Lecture 25 Anxiety and Insomnia Jim Simon, Qing-Li Wu and Ed LaVoie

Dietary Supplements and Herbal Products Used for Anxiety and Insomnia

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5-HTP (5-Hydroxy-Tryptophan) Choline Feverfew Ginkgo biloba Kava Kava (Piper methysticum) Melatonin Phosphatidylserine SAMe (S-Adenosyl-L-Methionine) St. Johns Wort Valerian Vinpocetine (from Vinca minor)

5-HTP (5-Hydroxy-Tryptophan) A naturally occurring substance in human body that is also the rate limiting step in biosynthesis of serotonin.  L-tryptophan is converted into 5-HTP by tryptophan hydrolase, and then 5-HTP is converted into serotonin.  The highest dietary source of 5-HTP is from a plant 

Griffonia (Griffonia simplicifolia)  

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Griffonia (Griffonia simplicifolia): A Source of 5-HTP Seeds are used as an anti-depressant, to treat serotonin deficiency syndrome, and in the treatment of headaches and weight control. Can be found in the dietary supplement market for weight loss

H N HO

NH2 COOH

Mode of Action: 5-hydroxytryptophan, the main chemical found in griffonia is the bio-active component in Griffonia.  Several double-blind placebo-controlled clinical trials have been performed on this compound.  5-HTP, a serotonin precursor was found to reduce body weight, to treat headache, work as antidepressant drug, treat primary fibromyalgia syndrome, and inhibit panic and etc (Cangiano et al.1998; Hirai 1981; Schruers et al. 2002; Schruers et al.2002b, Ribeiro et al. 2000; Cangiano et al. 1992 and Caruso et al. 1990). 

Chemistry and QC • L-5-hydroxytryptophan, the main chemical in griffonia seed can reach 20% in fresh material (Lemaire and Adosrak. 2002). Found in the pods and in lower concentration in leaves of mature plants. • Indole-3-acetylaspartic acid, 5'-hydroxyindole-3-acetic acid, griffonin and griffonilide also detected in griffonia (Dwuma-Badu et al. 1976; Fellows et al. 1970) . • Fatty acid composition of seed oils is: 18:2 - 60 %; with 16:0, 18:0, 18:1 - 9-18 %; and 20:0 - 3-4 %. • Main sterol is -sitosterol - 60%; stigmasterol is 29% and campesterol ca. 11% (Petkov et al. 2003).

• As 5-HTP has been shown to be the bio-active component, it can be used as the marker compound for quality control of griffonia seed extract.

Additional considerations   

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Clinical studies demonstrating dietary ingestion of 5-HTP yield to higher levels of serotonin are needed. Use in alleviating depression is strong. Use for weight loss also looks good (didn‟t cover it in prior class but recognize it is a legitimate weight loss product) Evidence in treating insomnia and sleep disorders exist but limited. Evidence in treating chronic headaches are also limited 5-HTP was tested in a double blind placebo-controlled, crossover study of 48 students with recurring headaches and sleep disorders and study concluded product was effective in reducing headaches, sleep disorders (De Giorgis et al. 1987, Talbott and Hughes). Meta-analysis of papers published from 1966-2000 on use of 5-HTP nd L-tryptophan for depression found that only 2 of the 108 studies (one with 5-HTP) met the study criteria. Both 5HTP and L-tryptophan were better than the placebo.

Additional considerations For anxiety, using a 90-item check list for anxiety (Spielberger State-Trait Anxiety Inventory) in one double-blind, placebo-controlled comparison, 5-HTP did not later the associated depressive symptoms and compared to the control, whereas clomipramine showed significant improvements SAFETY/TOXCITY  Concern with use of 5-HTP with people contracting EMS (eosinophilia-myalgia syndrome). 5-HTP in the past had a preceived „contaminant‟, peak X.  Concern with use of 5-HTP in developing heart valve disease. No data to support concern. 

Representative HPLC chromatogram of Griffonia seed

5-HTP

0

1

2

3

4

5

6

7

8

9

min

Peak X in 5-HTP

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Initially reported in 1999 as major unpurity in 5-HTP. First reported structure for peak X was actually wrong, it had been a breakdown structure of 5-HTP. In 2003, same authors corrected the structure of peak X (in Journal of Rheumatology 2003, now called as Peak X1) as 4,5-trytophane-dione (Klarslov et al. 2003). The possible toxicity of Peak X1 is unknown.

Representative HPLC of peak x1 in 5-HTP 30.048

DAD1 A, Sig=350,16 Ref=off (GRIF\04052703.D) mAU

Based on peak areas, peak x1 is not a major impurity of 5-HTP

40

33.356

30

20

Peak X1

0

0

5

10

15

20

25

35

36.175

36.926

34.387 34.846

32.762

31.499 30

32.133

29.424

28.404

27.502

26.031 26.524

24.511

18.753 - Peak X1

11.242

12.941

6.548

4.352

3.461

2.217

10.652

10

min

Discussion of peak X1  

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Peak X1 level in griffonia and 5-HTP is very low Peak X1 is not the major impurity in 5-HTP and griffonia related products. 4,5-tryptophan-dione(Peak X1) is an oxidative form of 5-HTP Peak X or X1 can be moved away from 5-HTP through crystalization in solvent No longer an issue but halted the market for several years.

Choline 

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An essential B vitamin that is a precursor to acetylcholine (a neurotransmitter) and building block for phospholipids in cell membranes and lipoproteins. Choline is involved in liver function, cardiovascular health, brain devlopment. We do manufacture choline from methionine but do we synthesize enough is unclear as is the amount one needs. Folic acid and vitamin B12 both needed to process choline. The Food and Nutrition Board (FNB) of the NAS established adequate daily intake (AI) of choline at 550 mg/day for men and 425 mg/day for women. Exogenous Sources: milk, liver, eggs, peanuts, soybeans No real support for use in anxiety nor insomnia

Feverfew: Pain, Fevers, Migraines

Sourced >300 species of novel medicinals from Africa, Asia, North and South America. Feverfew collection (>50 selected lines) are being genetically developed to contain a matrix of compounds for comparative study (e.g. lines rich/absent in the parthenolide, camphor and crysanthol acetate). Anti-migraine value activity thought to due to inhibition of platelet aggregation and serotonin release.

Feverfew 

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Feverfew‟s used to treat headaches and anxiety and shows good evidence for migraine prevention Plant extracts shown to inhibit release of 5hydroxy-tryptamine (or serotonin), so here the effect is reduction in serotonin release, possible reduction in prostaglandin, thromboxane and leukotriene production Mainly due to parthenolide but not exclusively.

Kava Kava (Piper methysticum) 

An excellent student report by Noelle Leger was submitted to us in this class. We present her review for Kava!

Kava~Kava Piper methysticum Noelle Leger Herbals & Nutriceuticals October 2, 2008

http://www.igougo.com/journal-j12575-Fiji-Fiji.html#1152001

Kava Kava, (Piper methysticum, meaning “intoxicating pepper”) is a member of the pepper family, Piperacae. Indigenous to the South Pacific islands, it is a hardy and succulent perennial that requires adequate shade and moist conditions to flourish. Its large, heart-shaped leaf is smooth and green on both sides with a pointed tip, and can range from 8 to 25 centimeters in length. Kava is grown for its roots & rootstock (rhizome or “stump”), which are usually thick, knotted and tuberous. The plant is commonly harvested when it is about 2 to 2½ meters tall. The stumps are then mashed or ground and made into a cold beverage. It has a long history of ritual and medicinal use in Pacific Polynesia and is now a common herbal product.27,30 (Lebot and Cabalion 1986)

Traditional Preparation of Kava Most commonly, Kava is consumed as a cold beverage:27,30 The Kava rootstalk is harvested, cleaned and cut into small pieces.

Traditionally, pieces were masticated into a soft, pulpy mass, which was then spat onto a palm frond. Although the practice of mastication remains in some cultures, more modern methods of preparation include pounding, grinding and grating, with the use of a rock, coral, mortar & pestle or a machine. 

The pulp is then placed in a large, wide bowl and mixed with cold water or coconut milk.

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The mixture is then kneaded and stirred until the liquid becomes muddy, opaque and yellow in color.

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Once thoroughly mixed, the pulp is strained through palm fibers, cheesecloth or a nylon bag. http://www.fijiankava.com/f/ordering.html

Traditional Ritual & Recreational Uses Many of the Polynesian islands use Kava for their recreational and social gatherings:27,30 As a drink for high-ranking chiefs and elders As a form of welcome for distinguished visitors For preparation and completion of work or an event To validate status or initiation To observe births, marriages and deaths 1 Pope

John Paul II in Fiji, 1986.

Socially, it is consumed to induce relaxation, calm and pacify the soul, stimulate the imagination and inspire thought. Ceremonially, drinking Kava is an important part of formal discussions and decision-making. Ritualistically, it is used to communicate with the world of the dead and the supernatural.

1

http://www.janesoceania.com/fiji_visit/index.htm http://www.wowweemaui.com/index.cfm?event=KavaCeremony

Traditional Medicinal Uses Pacific Islanders have long recognized kava's healing & painkilling qualities:27 Although drinking Kava is the most common method of administration, fumigation of the leaves, and the topical application of macerated Kava are also methods of administration. Drinking: Sleep aid, headaches, chills, cramps, asthma, rheumatism, tuberculosis, GI upset, UTIs, dysmenorrhea, gonorrhea and appetite suppressant. Topical: Thrush, cuts, contusions, boils, skin infections, vaginal prolapsus and leprosy. Fumigation: General treatment for diseases.

Kava’s Chemical Components Kava contains many pharmacologically active constituents that act synergistically to produce effects greater than those achieved with any single compound.25 Currently, there are 18 lactones, three chalcones, bornyl ester of cinnamic acid derivatives and several flavanones that have been identified in Kava roots. These active chemicals in Kava are called the kavalactones.33 The six major kavalactones that have been identified are kavain, dihydrokavain, yangonin, desmethoxyyangonin, methysticin and dihydromethysticin.9 These compounds are known to cross the blood-brain barrier and enter the brain.25

Bio-Active NPs in Kava 33

Kavain

Dihydrokavain

Yangonin

Desmethoxyyangonin

Methysticin

Dihydromethysticin

Created in ChemBioDraw Ultra 11.0 by Leger, September 2008.

Kava’s Mechanism of Action GABA Receptors: Studies have claimed conflicting mechanisms of action for Kava in regards to the GABA neurotransmitter receptor-site (the same site which Benzodiazepines have their effect): – Some concluded that Kava worked directly through the GABA receptor-site23 – Other studies claimed there was no effect at all on the GABA receptor-site10,16 – A third type of study concluded that Kava inhibited the GABA receptor-site13

One of the more recent studies (2003) observed that even with the complete inhibition of the GABA receptor-site, that Kava still produced its sedative and antianxiety effects, concluding that Kava does not function through the GABA receptor site.16

Mechanism of Action, cont. Sodium & Calcium Ion Channels: It may reduce the electrical excitability of neurons by acting as Sodium and Calcium Channels Blockers in vitro. This may explain the anti-epileptic and local anesthetic effects.17,18

Norepinephrine & Dopamine Receptors: May also increase the effects of Norepinephrine and Dopamine neurotransmitters in certain areas of the brain, producing alertness. This effect is uncommon with other sedative drugs. This may explain why Kava produces a calm but alert state at lower doses.4 Conclusion: The mechanism of action of Kava is not yet completely understood. Multiple effectorsites seem to be involved, and Kava seems to create its effects through a combination of actions.

Commercial Uses of Kava Modern day commercial demand for Kava is though its use as an herbal supplement. According to Information Resources, Inc., Kava was the 25th top selling herbal dietary supplement in the Food, Drug and Mass Market Channel in the U.S. for 2007.6 Kava has become popular as an over-the-counter anxiolytic and sedative, and it is primarily consumed to help relieve stress, insomnia and anxiety.20

http://www.mauikava.com

Kava drinkers usually experience a calming, sedative effect, similar to that of alcohol, but without affecting mental clarity, as Kava and alcohol do not appear to have synergistic effects on cognitive and psychomotor impairment.21,31 In addition to anti-anxiety and sedation, Kava supplements sometimes claim to be helpful for the following: Relief of PMS, asthma, ADHD, Chronic Fatigue Syndrome, epilepsy and urinary tract infections.14

Products, Doses & Formulations Available Forms of Kava:24 Fresh Root Dried Root Powders Infusions Tinctures Extracts Capsules Tablets Variety of teas[1]

Additional Kava products:24 Teas Bottled Drinks Honey Balms Chocolate Milk Dissolving Strips Chocolates & Bars Lip Balms & Cosmetics Leaf Smoking Kits

Capsules[2]

Dosage: The effects of Kava are dose-dependent and as such, dosages for Kava will depend on which product is being used and its concentration of kavalactones.9

Honey Balm[4]

Infusions[5]

Stress Relief[6]

Extracts[7]

Powders[3]

Lip Balm[8]

Adverse Effects & Toxicity Side Effects 

Mild Use: Headache, dizziness, drowsiness, stomach upset, restlessness, tremor, contact dermatitis, impaired reflexes, visual disturbances and a hangover effect.2,5,12,24

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Chronic Use: Dermopathy, alopecia, partial loss of hearing, loss of appetite, lingual dyskinesia, torticollis, oculogyric crisis, painful twisting movements of the trunk, exacerbation of Parkinson's disease.1,2,7,12,24

Toxicities 

“Kava Dermopathy”: A scaly, yellow skin rash has been reported as a result of heavy, long-term Kava consumption, as is seen in Polynesia. Onset typically begins in the face and may be relate to interference with cholesterol metabolism. Ocular photosensitivity may accompany the rash as well.7

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Hepatotoxicity: Cases of severe hepatic toxicity may be associated with the inhibition of CYP450 enzymes responsible for the hepatic metabolism of a majority of drugs, elevating the plasma concentrations of these drugs to toxic levels.7,9

Herb-Drug Interactions Studies indicate that Kava may cause herb-drug interactions through the inhibition of the CYP450 enzymes responsible for the metabolism of many pharmaceutical drugs. Taking Kava with prescription medication or OTC products (including herbals) may result in elevated and potentially toxic drug concentrations in various organs and tissues.3 Possible herb-drug interactions: Alcohol: May produce an additive effect that enhances the hypnotic and sedative effects of alcohol. Also, the risks of impairment and liver damage are greatly increased.21 Antiseizure: May increase the effects of medications used to treat seizures.24 Antipsychotics: May increase the risk of side effects associated with medications used for the treatment of schizophrenia, including chlorpromazine and promethazine.24

Benzodiazepines: May indirectly increase the number of GABAA binding sites. Possible interaction due to the inhibition of CYP450 enzymes.23 Levodopa: Yagonin may decrease the efficacy of Levodopa and worsen the symptoms of Parkinson‟s disease.29 St. John’s Wort: Further studies are needed, but possible pharmacodynamic interactions may exist between SJW & Kava as they share similar MoA and are both used for mood elevation. 22 Warfarin: May increase the effects of anticoagulation due to interactions with CYP450 system.9

Cautions and Contraindications Parkinson’s Disease: People with Parkinson‟s disease should avoid Kava. There are reported cases of abnormal movements occurring in people with Parkinson‟s disease who took Kava.28 Liver Disease: People with pre-existing liver conditions such as cirrhosis or hepatitis, or patients already taking drugs suspected to have adverse effects on the liver should not consume Kava or take Kava supplements.22,24 Driving: Like alcohol, Kava may also have intoxicating effects and may impair ability to drive or operate heavy machinery.2 Duration of Use: Kava should not be taken on a daily basis for more than four weeks without supervision by a qualified health care professional. Physician Consultation: Consumers should consult with their primary health care provider prior to using Kava.

Kava Scientific evidence has demonstrated Kava‟s calming and sedative effects in both animal and human studies, even though the exact mechanism of action is still not completely understood. However, the lack of regulated and standardized preparations of Kava supplements most likely contributes to inconsistencies with dose and response between consumers. For most other supplemental claims, there is still insufficient evidence to suggest that Kava is effective for these uses. More research is necessary before these claims can be substantiated. KAVA: by Noelle Leger -

Excellent support for stress and anxiety reduction; Very good support for insomnia

http://vitasource.info/_wsn/page3.html

Melatonin        

A hormone produced by pineal gland and synthesized from tryptophan which is converted to 5-HTP then to N-acetylserotonin and then to melatonin. Suggested that by altering membrane characteristics, melatonin increases the binding of GBA to its receptors, resulting in decrease CNS activity Also integrally involved in our bio-rhythms, diurnal cycle, peaking at night related regulating our „internal clocks‟ Strong evidence showing it to be effective to induce sleep, lower alertness, lower body temperature, lower blood pressure. Thus, used as a sleep aid, alleviating jet lag but not for curing insomnia With insomnia, clinical trials show it generally improves sleep quality, onset, and duration but not effective in treating sleep-maintenance insomnia. Dietary supplements with melatonin are then used to promote sleep, reduce insomnia and jet lag symptoms. Also found in St. Johns Wort flowers, apples and other plants

Phosphatidylserine (PS) 

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An aminophospholipid, PS is synthesized by us, concentrated in brain cells and has shown good evidence in cognitive function but not in reducing anxiety and treating insomnia. Dietary supplements marketed for its use in maintaining brain function, boosting memory, and improving cognitive ability and in modulating stress response. Thus, PS found in those products marketed for immune function, exercise recovery and relaxation. Source: soybeans and cow brains (we recommend the former)

St John’s wort

Latin name: Hypericum perforatum L Part used as medicine: flowering tops Pharmacological activity: antidepressant OH

O

OH

HO

Me

HO

R

OH

O

OH

Hypericin, R=H Pseudohypericin R=OH

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Hypericin* Pseudohypericin* Hyperforin* Adhyperforin Hyperoside Quercitin Catechin Epicatechin 1,3,6,7-tetrahydroxyxanthone P-courmaric acid, ferulic acid, isoferulic acid, caffeic acid, chlorogenic acid

HPLC/UV (590 nm) chromatograms of St. John’s Wort samples In te n s.

0 5 0 6 2 9 0 6 .D: UV Ch ro m a to g ra m , 5 9 0 .1 6 n m

Pseudohypericin

25

SJW 104

20

15

10

Hypericin

5

0 0 5 0 6 2 9 0 5 .D: UV Ch ro m a to g ra m , 5 9 0 .1 6 n m 30

From Nature’s Way

Pseudohypericin 25

20

15

Hypericin

10

5

0 0

2

4

6

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18

T i m e [m i n ]

Total ion MS chromatograms of St. John’s Wort samples In te n s. x1 0 6

0 5 0 6 2 9 0 6 .D: T IC ±A l l

Pseudohypericin

SJW 104

6

4

Hypericin 2

0 x1 0 6

0 5 0 6 2 9 0 5 .D: T IC ±A l l

Pseudohypericin

From Nature’s Way

8

Hyperforin 6

O

OH O

Hypericin 4

O

Ashyperforin 2

0 2

4

6

8

10

12

14

16

18

T i m e [m i n ]

MS Spectra of Hypericin, Pseudohypericin, Hyperforin and Ashyperforin identified from St. John’s Wort samples (negative ion source) In te n s. x1 0 6

-M S , 2 .1 m i n (# 2 1 5 )

8

6

5 1 9 .7

[M-H]-, 519

Pseudohypericin

4

2

0 x1 0 6

-M S , 7 .8 m i n (# 6 6 7 )

2 .0

Hypericin

5 0 3 .8

[M-H]-, 503

1 .5

1 .0

0 .5

0 .0 x1 0 6

6

-M S , 4 .5 m i n (# 4 2 1 )

5 3 6 .0

Hyperforin

[M-H]-, 535

4

2

0 x1 0 6

-M S , 5 .3 m i n (# 4 8 4 )

1 .2 5

1 .0 0

Ashyperforin

5 5 1 .4

[M-H]-, 551

0 .7 5

0 .5 0

0 .2 5

0 .0 0 150

200

250

300

350

400

450

500

550

m /z

Valerian (Valeriana officinalis) 

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Used for liver and digestive problems, relaxation, anxiety, sleep and insomnia. Strong evidence for use as a sleep aid and to reduce anxiety. Bioactive products from roots Roots contain EOs In the EO: Valerenic acid, bornyl acetate, acetoxyvalerenic acid; and Roots also contain lipophilic iridoidsvalepotriates (bicyclic monoterpenes) Alkaloids also present- actinidine, valerianine