Neuropharmacology & Behavior:

Herbal Drugs

Brian J. Piper, Ph.D.

Goals

• Tryptophan

• Melatonin

• Ginseng

• Hypericum

DSHEA of 1994

• Dietary Supplement Health & Education Act: natural product ≠ drug

• Purity not regulated

• Efficacy not necessary

• Post-distribution safety

Advertising Gray Zone

Forbidden Permitted

Depression mood swings

Alzheimer’s cognitive improvement

Diabetes control blood sugar

Anxiety irritability

Some Organic Chemistry

• Enzyme- proteins that increases the rate of a chemical reaction without themselves undergoing any change, -ase (Bettelheim & March, 1991)

• Functional Groups: a combination of elements, includes Nitrogen (N), Oxygen (O), Hydrogen (H), or Carbon (C)

– Hydroxyl: OH– Carboxyl: COOH– Amino: contains N

Substrate ----> ProductEnzyme

Tryptophan (C11H12N2O2)

• Essential amino acid

• Dietary sources: milk, turkey, peanuts, fish• Uses: antidepressant

insomnia,

anxiety

See also: http://en.wikipedia.org/wiki/Tryptophan

5-HTP (5-Hydroxytryptophan)

Melatonin 1

2

3

4

5

2.1

Circadian Rhythm of Melatonin

a

b

Ginseng

• renshen: man root• Pharmacodynamics: ?• Pharmacokinetics: ?• Promoted uses: fatigue, stress, high blood

pressure, dementia, cancer, athletic performance, and hot flashes.

See also: http://en.wikipedia.org/wiki/Ginseng

Anxiety in mice? Elevated Plus Maze

Carr M.N. et al. (2006) European J Pharmacology, 531, 160-165.

Ag. Dest = distilled water

Drug Comparisons• Potency: amount of

drug to produce a response

• Efficacy: how well a drug produces a response

• (A= morphine, B=aspirin)

Hypericum perforatum

• St. John’s wort• Hypericin, Hyperforin,

others• “Side effect”:

photosensitivity

“Definitive” study?

• Scientific literature includes many conflicting reports about the antidepressant effects of hypericum– Safety: better than

standard antidepressants

– Efficacy: useful for moderate and severe depression?

Hypericum Depression Trial Study Group (2002). JAMA, 287, 1807-1814.

Sertaline= Zoloft, a serotonin reuptake inhibitor

6.0

Hypericum safety

Drug Interactions

• Drug metabolism is regulated by a family of enzymes in the liver (CYPs)

• CYP2D6 – #: gene family (18)– Letter: subfamily (43)– #: Gene

• One drug can interfere with the metabolism of another – Normal: Substrate ---------> Product

– Activation: Substrate ---------> Product– Inhibition: Substrate ---------> Product

See also: http://en.wikipedia.org/wiki/Cytochrome_P450

Enzyme

Enzyme

Enzyme

Example: Grapefruit juice2.0

CYP3A4

• Substrates: largest of all CYP’s

• Hyperforin increases activity

• This can decrease plasma levels of other drugs including:– SSRI’s: e.g. fluoxetine– Benzodiazepines: e.g. valium– Testosterone– Estradiol

See also: http://en.wikipedia.org/wiki/CYP3A4

Ephedra

– from Ma Huang (herbal tea)

– isolated in 1920’s– bronchodilator for

asthma– pseudoephedrine is an

isomer of ephedrine– structure similar to

epinephrine

CH NHCH CH3

CH3

OH

Ephedrine

Epinephrine

Drug Comparison

Synthetic Herbal

History 100 1000

# Few Many

Research Common Uncommon

Safety Varied Varied

http://videocast.nih.gov/summary.asp?Live=3573 2:35-50:40