Transcript Herbs

New Botanical Medicinal
Breakthroughs
for the Management of
Anxiety and Sleep
Presented by:
Guy Chamberland, MSc, PhD, Master Herbalist
PARKE DAVIS & CO
Objectives of This Workshop – Learn About
• Pharmacological mechanism of action
• Traditional evidence and clinical evidence supporting the
use of herbs in the treatment of anxiety and sleep.
• Dose levels and additive effects.
• Importance of pharmacokinetics on clinical outcome:
– Duration of response
– Induction of sedation or hypnosis
– Dose level and dosing interval
Guy Chamberland, M.Sc., Ph.D.,
Master Herbalist
• B.Sc. In Agricultural Chemistry, McGill University.
• M.Sc., Ph.D. in toxicology (Biomedical sciences), University of Montreal.
• Natural Health Practitioner & Bioenergetics Practitioner diploma
(Oriental medicine), Alternative Medicine College of Canada.
• Proficiency in Herbal Prescription, Australian College of Phytotherapy.
• Chartered & Master Herbalist, Dominion College of Canada.
Guy Chamberland, M.Sc., Ph.D.,
Master Herbalist
• Over 16 years developing new drugs in pharmaceutical industry
(Canada & USA).
– Drug safety & Drug development.
• Research in herbal anxiety, sleep, pain/inflammation & wound
treatments.
– Since 2007.
– Preclinical & clinical research: inflammation/pain; wound
healing.
– 2 herb-based patents (pending): inflammation/pain; wound
healing.
– Clinical research treatment anxiety, sleep and
pain/inflammation.
Insomnia
• DSM-IV definition of insomnia:
– ‘Difficulty in initiating or maintaining sleep or …
nonrestorative sleep’ and as ‘causing clinically
significant distress or impairment in social,
occupational, or other important areas of
functioning’.
• Chronic insomnia:
– Can lead to significant morbidity.
• Both from lack of sleep and medications
prescribed.
Should your practice consider sleep quality
• Pain interferes with sleep.
– 50% - 88% patients treated for chronic pain
(nonmalignant) reported sleep impairment.
– Patients with high pain intensity had less sleep time,
more delayed sleep onset, and more nighttime
wakening than patients with low pain intensity.
• Disturbed sleep lowers pain threshold.
• Whether sleep disturbance precedes or follows
pain onset is unclear.
Should your practice consider sleep quality
• Chronic pain:
– Pain initiates and exacerbates sleep disturbance.
– Disturbed sleep maintains and exacerbates chronic
pain and related dysfunction.
• Sleep disruption, fragmentation, or restriction
produces hyperalgesia (increased sensitivity to
pain) and can interfere with analgesic
treatments
involving
opiodergic
and
serotonergic mechanisms of action.
Vicious cycle!
Poor sleep
Sleep disruption
Increases pain
sensitivity
Increased pain
Should your practice consider sleep quality
• REM sleep deprivation results in hyperalgesia
during the subsequent awake period.
• Nonrestorative sleep occurs in 73% to 76% of
fibromyalgia patients.
• Presence of restorative sleep in patients with
fibromyalgia predicted resolution of pain at 15
months.
SLEEP AID MEDICATION
-Worried about addiction?
-Do not tolerate the sleep-anxiety meds?
-Concerned about long-term safety?
-Patient wants a natural treatment.
TRUE or FALSE?
Botanical medicines are as
efficacious as prescription
drugs in the management of
insomnia & anxiety.
A Sedative effect: True or False?
•
170 mg/lb (375 mg/kg) extract Passiflora incarnata (5:1
PE) has anxiolytic effect equivalent to 0.68 mg/lb (1.5
mg/kg) diazepam.
•
Dose of 375 mg/kg of Passiflora extract in mice converted to Human
Equivalent Dose (HED) using body surface area =
•
•
375 mg / kg X 5:1 = 852 mg/lb (1875 mg/kg) dried herb.
HED = 1875 mg /12.3 (conversion factor) = 69 mg/lb (152.4 mg/kg) HED.
•
152.4 mg/kg X 70 kg (154 lb) subject = 10.7 grams dried herb.
•
Human Equivalent Dose of diazepam = 8.4 mg for 154 lb (70 kg) subject.
© Guy-Chamberland-MasterHerbalist
A Sedative effect: True or False?
Benzodiazepines are generally started at a low dose and titrated up as
needed based on response:
• Clonazepam: started at 0.25 to 0.5 mg 1or 2 daily and titrated
up to 1 mg 2 or 3 times daily as needed.
•
Diazepam: started at 2.5 to 5 mg orally 1 or 2 daily and
titrated up to 10 mg 2 or 3 times daily as needed.
•
Lorazepam: a benzodiazepine with an intermediate onset of
action and shorter half-life, can be started at 0.5 to 1 mg orally
three times daily and titrated up to 1.5 mg four times daily as
needed.
Rx Information from www.uptodate.com
Passion flower – Tea Bag
Average herbal tea: 1-1.5 grams per bag of dried herb top.
Would take a tea made with several bags!!!
375 mg / kg Passiflora incarnata extract (5:1 PE) had anxiolytic effect
comparable to 1.5 mg / kg diazepam.
Dose of 375 mg / kg in mice of an extract of Passion flower converted into
human equivalent dose (HED) using body surface area =
• 375 mg/kg X 5:1 ratio = 852 mg dried herb/lb (1875 mg/kg).
• HED = 1875 mg / 12.3 conversion factor = 69 mg/lb (152.4 mg/kg) HED.
• 152.4 mg/kg X 154 lb (70 Kg) subject = 10.7 grams of dried herb (4 doses
of the above blend).
Human Equivalent Dose of diazepam = 8.4 mg for 154 lb (70 kg) BW.
© Guy-Chamberland-MasterHerbalist
A Sedative Effect: True or False?
• Based on animal data = TRUE!
• Caveat: A question of dose level.
Not surprising since Drugs mimic herb
activities (pharmacology!!!).
Tranquilizer Effect: True or
False?
• Clinical trial in human patients
with Generalized Anxiety Disorder.
• Double blind
• Oxazepam active control
Tranquilizer < Sedative < Hypnotic
Tranquilizer Effect: True or
False?
Study Design:
Passiflora extract + placebo
vs
Oxazepam (30 mg/day)+ Passiflora.
36 patients (non-hospitalized).
Diagnosed with GAD based on DSM IV.
4-week treatment.
Oxazepam (Serax):
Anxiety, mild-to-moderate: 10-15 mg 3-4 times daily.
Anxiety, severe: 15-30 mg 3-4 times daily.
Tranquilizer Effect: True or
False?
• Both treatments were equally
effective.
• No significant difference.
• Oxazepam group had more rapid onset
• Oxazepam group had negative impact on
job performance
• Passiflora group had negligible impact on
job performance
Tranquilizer Effect: True or
False?
• Based on human data =
TRUE!
• Caveat: A question of dose level.
Summary – Botanical Medicines
•
As efficacious as a drug in the treatment of
insomnia & anxiety.
•
Disadvantage: Speed of onset (applies to
management of anxiety conditions).
•
Advantage: Safety.
•
•
•
•
No amnesia.
No negative effect on cognition or motor
coordindation.
No addiction.
No rebound.
Botanical Medicines
• Should be used as a First Line
in mild-to-moderate conditions
• Safety!
• Emergency situations – standard of care
unless non-tolerated.
• Keep in mind delay to onset!
Review of the importance
of pharmacokinetics on
clinical outcome.
• Sedative
• Hypnotic
Dose dependent
Affinity-time spent on receptor
• Tranquilizer
Evidence Behind an
Effective Botanical-Based Treatment?
ANXIETY
SLEEP
Choice of
herb
Dose
√
√
√
√
Frequency
√
X
Absorption of Active Ingredient
Plasma concentration
intravenous
Oral absorption: acid hydrolysis
(enteric coating: protection of active ingredient)
Cmax
Tmax
X
Hypnosis
No Hypnosis
Low bioavailability of active ingredients.
24 hour period
Oral dosing
© Guy-Chamberland-MasterHerbalist
Pharmacokinetics: Dosing Interval
Efficacy dependent on plasma concentration
Plasma concentration
Cmax
Tmax
Duration of response: 4-6 hours
T1/2 = 5.6 hrs
Plasma half-life
Tmax = 1.3-2.5 hrs
Analgesic /
Anxiolytic effect
No Analgesic /
Anxiolytic effect
Cmin
24 hour period
Oral dosing
© Guy-Chamberland-MasterHerbalist
Dosing Frequency/Interval Dependent on
Plasma Half-life
Plasma concentration
Cmax
Analgesia
Cmin
No Analgesia
Optimize dosing interval to avoid periods of no efficacy
24 hour period
Oral dosing
© Guy-Chamberland-MasterHerbalist
Side Effects Dependent on Plasma
Concentration
Plasma concentration
Cmax
Intolerable AE
Efficacy
No Efficacy
Cmin
24 hour period
Oral dosing
© Guy-Chamberland-MasterHerbalist
Accumulation & Side Effects
Plasma concentration
Half-life ranges from 24-36 hours for hypericin
Cmax
Intolerable AE
Efficacy
No efficacy
Cmin
24 hour period
Oral dosing
© Guy-Chamberland-MasterHerbalist
Minimal Effective Dose
2 g California poppy – sedation
4 g Scullcap - sedation
↑Sedation
Minimal effective dose
Maximal effective dose
↑ Plasma Concentration of active ingredient(s)
© Guy-Chamberland-MasterHerbalist
Are there herbs that allow us
to develop a botanical
medicine that is similar in
potency to a prescription
drug?
Evidence behind an effective
Botanical-based treatment?
ANXIETY
SLEEP
Choice of herb
√
√
Dose
√
√
Frequency
√
X
• Sedative
• Hypnotic
Dose dependent
Affinity-time spent on receptor
• Tranquilizer
Herbs: Sedative or Hypnotic
• Many clinical trials.
• Main problems:
• Studies performed with combination of 2 herbs.
• ‘Traditional recipe’ and not a drug development
concept.
• Dose is critical for efficacy.
• Herbs used according to their pharmacology:
• mu1, benzodiazepine, serotonine.
• Activity = ‘atypical’
• eg., mu1 + 5-HT1 / 5-HT7 ou 5-HT1 + GABA-A
Herbs – Sedative or Hypnotic
Lemon balm (Melissa officinalis)
Passionflower (Passiflora incarnata)
Valerian (Valeriana officinalis L.)
Scullcap (Scutellaria lateriflora)
Hops (Humulus lupulus)
California poppy (Eschscholzia californica)
Sedative - typical
Sedative - atypical
Hypnotic - typical
Hypnotic - atypical
Allows to fall asleep & remain asleep.
Improves quality of sleep.
Botanics: Targets and Therapy 2012:2 21–39
Passionflower
(Passiflora incarnata)
• Anti-anxiety effect demonstrated using benzodiazepine
receptor antagonist.
• GABA-mediated anxiolytic activity; Sedation and potentiate
pentobarbital-induced sleep (animal model).
• Beware: Strong additive effect with drugs!!!
Clinical trials:
• See table.
Natural Standard:
• 0.5-2g of dried passion flower has been used 3-4 times
daily.
• No single herb study to support sleep quality indication.
Many combo with 1 other herb.
Study
Design
Double-blind, Randomized,
Placebo controlled
14 days, Double-blind,
Randomized
Pilot, Randomized, Double-blind
controlled oxazepam
Subjects
• 60 patients randomized into
two groups to receive either
oral Passiflora incarnata
(500 mg extract) (n = 30) or
placebo (n = 30) as
premedication
90
min
before surgery.
• Healthy volunteers.
• Clonidine + passiflora extract
versus Clonidine + placebo: 65
opiate addicts-detox.
• All patients met DSM-IV
criteria for opioid
dependence.
• Treatment of GAD: passionflower
extract + placebo vs Oxazepam +
passionflower.
• 36 outpatients diagnosed with
GAD using DSM IV criteria.
Herbs:
• Passiflora incarnata or
placebo as premedication
90 min before surgery.
• Daily dose was 60 drops of
passionflower extract and a
maximum daily dose of 0.8
mg of clonidine administered
in three divided doses.
• The patients were randomized: 18
patients Passiflora extract +
placebo and 18 patients Passiflora
+ oxazepam 30 mg / day; trial 4
weeks.
Results:
•
• Both were equally effective in
the treatment of the physical
symptoms of withdrawal.
• Passionflower + clonidine
showed significant superiority
over clonidine alone in the
management of mental
symptoms
• Both treatments were effective
(no significant difference).
• Oxazepam showed a rapid onset
of action, impairment of job
performance.
• Passionflower extract was
effective for GAD; low incidence
of impairment of job
performance.
Akhondzadeh et al. J Clin Pharm Ther.
2001; 26(5):369-373
Akhondzadeh et al. J Clin Pharm Ther 2001
Oct;26(5):363-7.
•
Reference:
NRS anxiety scores were
significantly lower in the
passionflower group
than in the control group
(P <0.001).
As premedication
reduces anxiety without
causing sedation.
Movafegh et al. Anesth Analg. 2008
Jun;106(6):1728-32.
Summary – Passionflower
•
As efficacious as a drug in the treatment of anxiety.
•
Clinical evidence in combo for sleep.
•
Speed of onset. Important in severity of condition!
•
•
•
•
Achieved reduction anxiety without sedation.
Was effective for GAD.
Low incidence of impairment of job performance.
Reduced physical symptoms of withdrawal
syndromes.
No addiction.
No rebound.
•
•
Lemon balm (Melissa officinalis)
• Binds GABA-A receptor & Inhibits GABA transaminase.
• Dose-dependent sedation, inducing sleep & potentiating
subhypnotic and hypnotic doses of pentobarbital (animal model).
• Beware: Strong additive effect with drugs!!!
Clinical trials:
• See table.
Natural Standard: 1.5-4.5 g herb doses several times a day.
• Human evidence supports anxiety.
• No single herb study for sleep quality indication.
Study
Design
Randomized, double blind,
placebo controlled, crossover
study
Subjects
• Test the stress-relieving • Assess the effects of Melissa
effects of lemon balm
officinalis on cognitive
extract in healthy subjects
function and mood (N=20)
(N=18).
• Children's' anxious behaviors during
dental examination (N=90).
• Children aged 6-7 years with a
dental anxiety diagnosis.
Herbs:
• Two separate doses (300mg
and 600mg) of standardized
lemon balm extract (or
placebo) on two separate
days. After 7-day washout
period, subjects crossed over
to alternate treatment.
• Six capsules containing a total of
300mg, 600mg, or 900mg of M.
officinalis extract or a placebo
equivalent beginning one hour
before testing sessions began.
• 1-week washout period, crossed
over to other study arms.
• 1.36 mg/lb (3mg/kg) dose lemon
balm ethanol extract; 2.73 mg/lb
(6mg/kg) dose ethanol extract; or
placebo.
• Outcome measures were assessed
30 minutes after treatment.
Results:
•
• Significant effect on accuracy of
attention tasks (p=0.001) but lacked a
significant effect on the speed of
attention.
• Significant effect on the quality of
memory (p=0.003), secondary
memory factor (p=0.04), working
memory (p=0.01), but significant
effect on speed of memory was
lacking.
• Significant effect on alertness (
p<0.002) and calmness (p<0.002), but
lacked significant effect on
contentment.
• Significant between-group
difference in dental examination
behavior (p=0.002).
• High-dose was significantly different
from both placebo (p=0.008) and
low-dose (p=0.017); however, a
difference between the low dose
and placebo group was lacking
(p=0.759).
Kennedy et al. Pharmacol.Biochem.Behav.
2002;72(4):953-964.
PARDO-ALDAVE et al. International Journal of
Paediatric Dentistry 2009;19(1):66-170
•
Reference:
The 600mg dose
significantly increase selfratings of calmness and
reduce self-ratings of
alertness.
The 300mg dose increased
speed in a mathematical
test lacking an effect on
accuracy.
Kennedy et al. Psychosom.Med
2004;66(4):607-613.
Randomized, double-blind,
placebo controlled balanced
crossover study
Randomized, double-blind, placebo
controlled trial
Summary – Lemon balm
• As efficacious as a drug in the treatment of
anxiety.
• Clinical evidence in combo for sleep.
• Speed of onset. Important in severity of
condition!
• Achieved
reduction
sedation.
• No addiction.
• No rebound.
anxiety
without
Skullcap (Scutellaria lateriflora)
Its mechanism of action is not yet fully elucidated however the
pharmacology of several of the active ingredients have been
studied.
The flavonoids baicalein and scutellarein bind to GABA-A
benzodiazepine receptor sites and cross the blood brain
barrier (Liao et al. 1998; Hui et al. 2000; Barceloux 2008).
Other pharmacological studies have described
binding/inhibits to the serotonin receptor 5-HT(7) (Gafner
et al. 2003).
Liao J.F., Wang H.H., Chen M.C., Chen C.C. & Chen C.F. (1998) Benzodiazepine binding site-interactive flavones from Scutellaria baicalensis root. Planta Medica 64, 571-2.
Hui K.M., Wang X.H. & Xue H. (2000) Interaction of flavones from the roots of Scutellaria baicalensis with the benzodiazepine site. Planta Medica 66, 91-3.
Barceloux D.G. (2008) Medical Toxicology of Natural Substances: Foods, fungi, medicinal herbs, plants, and venomous animals. John Wiley & Sons Inc., Hoboken, N.J.
Gafner S, Bergeron C, Batcha LL, Reich J, Arnason JT, Burdette JE, Pezzuto JM, Angerhofer CK. Inhibition of 3H-LSD binding to 5-HT7 receptors by flavonoids from Scutellaria
lateriflora. J Nat Prod 2003; 66(4):535-7.
Study Design
Randomised,
crossover study
Subjects:
• Mood (anxiety states).
placebo-controlled
Double-blind, placebo-controlled crossover design
• 19 healthy volunteers.
• N=43 subjects, both males and females.
Herbs:
• S. lateriflora (capsule with 350 mg of dried
herb) or placebo three times daily (6 hour
interval).
• Placebo (2 capsules), 350-mg capsule freeze-dried
skullcap, 100-mg capsule skullcap extract prepared, 2
capsules of 100 mg skullcap extract.
Results:
-Reduces symptoms of anxiety and enhances
mood in some individuals
- Reduction in anxiety scores on Beck Anxiety
Inventory (BAI) and Tension-Anxiety (T-A)
scores in healthy volunteers.
- Skullcap had significant anxiolytic and mood
enhancing effects in some people.
-There were no adverse reactions or sideeffects.
-There were no rebound reactions such as
tolerance, dependability or excitability.
• A clear anxiolytic property with consistency for all 19
subjects for all 3 versus placebo.
• No adverse reaction to the skullcap.
• Impact on energy and cognition was mild.
• A diminution of perceived anxiety without major
impairment of intellect or vitality.
• With increase in dosage —the 2 versus the single
capsule—there was a notable impact on cognition
ratings, suggesting a greater degree of sedation at the
higher dose.
• Duration of action:
- Dose dependent
- Mild anxiolytic at 2 hrs.
Reference:
American Skullcap (Scutellaria lateriflora L): a study
of its effects on mood in healthy volunteers.
Christine A. Brock, Ph.D., Medical Herbalist
Wolfson et Hoffmann. Alternative Therapies in Health and Medicine
2003 Mar-Apr;9(2):74-8
Summary – Skullcap
•
As efficacious as a drug in the treatment of
anxiety.
•
Speed of onset.
condition!
•
Achieved reduction anxiety without sedation.
Important in severity of
• Was effective for GAD.
• Low incidence of impairment
performance.
•
•
No addiction.
No rebound.
of
job
California poppy (Eschscholzia californica)
Historical Use:
• Relaxing nervine in anxiety and nervousness
• Sedative in insomnia; and
• Anodyne in pain.
• A more recent usage is in the treatment of heroin addiction
and withdrawal.
Although remedies such as Opium Poppy are of great use as an
anodyne and analgesic, Felter and Lloyd considered
Eschscholzia to be an “…analgesic and soporific without the
dangers attending opiates, quieting pain and producing (a) calm
sleep” (1893).
California poppy (Eschscholzia californica)
• Pharmacologic Class:
– Opioid & 5-HT1A + 5-HT7
– Analgesic + Hypnotic/sedative
• Key clinical advantage:
– Safety profile:
• No addiction/physical dependence
• High tolerability versus conventional narcotics.
• 3 key alkaloids:
– At least 0.8% Isoquinoline alkaloids:
• Californidine
• Escholtzine
• Protopine
Pharmacology - 5:1 extract of
California poppy - mice
• Sedative activity at 200 mg/kg in mice
– 200 mg/kg X 5:1 extract ratio = 1000 mg dried herb per
kg.
– Conversion to Human Equivalent Dose:
• 1000 mg/kg / 12.3 = 37 mg/lb (81.3 mg/kg).
• For a 154 lb (70 kg) subject =
• 5.7 grams of dried herb (1200 mg extract (5:1)).
– partly antagonized by flumazenil.
• Equivalent to 2 capsules of a 500 mg
standardized extract.
© Guy-Chamberland-MasterHerbalist
Pharmacology - 5:1 extract of
California poppy - mice
• Sedative activity at 90.9 mg/lb (200 mg/kg) in mice
– 200 mg/kg X 5:1 extract ratio = 1000 mg dried herb per kg.
– Conversion to Human Equivalent Dose: 1000 mg/kg / 12.3 = 37 mg/lb (81.3 mg/kg).
– For a 154 lb (70 kg) subject:
• 5.7 grams of dried herb (1140 mg extract (5:1)).
• Anxiolytic effect demonstrated at 11.4 mg/lb (25 mg/kg) (125 mg
dried herb per kg).
– For a 154 lb (70 kg) subject:
• 0.7 grams of dried herb (142 mg extract (5:1)).
• Use of a 500 mg 5:1 standardized PE:
– 1 capsule too strong to be used as a calmative!
• 8-fold stronger than dose tested.
© Guy-Chamberland-MasterHerbalist
Pharmacology - 5:1 extract of
California poppy - mice
• Antidepressant: No effect against reserpine*-induced ptosis,
akinesia or hypothermia, when it was tested at 22.7, 45.5, 90.9,
181.8 and 363.6 mg/lb (50, 100, 200, 400, 800 mg/kg).
– For a 154 lb – 90.9 mg/lb (70 kg subject - 200 mg/kg):
• 5.7 grams of dried herb (1140 mg extract (5:1)).
– For a 154 lb – 363.6 mg/lb subject (70 kg - 800 mg/kg):
• 22.8 grams of dried herb (4553 mg extract (5:1)).
NO ANTIDEPRESSANT-LIKE EFFECT.
Explains in part the good tolerability in patients versus
meds!
*Reserpine irreversibly blocks the vesicular monoamine transporter. This normally transports
free intracellular norepinephrine, serotonin, and dopamine in the presynaptic nerve terminal
into presynaptic vesicles for subsequent release into the synaptic cleft.
© Guy-Chamberland-MasterHerbalist
California poppy (Eschscholzia californica)
• Pharmacological properties demonstrated:
– Dose-response effect observed for analgesia.
– Opioid & 5-HT1A & 5-HT7 serotonin activity.
– Dose-dependent sedative & anxiolytic properties.
– No antihistaminic effects.
– No anticonvulsant or myorelaxant effects.
– No anticholinergic effects.
– No muscle relaxant and antipsychotic properties.
– No antidepressant-like properties.
Study
Pilot study; 7-day acute Pilot study; 28-day chronic
pain
pain
Proof-of-concept; multicentre;
open-label
Subjects:
• 10 patients
•
• Patients with acute pain •
(VAS > 4)
• No drug therapy
•
10 patients
•
Patients with chronic pain •
(VAS > 4)
No drug therapy
•
20 patients
Uncontrolled, moderate-severe,
chronic pain
Fibromyalgia with/without
myofascial syndrome
• Arthritis
• NSLBP
• Neuropathic pain
Herbs:
• California poppy (1 at
night)
• Devil’s claw (tid)
• Scullcap (tid)
•
•
•
•
California poppy (1 at night)
Devil’s claw (tid)
Scullcap (tid)
Gel
Results:
•
•
•
•
•
Improved sleep
Significantly reduced pain
Significant  mobility &
flexibility
 swelling
 tenderness
 stiffness
•
•
Reference:
Improved sleep
Significantly reduced
pain
 swelling
 tenderness
Chamberland G. unpublished
•
•
•
Chamberland G. unpublished
© Guy-Chamberland-MasterHerbalist
•
•
•
•
California poppy (1 or 2 daily)
Concomitant pain meds.
Short form McGill Pain Scale
Sleep questionnaire
• Approximately 50% patient
obtained a significant clinical
benefit in pain relief or sleep.
• Delta-VAS: 2.4 (VAS <1.0 =
failure)
• Improved sleep (night pain):
67%
• Improved sleep (all): 45%
• Significant improvement pain:
55%
Chamberland G. unpublished
Summary – California poppy
• Induces sleep at correct dosage.
• Clinical evidence effective treatment night
pain.
•
•
•
•
No impact on cognition.
No impact on motor incoordination.
No addiction.
No rebound.
Recommended & Current Uses
California poppy (Eschscholzia californica)
• Night Pain:
–
–
–
–
1 or 2 capsules at night.
Analgesic & Hypnotic.
Better sleep quality.
Reduced doses of morphine at night.
• Co-analgesic (Adjuvant):
– 1 capsule bid (off-label use by physicians).
– Patients intolerant to meds such as Lyrica and/or Cymbalta.
• Reduce doses of other pain meds.
• Insomnia:
– 1 or 2 capsules 30 minutes before bedtime.
– Sedative & Hypnotic.
*capsule = 500 mg extract (dried herb top, 0.8% standardized, 5:1 PE)
Current Clinical Research
California poppy (Eschscholzia californica)
• Focus is on Night Pain
• Rationale:
– It induces fantastic dreams on 30-40% of occaisons used.
– Patients reported ‘restorative’ sleep.
• Hypothesis:
– Treatment with California poppy will favor restorative sleep in patients with
chronic pain.
– Will favor quality of life in patients.
– Superior healing due to restorative sleep.
*capsule = 500 mg extract (dried herb top, 0.8% standardized, 5:1 PE)
Hops (Humulus lupulus)
• Sedative & hypnotic effects;
• Dose-dependent reduction of locomotor activity and increase in
narcotic-induced sleep duration (animal model).
• Activity similar to Methylpentynol (ingredients similar activity).
• Beware: Strong additive effect with drugs!!!
Hops (Humulus lupulus)
Clinical trials:
•
•
•
Mainly combos.
Improved sleep latency and quality of sleep.
Anxiolytic, Sedative & Hypnotic effects.
•
Using quantitative topographical EEG:
• increase in delta-, decrease in alpha-, and a weak
decrease in beta-power.
• Acted via a central adenosine mechanism, which is
possibly the reason for its sleep-inducing and sleepmaintaining activity.
•
Possibly reduce alertness.
Herbs – Insomnia - Valerian
• Clinical Studies in humans with valerian:
– Did not have a negative impact on reaction time, alertness &
concentration morning after
– Overall evidence supports that valerian is safe but does not
support efficacy of valerian as sleep aid for insomnia
• Valerian contains valerenic acid:
– Interacts with the GABA(A)-ergic system, a mechanism of action
similar to the benzodiazepine drugs
– Valerian clinical trial: C(max) and AUC decreased and T(1/2)
increased with increased body weight.
– Human trial: Large variability in pharmacokinetics valerenic acid.
Explain inconsistent effect of valerian as sleep aid
•
Up to maximum dosages of 227 mg/lb (500 mg/kg) or 455 mg/lb (1000
mg/kg) BW none of the valerian extracts displayed sedative effects.
• Anxiolytic and antidepressant activity of valerian demonstrated
Designing an Effective
Treatment
ANXIETY
SLEEP
Choice of herb
√
√
Dose
√
√
Frequency
√
X
Why use Lemon balm + Passion
flower
• Established combined use in traditional medicine.
• Health Canada recognizes that these herbs are effective at adequate
doses to help relieve nervousness, as a sleep aid for cases of
restlessness or nervousness, or for insomnia due to mental stress.
• According to Health Canada, these herbs are considered safe for
use in adults and adolescents 13 years and older.
• Sleep: Trials were randomized & placebo controlled & combination of 1
or 2 herbs.
• Several trials in humans demonstrated the use of Lemon balm for
treating anxiety and insomnia.
• Several double-blind clinical studies showed the benefits of Passion
flower for treating restlessness or anxiety.
Why use Lemon balm + Passion
flower
BASE DOSE: extract equivalent to 2.8 grams dried herb top Lemon
balm (Melissa officinalis) and 2.4 grams dried herb top Passion flower
(Passiflora incarnata).
170 mg/lb (375 mg/kg) extract Passiflora incarnata (5:1 PE) has
anxiolytic effect equivalent to 0.68 mg/lb (1.5 mg/kg) diazepam.
• Dose of 375 mg/kg of Passiflora extract in mice converted to Human
Equivalent Dose (HED) using body surface area =
• 375 mg / kg X 5:1 = 852 mg/lb (1875 mg/kg) dried herb.
•
HED = 1875 mg /12.3 (conversion factor) = 69 mg/lb (152.4 mg/kg)
HED.
•
152.4 mg/kg X 70 kg (154 lb) subject = 10.7 grams dried herb.
•
Human Equivalent Dose of diazepam = 8.4 mg for 154 lb (70 kg)
subject.
© Guy-Chamberland-MasterHerbalist
Why Use Lemon balm + Passion
flower
Average herbal tea: 1-1.5 grams per bag of dried herb top.
Would take a tea made with several bags!!!
•
170 mg/lb (375 mg/kg) extract Passiflora incarnata (5:1 PE) has
anxiolytic effect equivalent to 0.68 mg/lb (1.5 mg/kg)
diazepam.
•
Dose of 375 mg/kg of Passiflora extract in mice converted to Human
Equivalent Dose (HED) using body surface area =
• 375 mg / kg X 5:1 = 852 mg/lb (1875 mg/kg) dried herb.
• HED = 1875 mg /12.3 (conversion factor) = 69 mg/lb (152.4 mg/kg) HED.
•
152.4 mg/kg X 70 kg (154 lb) subject = 10.7 grams dried herb.
•
Human Equivalent Dose of diazepam = 8.4 mg for 154 lb (70 kg) subject.
© Guy-Chamberland-MasterHerbalist
http://www.uptodate.com
1 capsule (1 Base Dose) of blend of herbs
is equivalent to 3.3 mg Diazepam
Diazepam dosing for anxiety:
2 to 10 mg 2-4 times daily if needed.
1 capsule with Base Dose every 4-6 hours as needed.
© Guy-Chamberland-MasterHerbalist
Treating Anxiety
• Example using Lemon balm + Passion flower:
– 2.8 grams dried herb top Lemon balm + 2.4 grams
dried herb top Passion flower = 50% additive
activity / intake.
Doses below will cause too much sedation
(be careful not to give hypnotic dose!):
5.6 grams Dried Herb Equivalent (DHE) Lemon balm +
4.8 grams DHE Passion flower =
75% additive activity/intake.
Safe Daily Dose:
13.5 g/day DHE Lemon balm
8 g/day DHE Passion flower
© Guy-Chamberland-MasterHerbalist
Treating Anxiety - Scullcap
• Scutellaria lateriflora – dried herb top – All very safe
if on a as needed basis.
• 2 grams DHE = 17% - mild symptoms of anxiety
• 4 grams DHE = 33% - moderate symptoms of anxiety
• 6 grams DHE = 50% - severe symptoms of anxiety
• Dosing: Balance drowsiness - tranquilization versus anxiety.
• Prescribe every 4 to 6 hours, as needed. If taken 3 times a
day:
• 2 g DHE = 51% additive
• 4 g DHE = 99% additive
• 6 g DHE = 150% additive
– When just treating anxiety, regimen is very safe if no
contraindications.
© Guy-Chamberland-MasterHerbalist
Treating Anxiety
Better dose range between
tranquilization dose
and
hypnotic effect
than with Passionflower + Lemon balm.
© Guy-Chamberland-MasterHerbalist
Pharmacokinetics: Time-to-Cmax (Tmax)
Plasma concentration
Start of PANIC attack.
Consider delay
to Cmax.
Cmax
Tmax
Tmax = 1.3-2.5 hrs
Cmin
24 hour period
Oral dosing
© Guy-Chamberland-MasterHerbalist
Botanical Medicines - Anxiety
• Should be used as a First Line
in mild-to-moderate conditions:
• Safety!
• Emergency situations – standard of care
unless non-tolerated.
• Keep in mind delay to onset!
Botanical Medicines - Insomnia
• Always implement:
• Good sleep hygiene
• A SCT therapy
Botanical Medicines - Insomnia
• To avoid addiction to meds,
physicians try to have patient take
drugs only several times a week.
• With herbs, no addiction problem
but try to cycle use to avoid
tolerance.
Sleep Hygiene
• Avoid caffeine, alcohol, nicotine
• No large meals close to bedtime
• No clock watching
• A quiet, dark and comfortable sleep environment
• Winding down for 1-2 hours before bedtime
• Maintain a sleep routine: bed and wake time
Stimulus Control Therapy
• To reduce the state of arousal at night and emphasize
that the bed is for sleep.
– 1. Lie down to sleep ONLY when sleepy.
– 2. Do not use bed for anything except sleep, sex, and
sickness.
– 3. If unable to fall asleep for ≥ 10 minutes, get up and go
into another room and return to bed when sleepy. AVOID
CHECKING THE CLOCK.
– 4. Repeat step 3 as often as necessary throughout the
night.
– 5. Set alarm and get up at the same time every morning,
respective of how much sleep was achieved at night.
– 6. Do not nap during the day.
Treating Insomnia (anxiety-associated)
• Example using Lemon balm + Passion
flower:
– 2.8 grams dried herb top Lemon balm + 2.4
grams dried herb top Passion flower = 50%
additive activity/intake.
Mild insomnia
– 5.6 grams DHE Lemon balm + 4.8 grams
DHE Passion flower = 75% additive
activity/intake.
Moderate
insomnia
– 5.6 grams DHE Lemon balm + 4.8 grams
DHE Passion flower (75% Additive) + 4
grams DHE Scullcap (33% Additive) = 108%
additive activity/intake.
Severe insomnia
Safe Daily Dose:
13.5 g/day DHE Lemon balm
8 g/day DHE Passion flower
© Guy-Chamberland-MasterHerbalist
California poppy (Eschscholzia californica)
• Night Pain:
– 1 or 2 capsules at night.
– Analgesic & Hypnotic.
– Better sleep quality.
• Insomnia:
– 1 or 2 capsules 30 minutes before bedtime.
– Sedative & Hypnotic.
*capsule = 500 mg extract (dried herb top, 0.8% standardized, 5:1 PE)
Treating Insomnia - Scullcap
• Scutellaria lateriflora – dried herb top
• 2 grams DHE = 17% - tranquilizer
• 4 grams DHE = 33% - tranquilizer, sedative
dose in some
• 6 grams DHE = 50% - sedative, hypnotic
dose in some
© Guy-Chamberland-MasterHerbalist
Safety Comparison
• Common with all hypnotics (benzodiazepines et
nonbenzodiazepines):
– Residual sedation , drowsiness, dizziness, vertigo, cognitive
impairment, motor incoordination, dependence.
• Herbs: fantastic dreams (remembering dreams).
• Long-term use:
– Dependence; rebound insomnia.
– Herbs: No physical or pharmacological dependence. No rebound
observed.
• Nonbenzodiazepines - AE similar to those of benzodiazepines, but
their frequency and severity is less.
– Associated with their shorter half-life.
– Herbs: shorter half-life could partially explain the safety profile, but
also because of the atypical pharmacology.
Case Study #1 – Insomnia
43 year old female with insomnia (inability to fall asleep) due to over-thinking.
Patient falls asleep very late and sleeps only a few hours; wakes up for work.
Tried Imovane and Rivotril. On the combo she wakes up for work (6:30 am) but
is still very tired and has difficulty being functional. Takes medication after not
being able to fall asleep; around midnight. Claims not to be dependent on
drugs.
Initial intervention:
- 1 to 2 Base Doses of Lemon balm + Passion flower 30 minutes before
bedtime. Base Dose = 2.8 g DHE Lemon balm + 2.4 g DHE Passion flower.
- Explain to patient need for relaxing before bedtime; making sure room dark
with no small lights from a DVD player or television; etc.
- If wake up around 2 or 4 am, take 1 Base Dose of Lemon balm+ Passion flower.
Case Study #2 – Anxiety
47 year old female with anxiety and insomnia; inability to fall asleep due to the
anxiety. Patient’s work environment creates the anxiety. Patient does not want
to take Ativan because of fear of becoming dependent but has daily episodes of
high anxiety.
Initial intervention:
- 2 g DHE tablet of Scutellaria lateriflora every 4 to 6 hours as needed (17%
Additive Intake per tablet).
- Episodes of strong anxiety: 4 g DHE. Important to explain ‘feeling’ of
tranquilizing effect to patient.
- Sleep critical: 1 Base Dose of Lemon balm + Passion flower (50% Additive
Intake). 30 minutes before bedtime.  energy & resistance.
- Increase resistance to anxiety – supplements: patient did not respond to
Ayurvedic remedies.