,848)• SJW – Saint John’s Wort (2,138)• Panax Ginseng (4,333)• Ashwaghanda (576)

• Deplin, EnLyte (by RX) = l-methylfolate

“B-vitamin deficiency” & The State of the Literature 9/1/2013

• “B-vitamin deficiency” with…– ADHD - 2 citations– Alzheimer’s dz - 44 citations– Anxiety disorder - 5 citations– Autism - 10 citations– Bipolar disorder - 4 citations– “clinical depression” 25 citations– Fibromyalgia - none specifically– Schizophrenia - 8 citations

Surf on over to www.pubmed.gov and investigate!

Magnesium & The State of the Literature 9/1/2013

• Magnesium with…– ADHD - 47 citations– Alzheimer’s dz - 149 citations– Anxiety disorder - 70 citations– Autism - 53 citations– Bipolar disorder - 119 citations– “clinical depression” 163 citations– Fibromyalgia - 29 citations– Schizophrenia - 96 citations

Surf on over to www.pubmed.gov and investigate!

PUFA’s & The State of the Literature 9/1/2013

• Polyunsaturated fatty acids with…– ADHD - 159 citations– Alzheimer’s dz - 335 citations– Anxiety disorder - 132 citations– Autism - 80 citations– Bipolar disorder - 189 citations– “clinical depression” 432 citations– Fibromyalgia - 31 citations– Schizophrenia - 426 citations

Surf on over to www.pubmed.gov and investigate!