J157v04n04_06.pdf

Catherine Ulbricht, PharmD, MBA(C), Column Editor Synonyms/Common Names/Related Substances:Beladona, belladone,
belladonnae herbae pulvis standardisatus, belladonna herbum, belladonna leaf,
belladonna pulvis normatus, belladonnae folium, belladonna radix, belladonne,
deadly nightshade, deadly nightshade leaf, devil’s cherries, devil’s herb, die
Catherine Ulbricht is affiliated with Massachusetts General Hospital, Ethan Basch is affiliated with Memorial Sloan Kettering Cancer Center, Paul Hammerness is af-filiated with Harvard Medical School, Mamta Vora is affiliated with NortheasternUniversity, John Wylie, Jr., is affiliated with Harvard Medical School.
Jen Woods is Editorial Assistant, Natural Standard Research Collaboration.
Natural Standard (www.naturalstandard.com) Copyright 2004. Reprinted with Journal of Herbal Pharmacotherapy, Vol. 4(4) 2004 Digital Object Identifier: 10.1300/J157v04n04_06 belladonna, die tollkirsche, divale, dwale, dwayberry, galnebaer, great mo-rel, herba belladonna, hoja de belladonna, naughty man’s cherries, poisonblack cherries, powdered belladonna, Solanaceae (family), solanum mortale,solanum somniferum, stryshon, strygium, tollekirsche, tollkirschenblatter.
Selected Combination Products: Bellergal®, Bellergal-S®, Bellergil®, Bel-Phen-Ergot S®, B&O Supprettes®, Cafergot-PB®, Distovagal®,
Phenerbel-S®, PMS-Opium & Beladonna®.
CLINICAL BOTTOM LINE/EFFECTIVENESS
Brief Background
Belladonna is an herb that has been used for centuries for a variety of indications, including headache, menstrual symptoms, peptic ulcer dis-ease, inflammation, and motion sickness. Belladonna is known to con-tain active agents with anticholinergic properties, such as the tropanealkaloids atropine, hyoscine (scopolamine) and hyoscyamine.
There are few available studies of belladonna monotherapy for any indication. Most research has evaluated belladonna in combination withother agents such as ergot alkaloids or barbiturates, or in homeopathic(diluted) preparations. Preliminary evidence suggests possible efficacyin combination with barbiturates for the management of symptoms as-sociated with irritable bowel syndrome. However, there is currently in-sufficient scientific evidence regarding the use of belladonna for this orany other indication.
There is extensive literature on the adverse effects and toxicity of bel- ladonna, related principally to its known anticholinergic actions. Com-mon adverse effects include dry mouth, urinary retention, flushing,papillary dilation, constipation, confusion and delirium. Many of theseeffects may occur at therapeutic doses.
Scientific Evidence for Common/Studied Uses
Indication
Evidence Grade
Historical or Theoretical Uses Which Lack Sufficient Evidence
Abnormal menstrual bleeding, acute inflammation, anesthetic, anti- spasmodic, anxiety,1,2 arthritis, asthma, chicken pox, colds, colitis, con-junctivitis, diarrhea, diuresis, diverticulitis, earache, encephalitis, fever,flu, gout, hay fever, hemorrhoids, hyperemesis gravidarum, hyperkinesis(excessive motor function), hyperhidrosis (excessive sweating), measles,menstrual irregularities,3 motion sickness, mumps, muscle and joint pain,mydriasis, nausea and vomiting during pregnancy, neuralgia, nocturnalenuresis, organophosphate poisoning, Parkinson’s disease, pancreatitis,peptic ulcer disease,4 rash, scarlet fever, sciatica, sedative, sore throat,teething, toothache, ulcerative colitis, urolithiasis, urinary retention,5warts, whooping cough.
Expert Opinion and Historic Precedent
Belladonna was used during ancient times as a poison, and likely a me- dicinal, although knowledge of its therapeutic action dates to the 19thCentury.6 A prominent 19th Century London physician, Charles Williams,studied belladonna as part of his investigations into the pathophysiology of TABLE 2. Natural Standard evidence-based validated grading rationale™. Gradesreflect the level of available scientific evidence in support of the efficacy of agiven therapy for a specific indication. Expert opinion and folkloric precedentare not included in this assessment, and are reflected in a separate section ofeach monograph (“Strength of Expert Opinion and Historic/Folkloric Prece-dent”). Evidence of harm is considered separately; the below grades apply onlyto evidence of benefit.
Level of Evidence Grade
Criteria
A (Strong Scientific Evidence)
Statistically significant evidence of benefit from > 2properly randomized trials (RCTs), OR evidence fromone properly conducted RCT AND one properlyconducted meta-analysis, OR evidence from multipleRCTs with a clear majority of the properly conductedtrials showing statistically significant evidence ofbenefit AND with supporting evidence in basicscience, animal studies, or theory.
B (Good Scientific Evidence)
Statistically significant evidence of benefit from 1-2properly randomized trials, OR evidence of benefitfrom Ն1 properly conducted meta-analysis OR evidence of benefit from > 1 cohort/case-control/non-randomized trials AND with supporting evidencein basic science, animal studies, or theory.
C (Unclear or Conflicting Scientific Evidence of benefit from Ն 1 small RCT(s) without
Evidence)
adequate size, power, statistical significance, orquality of design by objective criteria,* OR conflictingevidence from multiple RCTs without a clear majorityof the properly conducted trials showing evidence ofbenefit or ineffectiveness, OR evidence of benefitfrom Ն1 cohort/case-control/non-randomized trials AND without supporting evidence in basic science,animal studies, or theory, OR evidence of efficacyonly from basic science, animal studies, or theory.
D (Fair Negative Scientific
Statistically significant negative evidence (i.e., lack of evidence of benefit) from cohort/case-control/non-randomized trials, AND evidence in basic science,animal studies, or theory suggesting a lack of benefit.
F (Strong Negative Scientific
Statistically significant negative evidence (i.e., lack of evidence of benefit) from Ն1 properly randomized adequately powered trial(s) of high-quality design byobjective criteria.* Lack of Evidence†
Unable to evaluate efficacy due to lack of adequateavailable human data.
* Objective criteria are derived from validated instruments for evaluating study quality, including the5-point scale developed by Jadad et al., in which a score below 4 is considered to indicate lesserquality methodologically (Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, GavaghanDJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary?Controlled Clinical Trials 1996; 17[1]:1-12).
† Listed separately in reviews in the “Historical or Theoretical Uses which Lack Sufficient Evi-dence” section.
asthma.7 In the same era in Paris, belladonna was introduced in thetreatment of Parkinson’s disease by Ordenstein, a pupil of Charcot.8 Belladonna was also prescribed by the founder of homeopathy, the German physician, Samuel Hahnemann. By the principle of homeopa-thy, that ‘like cures like,’ belladonna in homeopathic dilutions is said tobe a remedy for inflammation characterized by the triad of redness,swelling, and pain. It is believed to act during the night, and to have anaffinity for the head, throat, and ears.9 While studies in the late 1970s examined the effects of belladonna on irritable bowel syndrome, more recent placebo controlled trials have ex-amined homeopathic prophylaxis of migraine,10 homeopathic treatmentof radiodermatitis,11 and the treatment of airway obstruction in in-fants.12 Brief Safety Summary
Possibly Safe: When taken by healthy individuals in recommended doses for a short duration, or when taken in homeopathic dilutions. No-tably, there are numerous available preparations of belladonna alka-loids, the majority of which have not been evaluated for safety incontrolled trials.
Possibly Unsafe: When taken by individuals with medical conditions such as congestive heart failure, hypertension, coronary artery disease,cardiac arrhythmias, constipation, partial or complete bowel obstruc-tion, narrow-angle glaucoma, prostatic obstruction, myasthenia gravis,or urinary retention.
Likely Unsafe: When taken in large doses by children or adults.
When taken by breast-feeding or pregnant women. When taken concur-rently with other agents that possess anticholinergic properties.
DOSING/TOXICOLOGY
General
Recommended doses are based on those most commonly used in available trials, or on historical practice. However, with natural productsit is often not clear what the optimal doses are to balance efficacy andsafety. Preparation of products may vary from manufacturer to manufac-turer, and from batch to batch within one manufacturer. Non-homeo- pathic dilutions of belladonna should clearly state the quantity of tropanealkaloids contained.
Standardization
There is no current widely used standardized preparation of bella- Doses of belladonna are generally calculated by milligrams of total al- kaloids. Atropa belladonna contains up to 20 different tropane alkaloidcompounds. Those present in the largest concentration in leaves includehyoscyamine (68.7%), apoatropine (17.9%), 3␣-phenylacetoxytropane (2.8%), cuscohygrine (2.5%), and scopolamine (0.8%). Those presentin the largest concentration in roots include hyoscyamine (36.7%),cuscohygrine (31.5%), 6-hydroxyhyoscyamine (8.9%), hygrine (6%),6-hydroxyapoatropoine (3.6%), scopolamine (2.9%), and apoatropine(1.7%).13 The commercial preparation Bellergal® contains 40 mg phenobarbi- tal, 0.6 mg ergotamine tartrate, and 0.2 mg levorotatory alkaloids of bel-ladonna.14-16 The commercial preparation Donnatal® contains 0.1037 mg hyoscyamine
sulfate, 0.0194 mg atropine sulfate, 0.0065 mg hyoscine hydrobromide,and 16.2 mg phenobarbital.17 Adult Dosing (18 Years and Older)
Traditional Dosing: Traditional doses of have included belladonna leaf powder 50-100 milligrams per dose with a maximum single doseof 200 mg (0.6 mg of total alkaloids, calculated as hyoscyamine) anda maximum daily dose of 600 mg (equivalent to 1.8 mg of total alka-loids calculated as hyoscyamine); or belladonna root 50 mg per dosewith a maximum single dose of 100 mg (0.5 mg of total alkaloids, cal-culated as hyoscyamine) and a maximum with a maximum daily doseof 300 mg (equivalent to 1.5 milligrams of total alkaloids calculatedas hyoscyamine); or belladonna extract 10 mg per dose with a maxi-mum single dose of 100 mg (0.5 mg of total alkaloids, calculated ashyoscyamine), and a maximum daily dose of 150 milligrams (equiva-lent to 2.2 milligrams of total alkaloids calculated as hyoscyamine).
These doses have been noted by the expert German panel, the Commis-sion E, principally for the treatment of “gastrointestinal spasm.” Other anecdotal reports have suggested a tincture of belladonna (27-33 mg ofbelladonna leaf alkaloids per 100 mL), at 1.5mg per day, divided into 3doses per day with a double dose at bedtime or 0.6-1 mL (0.18 to 0.3 mgof belladonna leaf alkaloids) 3-4 times daily.
Irritable Bowel Syndrome: Placebo controlled trials during the 1960s and 1970s examined several doses and preparations of bella-
donna for irritable bowel, including Hyoscine butylbromide 10 mg
taken four times daily or a combination preparation containing 0.25 mg
levorotatory alkaloids of belladonna plus 50 mg phenobarbital.18,19
Donnatal® tablets (0.1037 mg hyoscyamine sulfate, 0.0194 mg atropine
sulfate, 0.0065 mg hyoscine hydrobromide, 16.2 mg phenobarbital)
have also been used.17 A higher daily dose was used in one study, in-
cluding 8 mg belladonna and 30 mg phenobarbital, although due to the
known toxicity of belladonna, that dose may not be advisable.20 Tradi-
tional doses are listed above.
Autonomic Nervous System Disturbances: Limited data are avail- able in this area. One small clinical trial administered a combinationformula including 15 mg belladonna, 60 mg ergot alkaloids, 15 mgpropranolol, and 25 mg amobarbital, three times day for two weeks, andnoted improvements in 72% of subjects with autonomic dysfunction(diseases poorly described).21 Headache: Studies in the 1960s and 1970s reported unimpressive ef- fects on headache with the combination product Bellergal® (40 mg phe-
nobarbital, 0.6 mg ergotamine tartrate, 0.2 mg levorotatory alkaloids of
belladonna, taken twice daily).14-16
Premenstrual Syndrome: Bellergal® (40 mg phenobarbital, 0.6 mg
ergotamine tartrate, 0.2 mg levorotatory alkaloids of belladonna) takentwice daily for 10 days prior to menses was evaluated in one poorly re-ported 1970s trial.22 Menopausal Symptoms: A placebo controlled trial found no effects on menopausal symptoms with 4 weeks of Bellergal® Retard (total
daily dose: 80 mg phenobarbital, 1.2 mg ergotamine tartrate, 0.4 mg
levorotatory alkaloids of belladonna).23
Note: Homeopathic dosing is often dependent on the indication, presentation and philosophy of the practitioner, and dosing standardsmay range widely. In general, homeopathic preparations are initiallydiluted 1:10 or 1:100. Serial dilutions are continued until desired con-centrations are achieved. When a 1:10 dilution is diluted 30 times, it is said to be a 30X or 30D potency. When a 1:100 dilution is diluted 30times, it is referred to as a 30C potency. ‘Proving studies’ have beenconducted to investigate the effects of homeopathic belladonna inhealthy volunteers, and have used preparations of Belladonna 30CH(Deutsche Homöopathie Union, Karlsruhe; Germany)9 and BelladonnaC30 (Ainsworth’s Homeopathic Pharmacy; UK) 1 tablet twice daily.24 Radiodermatitis: Belladonna 7CH (Laboratoires Boiron; France), 3 granules sublingually twice daily has been used in a controlled trial inpatients with breast cancer.11 Musculoskeletal: The topical use of a belladonna plaster produced by Cuxson Gerrard (England) containing 0.25% belladonna alkaloids (hysoscine2%, atropine 1%) has been described in a case report, and may be asso-ciated with contact dermatitis after prolonged use.25 Pediatric Dosing (Younger Than 18 Years)
Traditional Dosing: Anecdotal use suggests a typical pediatric dose to be 0. 03 mL/kg three times daily or 0.8 mL/square meter three timesdaily (27-33 mg of belladonna leaf alkaloids per 100 mL). Maximumdose has been reported as 3.5 mL per day. Safety and efficacy have notbeen clearly demonstrated.
Airway Obstruction: A poorly reported controlled trial administered a tincture of belladonna, in a dose equivalent to 0.01 mg/kg weight of at-ropine, at bedtime to infants.12 Note: Death in children may occur at 0.2 mg/kg of atropine.26 Thus, 2 fruits may be lethal for a small child (2 mg atropine are often found in afruit).27 Note: Homeopathic dosing is often dependent on the indication, pre- sentation and philosophy of the practitioner, and dosing standards mayrange widely. In general, homeopathic preparations are initially diluted1:10 or 1:100. Serial dilutions are continued until desired concentra-tions are achieved. When a 1:10 dilution is diluted 30 times, it is said to be a 30X or 30D potency. When a 1:100 dilution is diluted 30 times, it isreferred to as a 30C potency.
Otitis Media: An observational study comparing homeopathic with conventional treatment for children with otitis media utilizedBelladonna 30X globules (brand and dose not specified).28 Favor-able results were reported, although the study was poorly designed anddescribed.
Toxicology
At a dose of up to 1.5 mg/day, belladonna is traditionally considered to be safe, although many people will experience anticholinergic sideeffects. The most common manifestations of belladonna overdose in-clude anticholinergic symptoms such as dilated pupils, flushing, drymouth, tachycardia, confusion, agitation, and hallucinations.6,29 Theanticholinergic effects of belladonna can be dangerous at high doses,and may result in severe side effects or death. Death in children may oc-cur at 0.2 mg/kg atropine.26 Thus, 2 fruits may be lethal for a small child(2 mg atropine are often found in a fruit).27 Cases of belladonna poisoning with plant ingestions have long been reported in the literature, including an early (1921) report ofbelladonna poisoning from eating rabbit that had been feeding onbelladonna.30 Case reports include anticholinergic poisoning symp-toms in children and adults after ingestion of deadly nightshadeberries.27,31,32 Several case reports exist of belladonna poisoning af-ter ingestion of tomatoes grown from a plant grafted to jimson weed(Datura stramonium).33 A case report describes a 68-year-old Italianman who presented with agitation, hallucinations, slurred speech, tachy-cardia, dilated pupils, hypertonia, and myoclonic jerks after ingestionof berries from deadly nightshade (Atropa belladonna).34 A study ofplant intoxications in Switzerland over 29 years revealed 152 severecases, of which 62 were caused by Atropa belladonna, Datura stramonium,and Hyoscyamus niger.29 A case report from Chicago describes a four year-old girl with symptoms consistent with anticholinergic poisoning after ingestion ofwoody nightshade (Solanum dulcamara), a relative of belladonna thatcontains solanine, not generally thought to have anticholinergic ef-fects. She was administered 0.2 mg (0.02 mg/kg) of physostigminethree times in an hour with complete resolution of symptoms. Despitethe unusual plant exposure, this report serves as evidence of the efficacyof physostigmine as an antidote for anticholinergic poisoning.35 How- ever, a recent case report of two adults with belladonna poisoning re-ports supportive therapy, not physostigmine, to be efficacious.27 Belladonna toxicity has been reported with various routes of admin- istration, including topical plaster.36 There are several case series of in-gestion of approximately 0.5-1.5 teaspoons of Asthmadore powder(belladonna and stramonium alkaloids, 0.23-0.31%; R. Schiffman Co.,Los Angeles) for the purpose of experiencing hallucinatory effects re-sulting in hallucinations, agitation, tachycardia, tachypnea, dilated pu-pils, blurred vision, and unsteady gait. After 7-24 hours of observation,the subjects in these case series fully recovered.37-39 Belladonna overdose should be considered serious and should be treated by qualified medical professionals. Due to the anticholinergicinhibitory effects on gastric emptying, delayed ingestion with resultantprolonged toxicity may occur.26 PRECAUTIONS/CONTRAINDICATIONS
Allergy
Known allergy/hypersensitivity to belladonna and anticholinergic Known allergy to other members of the Solanaceae (nightshade) family such as bell peppers, potatoes and eggplants.
Allergic contact dermatitis may develop with prolonged use of topi- cal belladonna preparations, even at low concentrations.25 Adverse Effects
General: Adverse reactions are common with belladonna alkaloid use. Doses of 0.5 mg or greater may cause anticholinergic side effects ofvarying severity. Anticholinergic effects may include dry mouth, uri-nary retention, flushing, pupillary dilation, constipation, and confusion.
There is some evidence that in homeopathic (dilute) concentrations,oral belladonna may not elicit clinically relevant anticholinergic signsor symptoms.40 Dermatologic: Case reports of toxicity have described redness of the skin, flushing, and dry skin. Allergic contact dermatitis hasbeen reported with use of topical belladonna plaster, even at diluteconcentrations.25 Two incidences of rash and hives were noted withbelladonna-phenobarbital-ergotamine treatment.16 Anecdotal reports have mentioned such other adverse effects as fixed drug eruptions, StevensJohnson Syndrome and photosensitivity.
Neurologic/CNS: Case reports have described headache, excitement, agitation, dizziness, lightheadedness, drowsiness, unsteadiness, confu-sion, hallucinations, slurred speech, sedation, hyperreflexia, convul-sions, vertigo and coma.29,30,33,34,37-39,41 Ocular/Otic: Ocular effects may include mydriasis, photophobia, blurred vision, and dilation of pupils.30,35,37-39,41,42 Belladonna splintersplaced in the eye have been associated with fixed mydriasis.43 Psychiatric: Hallucinations and acute psychosis have been docu- mented in cases of toxicity.26,27,29,34,37-39 Respiratory: Rapid respiration has been reported in cases of toxic- ity,37 as well as coma with respiratory arrest requiring mechanical venti-lation.26 Cardiovascular: Tachycardia has been reported in cases of toxic- ity.26,30,37,38,41,44 Belladonna contains atropine, which is commonly usedin hospitals to increase heart rate. In one case-report, infants who re-ceived hyoscyamine sulfate developed heart rates of 155-220 beats perminute when given 2-4 mL of hyoscyamine.42 Severe hypertension hasbeen documented,45 as have ventricular premature beats, among pa-tients with belladonna poisoning.46 Gastrointestinal: Case reports have noted dry mouth resulting from belladonna use or toxicity.30,33,37-39,41,44 Other anecdotal or theoreticaleffects include abdominal distention, and reduction in salivary flow.33 Genitourinary: Urinary retention has been documented.38,44Endocrine: Case reports have documented decreased perspiration.35 Anecdotal references note a possibility of decreased flow of breastmilk.
Musculoskeletal: Anecdotal reports have noted muscle tremor, rigid- Precautions/Warnings/Contraindications
Avoid in elderly patients and in children, based on numerous case re- ports of serious effects of belladonna poisoning in these age groups.
Avoid in patients using other anticholinergic agents.
Use cautiously in patients with cardiac disease, including coronary heart disease, congestive heart failure, hypertension, cardiac arrhythmias,or unstable cardiovascular status, due to case reports of cardiac effects(hypertension, tachycardia, arrhythmias) with belladonna poisoning.
Use cautiously in patients with gastrointestinal tract disease such as ulcers, esophageal reflux, hiatal hernia, obstructive gastrointestinaldisease, constipation, ileus or atony, colitis, ileostomy or colostomy.
Belladonna’s anticholinergic effects may delay gastric emptying anddecrease esophageal pressure.
Use cautiously among patients with urinary retention, prostatic hy- pertrophy or obstruction, or obstructive uropathy. Due to belladonna’santicholinergic effects, these conditions may be aggravated.
Use cautiously among patients with narrow-angle glaucoma due to a theoretical increase in ocular tension.
Use cautiously in patients with Sjogrens syndrome, xerostomia or lachrymal problems due to belladonna’s anticholinergic effects.
Use cautiously in patients with neuromuscular disorders such as my- asthenia gravis, as belladonna may cause neuromuscular blockade re-sulting in weakness or paralysis.
Use cautiously among patients with fever.
Use cautiously among patients with Down’s syndrome, as they may be particularly sensitive to anticholinergic effects of belladonna.
Pregnancy and Lactation
Not recommended due to the potential for toxicity and adverse outcomes.
Belladonna is listed under category C according to the U.S. Food and Drug Administration. Belladonna alkaloids are excreted in breast milk,thereby exposing infants to potential toxicity.
One small, case-control study of neonatal death and congenital malfor- mations showed no increase in these outcomes in mothers ingesting bella-donna alkaloids.47 In another study, there was an increase in birth defects inthe offspring of mothers who had taken belladonna, although no relation-ship between first trimester use of atropine and birth defects was found.48 There have been anecdotal reports that use of belladonna during pregnancy may increase risk of respiratory abnormalities, hypospadias(penile urethral anomalies in males), and eye/ear malformations.
INTERACTIONS
Belladonna/Drug Interactions
Oral Medications: Belladonna may delay gastrointestinal transit time and thereby affect absorption of some medications.
Drugs that Interact with Anticholinergic Agents: Numerous drugs and drug classes may interact with anticholinergic agents. Examples include:acetophenenazine, amantadine, amitriptyline, atropine, benztropine, beth-anechol, biperiden, brompheniramine, carbinoxamine, chlorpromazine,clemastine, clindinium, clozapine, cyclopentolate, cyproheptadine, dicyclomine,diphenhydramine, dixyrazine, ethopropazine, fenotherol, fluphenazine,haloperidol, homatropine, hyosciamine, ipratropium, loxapine, mesorida-zine, methdilazine, methotrimeprazine, olanzapine, oxybutynin, perazine,periciazine, perphenazine, pimozide, pipotiazine, prochlorperazine, pro-cyclidine, promazine, promethazine, propiomazine, quinidine, scopol-amine, thiethylperazine, thioridazine, thiothixene, trifluoperazine, triflu-promazine, trihexyphenidyl, trimeprazine, triprolidine.
Drugs that Interact with Atropine: Atropine is a constituent of bella- donna. Theoretically, drugs that interact with atropine may also interactwith belladonna. Examples include: ambenonium, arbutamine, bella-donna, cisapride, cromolyn, halothane, methacholine, procainamide.
Tricyclic Antidepressant Drugs: Due to the anticholinergic proper- ties of belladonna, interactions may occur with tricyclic antidepressantdrugs.
Cisapride: Atropine, a constituent of belladonna, has been reported to block the effects of cisapride on peristaltic contractions:49 When atro-pine was administered before cisapride, the effects of cisapride onlower esophageal sphincter pressure were antagonized. The effect didnot occur when atropine was administered after cisapride.
Antiarrhythmic Drugs: Administering belladonna with procainamide may result in additive anti-vagal effects on atrioventricular nodal conduction.
Alcohol: Concomitant use of alcohol with belladonna may theoreti- cally result in additive CNS depression.
Tacrine (Cognex®): In mice, cognitive deficits associated with bella-
donna alkaloid administration are attenuated by tacrine.50 Belladonna/Herb/Supplement Interactions
Oral Agents: Belladonna may delay gastrointestinal transit time and thereby affect absorption of some agents.
Anticholinergic Herbs and Supplements: Combination use of bella- donna with anticholinergic agents may potentiate its therapeutic and ad-verse effects. Examples of anticholinergic herbs include bittersweet(Solanum dulcamara), henbane (Hyoscyamus niger), and Jimson weed(Datura stramonium).
Belladonna/Food Interactions
Belladonna/Lab Interactions
MECHANISM OF ACTION
Pharmacology
Belladonna alkaloids are competitive inhibitors of the muscarinic ac- tions of acetylcholine, acting at receptors located in exocrine glands,smooth and cardiac muscle, and intramural neurons.
The belladonna constituent scopolamine exerts greater effects on the CNS, eye, and secretory glands than the constituents atropine andhyoscyamine. Atropine exerts more activity on the heart, intestine, andbronchial muscle, and exhibits a more prolonged duration of actioncompared to scopolamine. Hyoscyamine exerts similar actions to atro-pine but has more potent central and peripheral nervous system effects.
A single-blind placebo controlled study was conducted to investigate the cardiorespiratory effects of belladonna, as a surrogate measure ofvagal activity.51 Single doses of an oral belladonna tincture containing0.1 mg/mL alkaloid concentration were administered, with a proportionof atropine to scopolamine of 20:1. In eight healthy young subjects,heart rate and noninvasive arterial finger blood pressure were recordedfor 4 hours following oral application of 1 mL, 2 mL, or 5 mL of thisbelladonna tincture, or placebo. The authors reported that 1 hour afteradministration of 5 mL, mean respiratory rate, heart rate, and baroreflexsensitivity decreased significantly in six of eight subjects. In contrast,following administration of 1-2 mL, mean respiratory rate and heart rateincreased compared to placebo.
Pharmacodynamics/Kinetics
The belladonna constituent atropine has a reported half-life of sev- eral hours and is rarely detectable in the plasma after 24 hours. Elimina-tion half-life of atropine from raw or cooked belladonna berries was reported to be approximately 120-140 minutes in a case report of toxicingestion.26 Atropine is primarily renally excreted. Renal clearance of atropine following ingestion of raw or cooked belladonna berries is variable, de-pending on the form ingested, but may be as high as 3.6 mg/24 hours.26 HISTORY
The name belladonna means “beautiful woman” in Italian, and is de- rived from the use of this herb by 16th century Venetian women toself-induce dilated pupils and flushed cheeks in order to make them ap-pear more attractive.
Possible references to the intoxicating properties of belladonna alka- loids appear throughout historical literature, including Homer’s Iliadand Odyssey. The poison used by Friar Lawrence to put Juliet to sleep inShakespeare’s Romeo and Juliet may have been belladonna.
Belladonna has been used for centuries in the religious rites of Native North and South Americans, including the Algonquians and Incas. Itwas reported to be the agent in a poisoning of soldiers in Jamestown,Virginia in 1676, where Datura stramonium (a relative of Atropa bella-donna) was known as “Jamestown weed.6” Condition
Statistically
Quality of
Magnitude ARR
Comments
Significant?
of Benefit
0-2 = poor
3-4 = good
5 = excellent
studied (0.25mgbelladonna alkaloids &50mg phenobarbital).
(hyoscyamine,atropine, hyoscineplus phenobarbital) vs.
Valpin (anisotropine+/Ϫ phenobarbital).
compared to placebo.
27% dropout.
Condition
Statistically
Quality of
Magnitude ARR
Comments
Significant?
of Benefit
0-2 = poor
3-4 = good
5 = excellent
ispaghula husksignificantlyimprovedsymptoms.
studied(containedethanol) in infantswith breath-holding spells.
barbituratescompared; superiorresults with formulacontaining higherconcentration ofbelladonna andpropranolol. Noplacebo control.
associated withrespiratory andheart rate.
Tinctures containethanol.
(belladonna,ergotamine,phenobarbital)associated withbenefits in onestudy arm but notanother. 28%dropout.
pared to othertherapies or pla-cebo. Poorly de-scribed study.
belladonnapreparation.
Benefits reportedvs. antibiotics.
Condition
Statistically
Quality of
Magnitude ARR NNT
Comments
Significant?
of Benefit
0-2 = poor
3-4 = good
5 = excellent
studied over 3menstrual cycles.
Reducedsymptomsreported. 23%dropout.
effects in totalseverity score only.
belladonna studied.
Trend towardsimprovement at 2-4weeks, but noeffect at 8 weeks.
In the late 1960s, several reports appeared that Asthmador, a com- pound of belladonna and stramonium alkaloids, was being used in anumber of different communities in the United States as a hallucinogen.
There are case reports in the medical literature describing overdoses ofAsthmador taken for this effect.52 Condition
Refers to the medical condition or disease targeted by a therapy.
Study Design
Randomized Controlled Trial (RCT): An experimental trial in which par- ticipants are assigned randomly to receive either an intervention being testedor placebo. Note that Natural Standard defines RCTs as being placebo-con-trolled, while studies using active controls are classified as equivalence trials(see below). In RCTs, participants and researchers are often blinded (i.e., un-aware of group assignments), although unblinded and quasi-blinded RCTsare also often performed. True random allocation to trial arms, proper blind-ing, and sufficient sample size are the basis for an adequate RCT.
Equivalence Trial: An RCT which compares two active agents. Equiv- alence trials often compare new treatments to usual (standard) care, andmay not include a placebo arm.
Before and After Comparison: A study that reports only the change in outcome in each group of a study, and does not report between-groupcomparisons. This is a common error in studies that claim to be RCTs.
Case Series: A description of a group of patients with a condition, treatment, or outcome (e.g., 20 patients with migraine headache under-went acupuncture and 17 reported feeling better afterwards). Case se-ries are considered weak evidence of efficacy.
Case-Control Study: A study in which patients with a certain out- come are selected and compared to similar patients (without the out-come) to see if certain risk factors/predictors are more common inpatients with that outcome. This study design is not common in thecomplementary & alternative medicine literature.
Cohort Study: A study which assembles a group of patients with cer- tain baseline characteristics (for example, use of a drug), and followsthem forward in time for outcomes. This study design is not common inthe complementary & alternative medicine literature.
Meta-Analysis: A pooling of multiple trials to increase statistical power (often used to pool data from a number of RCTs with small samplesizes, none which demonstrates significance alone but in aggregate canachieve significance). Multiple difficulties are encountered when design-ing/reviewing these analyses; in particular, outcomes measures or thera-pies may differ from study to study, hindering direct comparison.
Review: An author’s description of his or her opinion based on per- sonal, non-systematic review of the evidence.
Systematic Review: A review conducted according to pre-specified criteria in an attempt to limit bias from the investigators. Systematic re-views often include a meta-analysis of data from the included studies.
Author, Year
Identifies the study being described in a row of the table.
N
The total number of subjects included in a study (treatment group plus placebo group). Some studies recruit a larger number of subjectsinitially, but do not use them all because they do not meet the study’s en-try criteria. In this case, it is the second, smaller number that qualifies asN. N includes all subjects that are part of a study at the start date, even ifthey drop out, are lost to follow-up, or are deemed unsuitable for analy-sis by the authors. Trials with a large number of drop-outs that are not included in the analysis are considered to be weaker evidence for effi-cacy. (For systematic reviews the number of studies included is re-ported. For meta-analyses, the number of total subjects included in theanalysis or the number of studies may be reported.) Statistically Significant
Results are noted as being statistically significant if a study’s authors report statistical significance, or if quantitative evidence of significanceis present (such as p values).
Quality of Study
A numerical score between 0-5 is assigned as a rough measure of study design/reporting quality (0 being weakest and 5 being strongest). This num-ber is based on a well-established, validated scale developed by Jadad et al.
(Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports ofrandomized clinical trials: is blinding necessary? Controlled Clinical Trials1996;17[1]:1-12). This calculation does not account for all study elementsthat may be used to assess quality (other aspects of study design/reporting areaddressed in the “Evidence Discussion” sections of reviews).
A Jadad score is calculated using the seven items in the table below.
The first five items are indications of good quality, and each counts asone point towards an overall quality score. The final two items indicate Jaded Score Calculation
Was the study described as randomized (this includes words such as randomly, Was the method used to generate the sequence of randomization described and appropriate (table of random numbers, computer-generated, etc.)? Was the method of double binding described and appropriate (identical placebo, Was there a description of withdrawals and dropouts? Deduct one point if the method used to generate the sequence of randomization was described and it was inappropriate (patients were allocated alternately, oraccording to date of birth, hospital number, etc.) Deduct one point if the study was described as double blind but the method of blinding was inappropriate (e.g., comparison of tablet vs. injection with no doubledummy).
poor quality, and a point is subtracted for each if its criteria are met. Therange of possible scores is 0 to 5.
Magnitude of Benefit
This summarizes how strong a benefit is: small, medium, large, or none. If results are not statistically significant “NA” for “not applica-ble” is entered. In order to be consistent in defining small, medium, andlarge benefits across different studies and monographs, Natural Stan-dard defines the magnitude of benefit in terms of the standard deviation(SD) of the outcome measure. Specifically, the benefit is considered: • Large: if >1 SD• Medium: if 0.5 to 0.9 SD• Small: if 0.2 to 0.4 SD In many cases, studies do not report the standard deviation of change of the outcome measure. However, the change in the standard deviationof the outcome measure (also known as effect size) can be calculated,and is derived by subtracting the mean (or mean difference) in the pla-cebo/control group from the mean (or mean difference) in the treatmentgroup, and dividing that quantity by the pooled standard deviation (Ef-fect size = [Mean Treatment – Mean Placebo]/SDp).
Absolute Risk Reduction
This describes the difference between the percent of people in the control/placebo group experiencing a specific outcome (control eventrate), and the percent of people in the experimental/therapy group expe-riencing that same outcome (experimental event rate). Mathematically,Absolute risk reduction (ARR) equals experimental event rate minuscontrol event rate. ARR is better able to discriminate between large andsmall treatment effects than relative risk reduction (RRR), a calculationthat is often cited in studies ([control event rate – experimental eventrate]/control event rate). Many studies do not include adequate data tocalculate the ARR, in which cases “NA” is entered into this column.
Number Needed to Treat
This is the number of patients who would need to use the therapy un- der investigation, for the period of time described in the study, in order for one person to experience the specified benefit. It is calculated by di-viding the Absolute Risk Reduction into 1 (1/ARR).
Comments
When appropriate, this brief section may comment on design flaws (inadequately described subjects, lack of blinding, brief follow-up, notintention-to treat, etc.), notable study design elements (crossover, etc.),dosing, and/or specifics of study group/sub-groups (age, gender, etc).
More detailed description of studies is found in the “Evidence Discus-sion” section that follows the “Evidence Table” in Natural Standardreviews.
EVIDENCE DISCUSSION
Summary: Anticholinergic medications have been used for years in the treatment of irritable bowel syndrome. Patients with this disorderare thought to have abnormal colonic motility, and their symptoms maybe replicated with a cholinergic agonist. Although the mechanism of ac-tion provides a compelling case for the use of belladonna, there haveonly been limited controlled trials of belladonna in combination withphenobarbital in heterogeneous samples, and one study showing a trendtoward improved symptoms in patients treated with the belladonna con-stituent hyoscine (scopolamine). Therefore, there is currently insuffi-cient evidence to recommend belladonna as a monotherapy for thetreatment of irritable bowel syndrome.
Evidence: An early (1959) contribution to the literature was a 15- month double-blind trial of 75 patients with “irritable colon,” treated
with Belladenal® spacetabs (0.25 mg levorotatory alkaloids of bella-
donna plus 50 mg phenobarbital), placebo, or both (18). The percentage
of patients that improved was 70% with Belladenal® treatment, com-
pared to a 24% placebo response. The study provides limited detail, and
methods, outcome measurement techniques, and statistical analysis
were not adequately described.
A 1966 double-blind, crossover trial of 140 patients with gastrointestinal spasm compared Donnatal® tablets (belladonna [0.1037 mg hyoscyamine
sulfate, 0.0194 mg atropine sulfate, 0.0065 mg hyoscine hydrobromide]
plus 16.2mg phenobarbital) with Valpin® (anisotropine, with or without
phenobarbital).17 Baseline diagnoses of subjects were heterogeneous,
including spastic colon and peptic ulcer disease. The authors reported
“excellent” or “good” results in 96% of subjects treated with
anisotropine with phenobarbital, 86% of subjects treated with anisotropine
alone, and 70% of subjects treated with belladonna plus phenobarbi-
tal. However, inconsistent results were noted depending on the order
of crossover, suggesting a possible lack of adequate washout period.
In addition, greater variability was observed in the results for bella-
donna than for the other medications. This study was poorly designed
and reported, and evaluated outcomes subjectively. It is therefore of
limited clinical value.
In a randomized, double-blind trial, Rhodes et al., compared five dif- ferent sedative-anticholinergic medications with placebo in 22 patientswith irritable bowel syndrome.20 Treatments were administered seri-ally, and effects were measured via a patient questionnaire. Each treat-ment was given four times daily for one month. The dose of belladonnaadministered was 8 mg, combined with 30 mg phenobarbital. Thesymptom index questionnaire revealed no significant effect of any ofthe treatments vs. placebo. However, a significant number of patients(7/15) “preferred” the belladonna/phenobarbital combination to theother treatments. This study was limited by a small sample size, lack ofuse of a validated outcomes measure, inadequate descriptions of blind-ing, randomization, or statistical analysis, and a high dropout rate(27%).
The effects of hyoscine butylbromide 10 mg four times a daily, lorazepam, and ispaghula husk were studied in a sample of 96 patientswith irritable bowel syndrome.19 Eight groups of 12 patients were ran-domized to all possible combinations of these three therapies and pla-cebo. Each therapy demonstrated a trend towards improved symptomsover the three-month trial, although results were only significant forispaghula husk. Methods and statistical analysis were not well de-scribed.
Prevention of Airway Obstruction
Summary: Anticholinergic agents such as belladonna cause relax- ation of smooth muscles of the airway and a reduction in production ofmucus. Although the known mechanism of belladonna is compellingfor this use, there is only limited human research in this area. One study looking at treatment of airway obstruction during sleep in infants dem-onstrated a beneficial effect of belladonna. However, due to a lack ofother controlled trials, there is currently insufficient evidence to recom-mend belladonna for the prevention of airway obstruction.
Evidence: Kahn et al., studied obstructed breathing in the sleep of 20 infants (average age 12-weeks-old) with a history of breath-holdingspells.12 This randomized, double-blind, crossover trial lasted for 14days, with each infant spending one night undergoing polysomnographywith each treatment (placebo or belladonna). Tincture of belladonnawas administered in a dose equivalent to 0.01 mg/kg weight of atropineat bedtime. The authors reported a significant reduction in obstructedbreathing events, with response noted in 50% (10/20) of infants receiv-ing belladonna and in 20% (4/20) of infants in the placebo group. Dif-ferences between groups were statistically significant. No significantadverse effects were observed, although decreased “water evaporationrates” were noted in the belladonna-treated patients. It is unclear if a his-tory of breath-holding spells correlates clearly with physiological air-way obstruction. The authors recognized that belladonna overdose ininfants and children can be deadly, and that the long-term effects of bel-ladonna treatment are unknown. In addition, tinctures contain ethanol,which may have elicited effects in subjects.
Autonomic Nervous System Disturbances
Summary: Literature review reveals limited evidence regarding the use of belladonna for treatment of symptoms associated with autonomicnervous system dysfunction. Therefore, there is currently insufficientevidence to support the use of belladonna for symptoms of autonomicnervous system dysfunction.
Evidence: In a 1970 trial, Dobrescu compared two different combina- tion formulas, each taken three times daily by patients with disturbancesof the autonomic nervous system:21 “Formula I” contained a low con-centration of belladonna (0.25 mg belladonna, 0.3 mg alkaloids of er-got, 30 mg phenobarbital) and “Formula II” contained a higherconcentration of belladonna (15 mg belladonna extract, 60 mg ergot ex-tract, 15 mg propranolol, 25 mg amobarbital). A total of 36 subjectswere enrolled in this single-blind, crossover trial and received treatmentfor one week, followed by crossover to the alternate therapy for oneweek. “Very good” results were noted in 72% of subjects receiving For-mula II (higher belladonna concentration), compared with 36% treatedwith Formula I. Limitations of this study include the small sample size, lack of adequate randomization, use of subjective outcome measures,and failure to report the dropout rate. In addition, due to multiple varia-tions between the two formulas, it is not clear which constituent(s)might be responsible for the differing effects.
A single-blind placebo controlled study was conducted to investigate the cardiorespiratory effects of belladonna, as a surrogate measure ofvagal activity.51 Single doses of an oral belladonna tincture containing0.1 mg/mL alkaloid concentration were administered, with a proportionof atropine to scopolamine of 20:1. In eight healthy young subjects,heart rate and noninvasive arterial finger blood pressure were recordedfor 4 hours following oral application of 1 mL, 2 mL, or 5 mL of thisbelladonna tincture, or placebo. The authors reported that 1 hour afteradministration of 5 mL, mean respiratory rate, heart rate, and baroreflexsensitivity decreased significantly in six of eight subjects. In contrast,following administration of 1-2 mL, mean respiratory rate and heart rateincreased compared to placebo.
Headache
Summary: Studies comparing belladonna-containing compounds with placebo have been small and have reported limited or no benefits. How-ever, this research has been poor-quality and has examined combinationproducts containing other agents such as ergotamine or phenobarbital(which may be efficacious in the absence of belladonna), or used ho-meopathic (dilute) belladonna preparations. There is currently insuffi-cient evidence to support the use of belladonna for the treatment orprophylaxis of headache.
Evidence: A study conducted by Stieg compared a combination formula belladonna-ergotamine-phenobarbital (BEP) to placebo in a
randomized crossover and parallel group design trial.16 BEP is equivalent
to the commercially available product Bellergal-S®, which contains 40
mg phenobarbital, 0.6 mg ergotamine tartrate, and 0.2 mg levorotatory
alkaloids of belladonna. The trial enrolled 76 patients with recurrent
throbbing headaches at least once a week. No other prophylactic head-
ache medication was allowed, but the use of medications for symptom-
atic relief was allowed during the study period. BEP or placebo was
administered twice daily to subjects during the trial. The authors re-
ported that over a four-week period, there was no difference in drug ef-
fectiveness or headache severity between groups. A modest significant
decrease in headache severity and increase in days without headache
medication was noted in a crossover sub-study. Problems with this trial
include the use of subjective measures of effect, small sample size and28% dropout with no intention-to-treat analysis, and lack of descriptionof randomization.
In a poorly described 1965 study by Lance et al., Bellergal® was compared to methysergide, cyproheptadine, and placebo in thetreatment of 110 subjects with migraine headache.14 Compared withplacebo, Bellergal® was reported to elicit no significant effect. No ran-domization or blinding was described, no dropout rate was reported,and the methods of the study were not described.
Whitmarsh et al., conducted a randomized, placebo controlled study in 63 outpatients with migraine headache diagnosed by InternationalHeadache Society criteria.10 Subjects received either a belladonna- con-taining homeopathic remedy or placebo for 4 months. No significantdifferences were detected between groups, and overall, headache fre-quency was 19% in the homeopathy group, and 16% with placebo. Thesample size may have been too small to detect significant between-group differences, and the groups were dissimilar at baseline.
A 1965 placebo controlled trial compared methysergide, cyproheptadine, Bellergal® (40 mg phenobarbital). Uncontrolled studies have been re-
ported, reporting small benefits from belladonna-containing compounds.
Steele et al., reported a 1954 case series in which administration of
Bellergal® for headache yielded “satisfactory results” in 73.3% of pa-
tients.15
Otitis Media
Summary: There is currently insufficient evidence to support the use of belladonna for the treatment of otitis media.
Evidence: A German homeopath and four otolaryngologists per- formed an observational study comparing homeopathic with conven-tional treatment for children with otitis media.28 The homeopathicpractitioner chose from among 12 remedies for otitis, including bella-donna 30X globules (brand not specified). The homeopathic treatmentgroup was reported to experience significantly fewer recurrences ofotitis (29.3% vs. 43.5%), a shorter treatment duration, and a shorter du-ration of symptoms than the otolaryngologist-treated group (which re-ceived antibiotics). However, the frequency with which belladonna wasused from among the 12 remedies was not specified, and there was norandomization or blinding in this trial (allowing for the possible intro-duction of bias or confounding). Therefore, although these results arecompelling, they cannot be considered conclusive.
Premenstrual Syndrome
Summary: Bellergal®, a combination formula containing 40 mg phenobarbital, 0.6 mg ergotamine tartrate, and 0.2 mg levorotatoryalkaloids of belladonna, has been reported in one controlled humantrial to decrease symptoms associated with premenstrual syn-drome, including fatigue, breast tenderness, and irritability. Fur-ther study is warranted before an evidence-based recommendationcan be made.
Evidence: Robinson et al., performed a randomized, double-blind, placebo controlled trial in 32 patients experiencing symptoms associ-
ated with premenstrual syndrome.22 Patients were administered oral
Bellergal® or placebo three times daily, beginning 10 days prior to men-
ses. The primary outcome assessed was presence of any of nine “typical
symptoms” of premenstrual syndrome over three menstrual cycles. The
authors reported significantly less fatigue, breast tenderness, and leth-
argy in the treatment group vs. placebo. Although these results are sug-
gestive, limitations of this study included its short duration, small
sample size, 23% dropout, and unclear reporting of results or statistical
analysis. The use of a combination formula leaves open the question of
belladonna’s efficacy.
Radiodermatitis
Summary: Homeopathic application of belladonna for the man- agement of radiodermatitis has been proposed based on the ob-served similarities between symptoms of radiodermatitis and theeffects of belladonna (based on the dictum that “like cures like”). Onerandomized trial has reported modest benefits of a homeopathic (di-lute) oral belladonna preparation for this indication, although there isno known biochemical basis for this use. There is currently insuffi-cient evidence to support the use of belladonna for the management ofradiodermatitis.
Evidence: A randomized, double-blind, placebo controlled trial was conducted in 66 patients undergoing radiation therapy following sur-gery for breast cancer.11 Subjects were assigned to receive either the ho-meopathic dilution Belladonna 7CH (3 granules sublingually twicedaily), the homeopathic preparation X-ray 15CH (3 granules sublinguallyonce daily), or placebo. The authors reported that after 8 weeks, therewas a small significant improvement measured by a subjective index ofseverity in the two treated groups vs. placebo. This study was properly randomized and blinded, although dosing regimens varied by therapy,which may have revealed group assignments. The study was limited bythe use of a non-standard outcomes measurement scale. Further studymay be warranted in this area.
Menopausal Symptoms
Summary: Bellergal®, a combination formula containing 40 mg phe- nobarbital, 0.6 mg ergotamine tartrate, and 0.2 mg levorotatory alka-loids of belladonna, has been used historically and reported anecdotallyto reduce the incidence of hot flashes. One randomized control trial hasreported negative results. There is currently insufficient evidence to rec-ommend for or against the use of belladonna for the alleviation of meno-pausal symptoms.
Evidence: Bergmans et al., conducted a randomized, double-blind, placebo controlled trial in 71 patients experiencing menopausal symp-toms.23 After 8 weeks of follow-up, no benefit of Bellergal® was ob-served vs. placebo. Notably, a trend towards improved symptoms wasseen at 2-4 weeks. These results cannot be considered conclusive due tolimitations, including a 46% dropout rate.
PRODUCTS STUDIED
Brands Used in Statistically Significant Clinical Trials
Bellergal® (40 mg phenobarbital, 0.6 mg ergotamine tartrate, and 0.2 mg levorotatory alkaloids of belladonna).14-16 Also available: Bellergal-R®,Bellergal-S®.
International Brand Names
Astrobel®, Belladonnysat Burger®, Bellafolin®, Bellafolina®, Bellanorm®,
Tremoforat®.
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