Effect of Ultra-diluted Medicines in Depression and Anxiety:

A Narrative Review

 

Nandini Prashanth Bhat¹, Pugazhandhi Bakthavatchalam², Hareesh Krishnan³, Ashwija Shetty¹,

Prasanna Lokadolalu Chandracharya¹*

¹Department of Anatomy, Kasturba Medical College Manipal,

Manipal Academy of Higher Education, Karnataka, India.

²Department of Anatomy, Melaka Manipal Medical College (Manipal Campus),

Manipal Academy of Higher Education, Karnataka, India.

³Medical Officer [Homoeopathy], Govt Homoeo Dispensary, Melur - PO, Kannur.

 

ABSTRACT:

Background: Generalized anxiety disorder (GAD) and depression are the common mental health diseases affecting millions of people globally. The conventional treatment with medications causes a lot of adverse effects leading patients to seek relief from alternative systems of medicine. The alternative mode of treatment, Homeopathy, uses ultra-diluted drugs to treat GAD and Depression. Objective: This review is to narrate and assess the effectiveness of homeopathy in anxiety and depressive disorders. Also, the related animal studies and in-vitro studies have been evaluated. Methods: The search used combinations of Medical Subject Heading terms ultra-diluted, anxiety, and depression. Lists of articles under references were reviewed to identify additional studies. Results: Studies suggest that ultra diluted, dynamised medicines are used by homeopathic practitioners to treat anxiety and depression. Homeopathic physicians prescribe individualized drugs after a detailed case taking. These have a favorable effect on the patients compared to control and also to conventional medicines. In- vivo studies show encouraging results as ultra- diluted drugs act as anxiolytics without altering the motor abilities of the animal models. In-vitro studies are lacking to reach a decisive inference. Conclusion: Although there are enough preliminary studies establishing proof of the effect of homeopathy in mental health ailments, further exploration is essential and ought to embrace well premeditated controlled studies with sufficient sums of participants.

 

 

 

INTRODUCTION:

National survey on Drug use and Health data from 2015 from the US reveal that mental disorders are 17.9% prevalent among the general population. The incidence of mood disorder and anxiety disorder is 20.8% and 28.8%, respectively.¹ Anxiety disorders decrease in frequency as age advances and it follows a prolonged course at a younger age.^2,3 The current global prevalence of anxiety disorders across 44 countries is 7.3%.⁴ Patients with comorbid anxiety disorders and depression occur in more than 50% of patients in primary health care.⁵

 

Most of the depression patients have significant secondary anxiety disorders and vice versa. Both these ailments require appropriate treatment.⁶ Below, par treated mental disorders end in increased burden to the society concerning lost working hours and high utilization of the primary healthcare system.⁷

 

Conventional treatment for mental disorders include first and foremost psychotherapy followed by medications such as benzodiazepines⁸ and selective serotonin reuptake inhibitors. Its adverse effects and also the risk of abuse limits the use of these drugs.^9,10,11

 

 Complementary and alternative systems are often used to treat mental disorders.^12,13,14 Homeopathy users report high levels of perceived helpfulness, mainly when they see a practitioner for therapy. Homeopathy is an alternative system used by individuals for the treatment of chronic disease.^15,16 The characteristics of individuals using the homeopathic treatment for psychiatric patients was studied in a sample of 36,785 persons with mental problems, 1.3% of patients used homeopathic treatment mainly to reduce anxiety.¹⁷

 

Samuel Hahnemann, a German physician in the late 18^th Century, founded Homeopathy, and it is based on the idea of 'let like be cured by like.¹⁸ Homeopathy uses ultra-diluted and potentized medicines for the treatment of patients.¹⁹ Survey shows that every year a slight but noteworthy increase is seen among the population that uses homeopathic medication.²⁰ The ultra-diluted doses of substances are dynamized to arouse the regulatory and self-curing properties of an individual. The drug selection is based on symptom similarity by corresponding a patient's symptoms with symptoms produced by the drug in healthy persons.²¹ Medications prepared thus claim to imprint the information of parent substance into the water.²² Ultradiluted medicines are prepared in centesimal (C) potency. It is produced first by diluting a drop of parent substance in 99 drops of alcohol and agitating the solution to make 1C potency.  This is repeated consecutively to produce higher dilutions. The higher the potency, the greater is the dilution. 30C or 200C used by homeopaths are 30 or 200 consecutive dilutions followed by the agitation of the solution.^23,24 This review aims to analyze the clinical, in-vivo, and in-vitro studies, which include ultra-diluted medicines as a mode of treatment for anxiety and depression.

 

RESULTS AND DISCUSSION:

A randomized control study was conducted on patients with depression or anxiety for one year by homeopaths. The trial was on patients who presented with self-described mental symptoms. One-third of the cases were selected randomly and provided individualized homeopathic treatment.  After six months of follow up, the outcome was assessed by the Patient Health Questionnaire, and after 12 months depression scores and GAD outcome was evaluated. A moderately favorable rating was shown in treated cases as compared to others. No adverse effects were seen with the intervention of the homeopathic treatment.²⁵ This study provides support to ultra-diluted homeopathic drugs as a treatment option for depression and anxiety disorders.

 

In another study, ultra-diluted homeopathic remedies that were individually selected were used on patients with depression, phobia, or panic disorder. The review was on twelve adults for 1.5 years who opted homeopathy treatment or were advised by the physician due to inadequate or adverse effects of standard conventional therapies. They were assessed with a global clinical scale and a brief social phobia scale. Responses showed homeopathy to be beneficial in the management of depressive and anxiety disorders in cases with mild to severe symptoms.²⁶ This study used a small sample size, and there is no comparison with control or other conventional treatment. It is a significant preliminary study.

 

A similar survey was done on ten male male and twenty female patients having complaints of anxiety and depression. The average patients age was 45 years.  The patients were randomly divided into interventional and control groups. A methodology of the pretest, follow up, and post-test was designed and adhered to.  The cases were assessed based on the Beck Depression Inventory (BDI) and the Spielberger State-Trait Anxiety Inventory (STAI)-Y. Differences were noted between the groups which were statistically significant. It was concluded that individualized homeopathic therapy is effective in treating anxiety and depression disorders.²⁷ This is a randomized control study with small sample size. However, an appropriate assessment scale and protocol were followed, making it a relevant preliminary study. 

 

An epidemiological cohort study was done in France on patients with anxiety. It was a comparative study between psychotropic and individualized ultra-diluted homeopathic drugs. The patients were measured by means of the Hospital Anxiety and Depression Scale (HADS). The improvement was observed more in the homeopathic set compared to the conventional set. Correspondingly the patients reported decreased use of psychotropic drugs.²⁸

 

A double-blind, randomized trial survey was conducted on 61 patients to understand the effects of two homeopathic compositions, Homéogène 46 and Sédatif PC, in place of Benzodiazepine in patients for three months.²⁹ This study reports that no change was seen between the placebo and Homeopathic compositions. The reason for this may be as it was not individualized homeopathic treatment; no difference was observed between groups. It may be concluded that the homeopathic ultra-diluted drugs are valid only when individualized and not as combinations.

 

In a study involving menopausal related emotional disturbance, Ignatia Amara containing complex homeopathic remedy showed good results. Improvement in the majority of women in psychological and psychosomatic symptoms was observed. Compared to conventional treatment, homeopathy was tolerated better. Although the authors conclude, its results were similar to the placebo.³⁰ Further studies with a larger sample size can be conducted for the same.

A randomized double-blinded study was conducted on 44 patients with GAD. The trial was for ten weeks period; individualized ultra-diluted homeopathic medicine was administered to half the patients, and the other half were in the placebo group. Hamilton Rating Scale for Anxiety (HAM-A) was used as the chief result outcome. Substantial progress was seen in both groups after the trial period. It was concluded that the homeopathic treatment was no better than placebo.³¹

 

A study was done by Van den Meerschaut et. al to compare the effects of Nervoheel, a homeopathic combination drug with those of Benzodiazepine. It was a non-randomized cohort study conducted on 248 patients over four weeks. Patients with complaints of anxieties and similar nervous conditions were treated with lorazepam or Nervoheel N and evaluated through follow up after two and four weeks. Both the groups conveyed significant improvements, and interventions were well tolerated. It was concluded that for short term relief of nervous ailments, the efficacy of homeopathic preparation is similar to Benzodiazepine.³² Although a relevant study for short term relief, the groups were not randomized, and assessment of outcome measure was not on a standard scale, and there was no comparison with placebo.

 

Table 1:  Summary of Clinical studies

 

 

 

Homeopathy as an anxiolytic in animal models:

Experimental animal models are suitable and advantageous to study the basis of mental disorders and to develop improved, efficient pharmacological treatment modules. These models provide details on the brain and behavioral mechanisms that are involved in the physiology of psychiatric disorders.^33,34,35

 

A blind randomized study was done on laboratory emotional response CD1 mice models to evaluate the efficacy of ultra diluted Gelsemium sempervirens compared to diazepam and placebo. Fourteen separate replications were conducted, and pooled analysis was assessed. The outcome measures were evaluated using behavioral tests such as open field (OF) test and the light-dark (LD) test. Results demonstrated noteworthy effects of Gelsemium s. on the OF parameter "time spent in the central area" and on the LD parameters "time spent in the lit area" and "number of light-dark transitions," lacking any tranquilizing action or antagonistic effects on motion. This endorses and strengthens the proof that Gelsemium s. 5C, 9C, and 30C adjusts emotive reactions and performance of experimental models of mice in a nonlinear fashion with dilution.³⁶

 

Ultradiluted Pulsatilla nigricans has been evaluated as an anxiolytic on swiss albino mice. It was compared with control and conventional Benzodiazepine drug diazepam. Four groups of six animals each, control received ethyl alcohol, the standard group received diazepam, and the two test groups received Pulsatilla 3x and 6x respectively for two weeks. The efficacy was tested using the Elevated Plus Maze (EPM) and OF Test on 1^st day and then every week. The Diazepam group and Puls group showed similar results; the effect is higher for the 3x compared to the 6x ultra dilution of Pulsatilla. It was concluded that Pulsatilla had similar anxiolytic effects as compared to the standard drug diazepam.³⁷

 

A similar study was conducted to appraise the anxiolytic property of Argentum Nitricum 30C, comparing it with escitalopram. Animals were divided into three groups and administered distilled water (control),  Argentum nitricum 30C (test), and escitalopram (standard drug). They were analyzed for anxiolytic activity on the 30^th and 60^th day using several behavioral tests such as LD test, OF test, head dip test, and home cage activity. There was a significant decrease in head dips and cage crossing; also, the time explored in the light compartment was increased related to control after the 60^th day. The researchers concluded that Argentum nitricum 30C had anxiolytic properties.³⁸

 

Ultradiluted Aconite napellus was assessed for anxiolytic action. 48 Wistar rats were randomly divided into six groups of which control was given diazepam, a negative control was given saline solution, and the treatment groups were given Aconite 6C, 12C, 30C. Behavioral parameters were randomly and blindly evaluated in an EPM and OF test. Aconite in ultra-dilutions of 12C and 30C displayed potential anxiolytic properties since they increased the number of entries in the open arms of EPM. Aconite did not demonstrate any adverse effects on the motor system of the rats. The study concluded that ultra-dilutions 12C and 30C of Aconite demonstrated anxiolytic effects on the Central nervous system in an experimental animal model.³⁹

 

Table 2: Summary of Animal studies

 

 

Homeopathy drug studies with cell culture models:

Brain serotonergic and GABAergic inhibitory neurons play a critical role in modulating anxiety disorders.⁴⁰ A study demonstrates that receptors of serotonin are involved in the modulation of anxiety-related behaviors and propose that a decline in serotonin receptor concentration due to stressors may result in intensified anxiety.⁴¹

 

The primary inhibitory neurotransmitter is Gamma-aminobutyric acid (GABA) that is identified to compensate and counterbalance the action of glutamate, which is an excitatory neurotransmitter.⁴² Antianxiety drugs target the receptors on the GABAergic neurons to modulate the levels of GABA.^43,44,45 It was shown that GABA_B receptor-deficient mice exhibited more anxiety compared to their wild-type counterparts as evaluated by multiple anxiety-related tests.⁴⁶ Benzodiazepines, an anxiolytic, achieves its pharmacological actions by specifically augmenting the effects of GABA, which are facilitated by GABA_A receptors.⁴⁷

 

Gelsemium is a homeopathic medicine mainly used as an anxiolytic. In a study, human neuroblastoma cells (Human SH-SY5Y) were exposed to serial dilutions of 2c, 3c, 4c, 5c, 9c, and 30c of Gelsemium sempervirens. By microarray, the transcriptome was compared for cells treated with control and vehicle solutions. It was found that Gelsemium 2C down-regulated 49 genes and up-regulated seven genes. Hence Gelsemium changed the expression of 56 genes. The effects were present even in higher dilutions, although the difference was in a small range. It concludes that human neurocyte is sensitive to high dilutions of Gelsemium.⁴⁸ In this study, the level of neurotransmitters was not assessed; hence it is not clear as to the action of Gelsemium in the modulation of anxiety-related neurons. The literature is lacking homeopathic in-vitro studies on Gabaergic and serotonergic neurons, which are the critical interneurons regulating mood disorders.

 

CONCLUSION:

Homeopathic treatment has a considerable prospect in the preclinical investigation of curative, physiological, and pharmacological effects of ultra-diluted medications. A suitable mechanism of action can be outlined with the help of current molecular methods of in-vivo and in-vitro trials. There are few articles in the literature which support the use of homeopathy in anxiety and depressive disorders. But these are not sufficient to come to a conclusive verdict on the effectiveness of homeopathy. More randomized control trials with structured experimental design and invitro design models are required to explore the biological activity of the homeopathic preparations.

 

REFERENCES.

1.   https://www.samhsa.gov/data/sites/default/files/NSDUH-DetTabs-2015/NSDUH-DetTabs-2015/NSDUH-DetTabs-2015.pdf

2.   Bandelow B and Michaelis S. Epidemiology of Anxiety Disorders in the 21st Century. Dialogues in Clinical Neuroscience. 2015;17 327-335.

3.   Raju V, Bell JJ, Merlin. NJ et.al Anxiety Disorders – A Review. Asian Journal of Pharmacology and Research. 2017; 7(4): 217-221.doi: 10.5958/2231-5691.2017.00033.8

4.   Baxter A, Scott K, Vos T et.al. Global Prevalence of Anxiety Disorders: A Systematic Review and Meta-regression. Psychological Medicine. 2012; 43: 897-910.

5.   Hirschfeld RM. The Comorbidity of Major Depression and Anxiety Disorders: Recognition and Management in Primary Care. Primary Care Companion to the Journal of Clinical Psychiatry. 2001;3(6):244‐254. doi:10.4088/pcc.v03n0609

6.   American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, fifth edition, American psychiatric publishing.

7.   Kessler RC, Aguilar-Gaxiola S, Alonso J, et al. The global burden of mental disorders: an update from the WHO World Mental Health (WMH) surveys. Epidemiologia e Psichiatria Sociale. 2009;18(1):23‐33. doi:10.1017/s1121189x00001421.

8.   Mahadik PS, Senthilkumar GP, Powar AS, et.al. Chemical and Biological Properties of Benzodiazepines- An overview. Research Journal of Pharmacy and Technology. 2012;5(2):181-189.

9.   Patel MA, Patel CM, Patel DB, et.al. A Review on Novel Strategies for Pharmacotherapy of Depression. Research Journal of Pharmacology and Pharmacodynamics. 2010;2(2):153-159.

10. Tiller J. Depression and Anxiety. The Medical Journal of Australia. 2012; 1: 28-31.

11. Bhagat V, Symbak NB, Husain R, et.al. The role of selective serotonin reuptake inhibitors and cognitive behavioral therapy in preventing relapse of Major Depressive Disorder. Research Journal of Pharmacology and Technology 2019;12(8):3818-3824.

12. Locke A, Kirst N and Shultz C. Diagnosis and Management of Generalized Anxiety Disorder and Panic Disorder in Adults. American Family Physician. 2015; 91: 617-624.

13. Jackson C. Trends in the Use of Complementary Health Approaches Among Adults in the United States. Holistic Nursing Practice. 2015; 29(3): 178-179.

14. Aswathi T, Venkateswaramurthy N and Kumar SR. A Review on Relevance of Herbal Medications for Psychiatric Patients. Research Journal of Pharmacy and Technology. 2019; 12(7): 3151-3156. doi 10.5958/0974-360X.2019.00531.6

15. Dossett ML, Davis RB, Kaptchuk TJ et.al. Homeopathy Use by US Adults: Results of a National Survey. American Journal of Public Health. 2016; 106(4): 743–745. doi: 10.2105/AJPH.2015.303025

16. Balaji DP. ADHD for Children in Homeopathy and Alternative Methdos. Research Journal of Humanities and Social Sciences. 2017; 8(2): 205-209.

17. Grolleau A, Bégaud B and Verdoux H. Characteristics associated with use of homeopathic drugs for psychiatric symptoms in the general population European Psychiatry. 2013; 28(2): 110-6. doi: 10.1016/j.eurpsy.2011.10.005. Epub 2011 Dec

18. Fisher P. What is Homeopathy an Introduction. Frontiers in Bioscience. 2012; E4: 1669-1682. 

19. Brien S, Lewith G and Bryant T. Ultramolecular homeopathy has no observable clinical effects. A randomized, double-blind, placebo-controlled proving trial of Belladonna 30C [published correction appears in Br J Clin Pharmacol. 2004;57(1):117]. British Journal of Clinical Pharmacology. 2003; 56(5): 562–568. doi:10.1046/j.1365-2125.2003.01900.x

20. Relton C, Cooper K, Viksveen P et.al. Prevalence of homeopathy use by the general population worldwide: a systematic review. Homeopathy. 2017; 106(2):69-78. doi: 10.1016/j.homp.2017.03.002.

21. Kent JT. The Art and Science of Homeopathic Medicine. New York: Dover Publications; 2002

22. Jonas WB, Kaptchuk TJ and Linde K. A critical overview of homeopathy. Annals of Internal Medicine. 2003; 138(5): 393-9.

23. Betti L, Trebbi G, Olioso D, et.al. Basic research in homeopathy and ultra-high dilutions: what progress is being made? Homeopathy. 2013; 102(2):151-4. doi: 10.1016/j.homp.2013.01.002.

24. Almirantis Y and Tsitinidis K. Ultra-High Dilutions and Homeopathy: Can They Be Explained without Non-Local Theory? Homeopathy. 2018;107(3):189-195. doi: 10.1055/s-0038-1656513.

25. Viksveen P, Relton C and Nicholl J. Depressed patients treated by homeopaths: a randomised controlled trial using the “cohort multiple randomised controlled trial” (cmRCT) design. Trials. 2017;18(1). doi: 10.1186/s13063-017-2040-2

26. Davidson JR, Morrison RM, Shore J, et.al. Homeopathic treatment of depression and anxiety. Alternative Therapies in Health and Medicine. 1997; 3(1): 46-9.

27. Bagherian M, Mojembari AK and Hakami M. The Effects of Homeopathic Medicines on Reducing the Symptoms of Anxiety and Depression: Randomized, Double Blind and Placebo Controlled. Journal of Homeopathic and Ayurvedic Medicine. 2015; 03 (04). doi: 10.4172/2167-1206.1000167

28. Grimaldi-Bensouda L, Abenhaim L, Massol J, et. al. Homeopathic Medical Practice for Anxiety and Depression in Primary Care: The EPI3 Cohort Study. BMC Complementary and Alternative Medicine. 2016; 16: 1-9.

29. Cialdella P, Boissel JP, Belon P; Groupe de recherche ASTRHO. Spécialités homéopathiques en substitution de benzodiazépines: étude en double-insu vs. placebo [Homeopathic specialties as substitutes for benzodiazepines: double-blind vs. placebo study]. Therapie. 2001; 56(4): 397‐402.

30. Wasilewski BW. Homeopathic remedies as placebo alternatives--verification on the example of treatment of menopause-related vegetative and emotional disturbances. Science and Engineering Ethics. 2004;10(1):179‐188. doi:10.1007/s11948-004-0075-8

31. Bonne O, Shemer Y, Gorali Y, et.al. A randomized, double-blind, placebo-controlled study of classical homeopathy in generalized anxiety disorder. Journal of Clinical Psychiatry. 2003; 64(3): 282-7.

32. Van den Meerschaut L and Sünder A. The homeopathic preparation Nervoheel N can offer an alternative to lorazepam therapy for mild nervous disorders. Evidence Based Complementary and Alternative Medicine. 2009; 6(4): 507‐515. doi:10.1093/ecam/nem144

33. Hart P, Bergner C, Smolinsky A, et. al. Experimental Models of Anxiety for Drug Discovery and Brain Research. Methods in Molecular Biology. 2009;299-321. doi: 10.1007/978-1-60761-058-8_18

34. Ghaisas MM, Wadikar AD, Gulati TB, et.al. Anxiolytic Effect of a Methanolic Extract of the Embelia ribes Burm F. in Mice. Research Journal of Pharmacy and Technology. 2010; 3(4): 1136-1139.

35. Venkatesha G, Kalaiyarasia C and Ramanathana M. Antidepressant like Effect of Gabapentin Decreases the Immobility Time in Despair Animal Models in Mice: Roll of Serotonergic System in it. Research Journal of Pharmacy and Technology. 2011; 4(11): 1702-1706.

36. Bellavite P, Conforti A, Marzotto M, et. al. Testing Homeopathy in Mouse Emotional Response Models: Pooled Data Analysis of Two Series of Studies. Evidence-Based Complementary and Alternative Medicine. 2012; 2012: 1-9.

37. Prabhu R, Ruckmani A, Venkatesan D, et.al. Anxiolytic Effect of Homeopathic Preparation of Pulsatilla Nigricans in Swiss Albino Mice. Homeopathy. 2012; 101: 171-174.

38. Anser H, Najam R, Khatoon H, et.al. Evaluation of Anxiolytic Activity of Homeopathic Remedy Argentum Nitricum of 30 C Potency after Chronic Administration in Rodents. International Journal of Pharmaceutical Sciences and Research. 2018; 9: 3908-3913.

39. Haine, GB, Ghandour SH, Ghandour SA, et.al. Assessment of homeopathic medicine Aconitum napellus in the treatment of anxiety in an animal model. International Journal of High Dilution Research. 2012; 11(38): 33-42

40. Soliman MA, Aboharb F, Zeltner N, et.al. Pluripotent stem cells in neuropsychiatric disorders. Molecular Psychiatry. 2017; 22: 1241-1249.

41. Ramboz S, Oosting R, Amara DA, et.al. Serotonin receptor 1A knockout: An animal model of anxiety-related disorder. Proceedings of the National Academy of Sciences. 1998;95(24):14476-14481. doi:10.1073/pnas.95.24.14476

42. Rey AA, Purrio M, Viveros M et.al. Biphasic Effects of Cannabinoids in Anxiety Responses: CB1 and GABAB Receptors in the Balance of GABAergic and Glutamatergic Neurotransmission. Neuropsychopharmacology. 2012; 37(12):2624-2634. doi:10.1038/npp.2012.123

43. Lydiard RB. The role of GABA in Anxiety Disorders. The Journal of Clinical Psychiatry. 2003;64: 21-27.

44. Kita A, Kohayakawa H, Kinoshita T, et.al. Antianxiety and antidepressant-like effects of AC-5216, a novel mitochondrial benzodiazepine receptor ligand. British Journal of Pharmacology. 2004;142(7): 1059-1072. doi:10.1038/sj.bjp.0705681

45. Khose RD, Jaydeokar AV, Patil US, et.al. Receptor Pharmacology of GABA: A Review. Research J. Pharm. and Tech. 2012; 5(6): 721-728.

46. Heldt SA, Mou L and Ressler KJ. In vivo knockdown of GAD67 in the amygdala disrupts fear extinction and the anxiolytic-like effect of diazepam in mice. Translational Psychiatry. 2012; 2(11). doi:10.1038/tp.2012.101

47. Tan KR, Rudolph U, and Lüscher C. Hooked on benzodiazepines: GABAA receptor subtypes and addiction. Trends in Neurosciences. 2011;34(4): 188–197. doi: 10.1016/j.tins.2011.01.004

48. Marzotto M, Olioso D, Brizzi M, et.al. Extreme Sensitivity of Gene Expression in Human SH-SY5Y Neurocytes to Ultra-low doses of Gelsemium Sempervirens. BMC Complementary and Alternative Medicine. 2014; 14: 1-9.

 

 

Received on 16.07.2020           Modified on 20.09.2020

Accepted on 23.10.2020         © RJPT All right reserved