ANTA The Natural Therapist Spring 2021

The

Natural

Therapist

EDITION 36 NO. 3 | SPRING 2021

ISSN 1031 6965

Spring 2021

The Official Journal of THE AUSTRALIAN NATURAL THERAPISTS ASSOCIATION

WWW.ANTA.COM.AU

Energy & Stress Multi’s Which multi supports your patient best...

PARA TONE?

Synergistic Formula

Evidence Based

Supports / Maintains Healthy stress response Indigestion & digestive weakness Energy production Healthy immune function Healthy thyroid function Focus & clarity

Always read the label Practitioner Dispensing Only

OR

SYM BALANCE?

Minimal Exipients

Australian Made & Owned

Supports / Maintains Calms excess nervous energy Healthy stress response Disturbed sleep Neuromuscular function Liver function Healthy heart & immune function Always read the label Practitioner Dispensing Only

NUTRITIONAL THERAPY 3BIOACTIVE 3BIOAVAILABLE 3QUALITY INGREDIENTS Call 02 9693 2888 Email info@interclinical.com.au Visit www.interclinical.com.au

TARGETING OPTIMAL HEALTH

Contents Edition 36 No. 3

|

Spring 2021

ANTA News

From the Chair 4

6 ANTA News 7 Round 1 Graduate Award Winners 2021

Executive Officer Report

9

15

Is Withania somnifera an effective therapeutic in the treatment of post-traumatic stress disorder?

ANTA Member, Miriam Cullen, explores

In menopausal females, is supplementation with Vitamin E effective in reducing the frequency and severity of hot flashes?

withania somnifera and its effectiveness in the

Bronwyn Campbell, ANTA Student Member,

treatement of Post-Traumatic Stress Disorder.

reviews the literature around Vitamin E and its effectiveness in menopausal females.

24

Effects of Fucoidans in Immune System Activity During Viral Infections George Thouas provides an overview of selected evidence to support the therapeutic potential of ficoidans in viral infections.

32

45

Common Sources of Error in Clinical Trial Literature - Part 2: Statistical and Other Issues in Clinical Research

Efficacy of N-acetylcysteine as an adjunctive therapy in improving the clinical outcomes of obsessivecompulsive disorder in adult patients

In this series, Tony Reid explains the common sources of error in clinical trial literature.

ANTA Member, Shiki Coppola, explores the literature around n-acetylcysteine as an effective therapeutic to help obsessivecompulsive disorder.

The

Natural Therapist

The Natural Therapist is published by the Australian Natural Therapists Association (ANTA) for natural therapy practitioners. The opinions and views expressed by the contributors and advertisers are not necessarily the opinions and views of ANTA. Every effort is taken to ensure accuracy and ANTA accepts no responsibility for omissions, errors or inaccuracies. ANTA relies on contributors and advertisers to make sure material provided for The Natural Therapist complies with the Australian Consumer Law under the Competition and Consumer Act 2010. ANTA accepts no responsibility for breaches of the Australian Consumer Law by contributors or advertisers.

Material in The Natural Therapist is subject to copyright and may not be reproduced in any form without the permission of ANTA and its contributors.

EDITION 36 NUMBER 3 – SPRING 2021

ISSN 1031 6965

ANTA BRANCH CHAIRPERSONS Warren Maginn • National Vice-President • Director of ANTA • National Nutrition Branch Chair • TGA Chair • Ethics Panel Chair • ANTAB Committee Member • ANRANT Committee Member Shaun Brewster • National Treasurer • Director of ANTA • National Myotherapy Branch Chair • ANTAB Chair • ANRANT Committee Member • Health Fund Chair Ananda Mahony • Director of ANTA • National Naturopathy Branch Chair Kaitlin Edin • Director of ANTA • National Acupuncture Branch Chair • ANTAB Committee Member • ANRANT Committee Member

Isaac Enbom • Director of ANTA • National Remedial Therapy Branch Chair • ANTAB Committee Member • ANRANT Committee Member Mark Shoring • Director of ANTA • National Multi-Modality Branch Chair • ANTAB Committee Member • ANRANT Committee Member Tino D’Angelo • Director of ANTA • National Chinese Herbal Medicine Branch Chair Tony Reid • Traditional Chinese Medicine Industry Advisor Jim Olds • Executive Officer • Company Secretary • Business Plan Chair • ANRANT Chair

The

Natural Therapist

Marketing & Production Tasha Kemsley Circulation Enquiries 1800 817 577

Editorial & Advertising Enquiries thenaturaltherapist@anta.com.au Membership Enquiries info@anta.com.au

ANTA NATIONAL ADMINISTRATION OFFICE T: 1800 817 577 | F: (07) 5409 8200 E: info@anta.com.au P: PO BOX 657 MAROOCHYDORE QLD 4558 W: www.anta.com.au

ANTA Executive Welcome Spring 2021

From the Chair At ANTA we are all well aware our Members have been facing challenges of an unforseen magnitude, duration and risk we could never have imagined.

We are equally aware the affect the Pandemic has had on your business, education, professional and personal lives. We feel as though we have tried to the best of our ability to ease your burden whether it be mental, physical, financial, or personal.

I will not try to convince you of our efforts, it suffices to say we are with you and will remain so throughout the next episodes, whatever they may bring. To endure this blight, we have collaborated with four other major associations to understand how we can present a uniform set of directions to you, our Members and your colleagues, each time the circumstances change. We do this to ensure you are not exposed to breaches or fines for unwitting actions or therapies at risk.

We have provided services and support along with concessions for those most effected by changing circumstances in your regions. This will continue while we look to the present circumstances and challenges you endure, while we are planning to support and assist with your business location and activity exposure. We want you to be discoverable when you are available and able to continue your practices again.

ANTA’s investement for the future includes, but is not limited to, broadening digitial services to our Membership to achieve economies of scale and avoid increasing fees when you are already hurting.

ANTA’s new website has taken some time to complete, and has gone live. The new and visible strategies we have in place will inform and support you while preparing to resume full time practice.

National Council have readily converted to ZOOM Board Meetings and online webinars to continue delivery of quality materials you can access online, free of charge to amass your Continuing Professional Education hours without leaving your home or office. We have managed to provide concessions for those members able to deliver telehealth services PAGE 4 | SPRING 2021 | THE NATURAL THERAPIST VOL 36 NO. 3

Spring 2021

and continue serving their clients’ needs during lockdown.

ANTA has also negotiated with relevant colleges to ensure Students can complete their training specified to ANTA standards and criteria under the Australian Minister for Education’s appeal for fairness to graduating students. ANTA is in a strong position to support Students and new Members through these uncertain times to ensure safe, high quality, affordable and efficacious therapies continue to be delivered across all the modalities ANTA has carriage over.

If I had been asked what I would be doing when I was appointed to the Executive Officer’s role with ANTA in 2018, I would have been unable to describe the actions that have become necessary to change the processes we have developed to support our Members over the last three years.

National Council

My colleagues on National Council (ANTA Board of Directors), have approached their roles with enthusiasm and great energy from their wide range of knowledge and skills. They are ready to lead you into the future.

Our Board consists of experienced, successful practitioners and educators from clinical practices and colleges they have worked at for many years.

These are your leaders and advisors in the specific modality you have trained to practice.

These practitioners provide great support from their experience in the field. They do this to guide the disbursement of your fees to ensure your future right to practice lawfully and professionally. They do this to provide a future for graduating Students and fledging business operators as well as experienced practitioners who find they also need support.

I am honoured to work with such a dedicated group of people who reflect the standards and values ANTA has established since 1955.

As one wise Director of the Board from my alma

ANTA Executive Welcome Spring 2021

mater once said: “We take off our hats with respect to the past. We take off our coats and roll up our sleeves, to work for the future!”

Continuing Professional Education (CPE)

Continuing Professional Education is a globally recoginsed requirement for maintaining current as a practitioner. CPE needs to be completed by all ANTA Members, each and every year. ANTA Members that are elgible for Private Health Funds, need to ensure that their 20 CPE points are lodged within the ANTA Member Portal before the 31st December each year.

terms and conditions of their membership with ANTA. Of course, the Private Health Funds audit our Member records regularly to assure we are complying with their respective terms and conditions. Any Members becoming concerned about their CPE status should contact the ANTA office to clarify their membership eligbility.

Regards

Jim Olds

ANTA Fellow ANTA Executive Officer & Company Secretary

ANTA Members are encouraged to access these resoures to either fulfil or complement the complusory ongoing training that is part of the

BHSc MST, BHSc Comp Med, GC Higher Ed, MSC, Dip Nut, Dip RM, Dip TCMRM

Back for a second year!

After the successful running of the 1st World Health Symposium, this event will be back for a second year.

Make sure you keep an eye out for more information via ANTA emails, social media and on the website!

The 2nd World Health Sympoium is going to be bigger and better than before.

Tickets will sell fast, so ensure you keep an eye out for annoucements coming soon.

--ANTA is also looking out for presenters. If you are interested, please email symposium@anta.com.au for more information.

With more presenters ranging from Acupuncture, Remedial Massage, Nutritional Medicine, Naturopathy, Myotherapy, and much more.

THE NATURAL THERAPIST VOL 36 NO. 3 | SPRING 2021 | PAGE 5

ANTA News Spring 2021

ANTA News

Audits of Clinics and Practitioners by Health Funds - A Friendly Reminder ANTA is aware that some of our members have failed audits conducted by health funds and have had their provider registration cancelled by private health funds, which subsequently results in termination of ANTA membership.

ANTA members need to be remindered that under the Private Health Fund Rules, health funds are continually conducting audits of practices and clinics without advanced warning.

ANTA members are reminded to ensure that their clinic and practice is maintained. Documents including Professional Ethics, Skin Penetration Guidelines, Virutal Consultations and much more can be found in the ANTA Member Centre.

Additionally, members are reminded to ensure that all receipts issued to clients accurately reflect the treatment or services provided and practitioners are to decline any requests from clients for receipts that do not accurately reflect the treatment or service that you have provided.

Practitioners must not: • Allow other practitioners to use your receipts or health fund provider numbers • Issue multiple receipts for a single treatment or service • Issue receipts with incorrect dates • Issue receipts that do not accurately show the treatment or service provided • Issue false or fictitious receipts • Refuse to supply a receipt for a treatement/service, if the client has paid for that treatement/service If you fail an audit by a health fund, your health fund provider registration can be suspended, terminated, or result in legal action against you. Health funds can also make formal complaints about the treatment, services or receipts issued by practitioners which are required to be dealt with by ANTA under our rules and regulations.

Ensuring that you maintain a high professional and ethical treatment and clinical standards, as well as accurate and detailed patient records and receipting processes at all times, will greatly assist you in achieving a successful audit by health funds.

Industry Associations Working Together ANTA is pleased to announce that we are working together with Massage Association of Australia, Myotherapy Association Australia, Massage and Myotherapy Australia and Australian Traditional Medicine Society for the future of Remedial Massage and Myotherapy.

This invitiative was created by the five associations involved, to demonstrate that there is work being done in the background, and that collaboration is for the benefit of the whole industry. ANTA is also working behind the scenes to support the other modalities that ANTA recognises.

PAGE 6 | SPRING 2021 | THE NATURAL THERAPIST VOL 36 NO. 3

ANTA News Spring 2021

Round 1 Graduate Award Winners 2021

Daqiang Pan

Jacqueline Hagidimitriou

Leilana Todd

Ryan Yerex

Shuyun Wu

Yumi Kawakami

Jihye Hong

Natasha Watkins

Renaee Giles

Siobhan Bradley

Marina Vuckov

Sarah Moscrop

THE NATURAL THERAPIST VOL 36 NO. 3 | SPRING 2021 | PAGE 7

Be part of something bigger.

There’s safety in numbers. And with safety comes confidence; the confidence to fly high and reach new heights, especially in your career.

At Guild, we’ve dedicated the last 58 years to building a network of professionals to provide the support to help you reach those heights.

We’ve partnered with ANTA to grow the network that’s dedicated to protecting you and safeguarding the future of the natural therapies profession.

We may not be front of mind, but we’ve got your back when you need us most. Because when you’re a part of Guild, you’re part of something bigger.

Whatever journey you decide to take, and whatever stage of your career you’re at, we’re here so that you don’t have to face challenges alone.

Find out more and get a quote today by visiting guildinsurance.com.au/ANTA or calling 1800 810 213.

1800 810 213 guildinsurance.com.au

Don’t go it alone Insurance issued by Guild Insurance Limited ABN 55 004 538 863, AFS Licence No. 233791 and subject to terms, conditions and exclusions. Guild Insurance supports ANTA ongoing projects, lobbying and research through the payment of referral fees. Please refer to the policy wording and policy schedule for details. For more information call 1800 810 213.

NAT147186 Full Page The Natural Therapist Ad 07/2021

ANTA Member Article Spring 2021

Miriam Cullen

DipHSc (Nutritional Medicine) BHSc (Naturopathy) ANTA Member

Is Withania somnifera an effective therapeutic in the treatment of Post-Traumatic Stress Disorder?

Abstract Objective: To evaluate the therapeutic effect of Withania somnifera root in the treatment of Post-Traumatic Stress Disorder.

Design: Systematic Review. Four databases were searched. Selection criteria included studies assessing anxiety, stress and Post-Traumatic Stress Disorder outcomes with a treatment intervention that included Withania somnifera root extract.

Results and Conclusions: 11 full manuscripts were reviewed. Scientific evidence supports the benefit of Withania somnifera in the treatment of anxiety, perceived chronic stress, insomnia and Post-Traumatic Stress Disorder-induced cognitive impairment. Evidence is unclear for the use of Withania somnifera in the treatment of Post-Traumatic Stress Disorder in a clinical setting when diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition. Future research recommendations are discussed.

Keywords: Post-Traumatic Stress Disorder, Herbal Medicine THE NATURAL THERAPIST VOL 36 NO. 3 | SPRING 2021 | PAGE 9

ANTA Member Article Spring 2021

Introduction

Post-Traumatic Stress Disorder (PTSD) affects 7.2% of the Australian population at some point in their lifetime and is extremely debilitating1. It is more common amongst emergency services men and women2. It is classified by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) as a trauma-related and stressor-related disorder whereby a traumatic event triggers symptoms of nervousness, anxiety, irritability, nightmares, flashbacks, insomnia, weight changes, depression, drug or alcohol addictions, social withdrawal and even suicide2. Individuals with PTSD often re-experience the trauma through distressing memories that may be triggered by symbols, smells, sounds, images or other features that resemble aspects of the initial trauma3. PTSD has a huge impact on families who have members affected by this disorder, due to the aggressive, reckless or selfdestructive behaviour that can be experienced by individuals suffering from PTSD4. In addition, PTSD negatively impacts an individual’s social interactions, capacity to work or other important areas of functioning4.

Pathophysiology, Aetiology and Medical Treatment

PTSD is caused by an initial stressor or trigger such as exposure to a traumatic event that involves actual or threatened death, injury or physical threat to the self or others3. The pathophysiology of this disorder is not fully understood, however it is believed that the amygdala perceives the threat and activates a Sympathetic Nervous System (SNS) response2. This results in the release of adrenaline, noradrenaline and cortisol2. Over time, chronic SNS activation causes down-regulation of central adrenergic receptors, decreased glucocorticoid levels and up regulation of glucocorticoid receptors5. Cerebral changes have also been observed in patients with PTSD, such as a decreased volume of the hippocampus, left amygdala and anterior cingulate cortex5. Current conventional treatments for PTSD include psychiatric counselling and antidepressant mediciations2. However, 50% of PTSD PAGE 10 | SPRING 2021 | THE NATURAL THERAPIST VOL 36 NO. 3

patients using these medications cease treatment due to the side effects2. As a result, there is a great need for exploration into alternative, safer, effective treatments for individuals with PTSD.

Herbal Intervention

Withania somnifera (WS) root, also known as Ashwagandha, has been traditionally used in Ayurvedic medicine to promote physical and mental vitality and longevity6. More specifically, it has been used as an adaptogen to modulate the stress response6. Comparative animal studies have demonstrated that WS can attenuate multiple negative biochemical parameters in a chronic stress state such as hyperglycaemia, glucose intolerance, increased glucocorticoid levels, cognitive deficits and mental depression7. By reducing adrenal weight and plasma cortisol levels, WS has the ability to protect against the negative effects of elevated cortisol levels and has a cortisol sparing action6.

WS also demonstrates neuroprotective actions, and constituents withanolide A, withanoside IV and withanoside VI have been shown to be involved in the reconstruction of neuronal networks, reversing synaptic loss in the hippocampus in mice8. As hippocampal loss plays a pathophysiological role in PTSD, WS has the potential to reduce the risk of cerebral changes in this condition also5.

Methodology Literature Search Methods

A comprehensive literature search was conducted using EBSCOHost (All databases), Cochrane Library, Cochrane Collaboration and PubMed. Search terms included Withania somnifera, Ashwagandha, PTSD, post-traumatic stress disorder, posttraumatic stress disorder, trauma, stress disorder, anxiety and anxiety disorder. These search terms were included because previous editions of the DSM classified PTSD as an anxiety disorder1. Boolean operators such as “and” and “or” were utilised between words or phrases in relevant databases. All peerreviewed articles after 2000 in English were included.

Study Eligibility

Systematic reviews, Meta-anaylsis, Randomised controlled trials (RCT’s), non-randomised controlled trials (CT’s), longitudinal

ANTA Member Article Spring 2021

clinical trials, experimental animal studies, comparative animal studies and research reviews were included where the sample size was greater or equal to five.

Data Extraction

The following data were collected: study design, objective, population group and sample size, trial length, intervention type, control type, outcome and details about conflict of interest.

Literature Review Results Description of Included Studies

Eleven full text articles were included in this final review. The Appendix with a full summary of included studies is available upon request.

All manuscripts were published between 2000 and 2019. There was one systematic review, four RCT’s, one non-RCT, one research review and four experimental or comparative animal studies. Only two studies included participants with PTSD, with the rest comprising of adults with insomnia, anxiety and PTSD. Outcomes varied considerably and included the following in the human studies: Short Form 36 (SF-36v2), Perceived Stress Scale (PSS), Beck Anxiety Inventory (BAI), Hamilton Anxiety Scale (HAM-A), Hamilton Depression Scale (HAM-D), and The Depression, Anxiety and Stress Scale (DASS-21).

Insomnia assessment tools included the Sleep Onset Latency (SOL) and the Pittsburgh Sleep Quality Index (PSQI). Blood testing parameters included DHEA,

ALT, AST, creatinine and serum corticosterone levels.

Animal experiments included outcome measures such as rat brain tribulin activity, the elevated plusmaze test, the social interaction test, the forced swim-induced ‘behavioural despair’ test and the rotarod test.

Results of Included Studies

All the human studies included in this review concluded that WS treatment reduced perceived stress, anxiety or depression. In addition, one RCT demonstrated the therapeutic benefits of WS on insomnia9. Each of the four comparative, experimental animal studies demonstrated that WS improves anxiety, stress tolerance or PTSD-induced cognitive impairment. None of the included studies sighted significant adverse events or safety concerns from WS treatment.

Discussion Implications for Clinical Practice

Although the conclusions of all 11 manuscripts were unanimous in their assertion of the anxiety, depression, insomnia or stress-lowering effects of WS, only two experimental animal studies specifically explored the role of WS in PTSD, which was the primary objective of this review.

Without human RCT’s specifically exploring the impact of WS root extract on PTSD parameters, a conclusive assertion for its role in clinical practice with PTSD patients is not possible. Most studies

THE NATURAL THERAPIST VOL 36 NO. 3 | SPRING 2021 | PAGE 11

ANTA Member Article Spring 2021

compared WS treatment with a placebo or no treatment, however one animal study compared WS glycowithanolides to a benzodiazepine medication, citing equal therapeutic effects10. Additional human studies comparing WS treatment with conventional medications is required in order to confidently implement this herbal treatment for PTSD as an alternative or an adjunct to conventional medications.

There is also difficulty ascertaining an appropriate, therapeutic dose for patients in a clinical setting due to the large variety of WS doses utilised in the human studies included in this review, which ranged from 125mg/day to 12,000mg/day. However, most of the included human RCT’s utilised doses of between 240mg-600mg/day with positive therapeutic results11. Interestingly, patients experienced similar therapeutic results when using standardised WS extract compared to the full-spectrum extract.

WS was concluded to be safe and tolerable in all included studies. There were no significant differences observed between treatment and placebo groups, with one study reporting no adverse effects at all12. There was also a low-drop-out rate in many of the included studies, attesting to the good tolerability of WS13,11. However, the side effects, complications and contraindications of a particular treatment often fail to present until an individual has been using the therapeutic for a considerable period of time2. A limitation of many included studies was the short trail length. PTSD can be a chronic condition, thus treatment must be confirmed to be safe for a longer period of time before long-term implementation in a clinical setting14. In addition, herb-drug and herb-herb interactions were not reported upon in any of the included studies; an area that requires further investigation to ensure clinical safety when prescribing WS in conjunction with other treatments.

Limitations

With such a large variety of outcome measures, it is difficult to compare and contrast the results from the 11 manuscripts, much less assess the cumulative significance of such differing parameters. In addition, many of the studies included demonstrated small sample sizes (from n=6) with short trial lengths15.

Two of the high quality RCT’s were conducted on populations with limited cultural diversity, limiting the applicability of the study to broader populations9,12. Two included studies explored the role of numerous therapeutic agents (including WS) and their impact on stress and anxiety symptoms, making it impossible to identify the isolated effect of WS within the study13,16. There was also notable conflicts of interest in multiple studies, as the manufacturers for some of the herbal treatments sponsored the trials16,11. Finally, the two studies included that specifically assessed the therapeutic impact of WS extract on PTSD parameters were animal studies15,17. It is difficult to develop suitable animal models of psychiatric disorders such as PTSD and to subsequently identify the clinical relevance for human beings.

Conclusion

All studies included in this review noted significant improvement in anxiety, stress, insomnia or cognitive function in the WS treatment group when compared to controls. With an understanding of the biochemical mechanism of action of WS, it can be assumed that its actions will attenuate the physiological changes that occur in PTSD and reduce associated symptoms.

However, without human RCT’s specifically exploring the impact of WS root extract on DMS-5 diagnosed PTSD parameters, a conclusive assertion for its role in clinical practice with PTSD patients is not possible. In addition, studies with larger sample sizes and a longer trial length are required to assess the long-term efficacy and safety of WS for PTSD patients.

For references log into your ANTA Member Centre > The Natural Therapist > Journal Articles PAGE 12 | SPRING 2021 | THE NATURAL THERAPIST VOL 36 NO. 3

Olive Leaf and Heart Health

By Ian Breakspear MHerbMed(USyd) ND DBM CertPhyto After rediscovering its value in infectious diseases during the mid to late 1900’s1, olive leaf (Olea europaea folia) has been investigated for, and is now highly valued in, managing cardiometabolic conditions. Clinical trials have shown that olive leaf extract (OLE) can reduce blood pressure2,3,4, help manage dyslipidaemia, reduce inflammation4,5 and improve insulin sensitivity6.

Key to this valuable clinical activity is the complex chemistry of a quality OLE, which includes oleuropein, hydroxytyrosol, various flavonoids and derivatives, oleacein, and other biophenols.

This combined chemistry leads to strong antioxidant activity, with the total biophenol profile exhibiting synergistic antioxidant activity7.

What is fascinating about recent research on OLE and its components is its beneficial activity on vascular endothelium8,9,10,11. Endothelial function and integrity is now known to be crucial in the development of various cardiovascular diseases12, and ties together many of the dietary and lifestyle factors long known within holistic medicine as contributing to hypertension and atherosclerotic change. The combination of antioxidant, anti-inflammatory, insulin sensitivity and other activities seen with olive leaf constituents gives it an important role in managing total cardiovascular risk.

However, it is essential that a high quality OLE is used clinically. My recently published research demonstrated

that there is substantial variation in the phytochemical profile of practitioner-only OLE’s, with some having quite low levels of the key constituent oleuropein13.

Additionally, none of the practitioner OLE’s assessed at the time declared oleuropein concentration on the label13. Whilst clinical research has utilised OLE containing around 100mg of oleuropein or more per daily dosage4, my research demonstrated that none of the tested practitioner-only extracts achieved even half this amount at their maximum daily dosage13.

So, what should you look for in a practitioner-only olive leaf extract?

Firstly, my research indicated that extracts made from fresh leaves as opposed to dry leaves tended to have far greater levels of oleuropein, and on average a slightly higher total biophenol level13. So, look for extracts made from fresh leaves.

Secondly, look for a practitioner liquid OLE which makes a clear statement as to its oleuropein concentration, so that you can adjust your dosages to be consistent with the various clinical trials.

Finally, like all herbal medicines, it pays to know the source. Complete traceability from tree to bottle is important in ensuring quality and enables the practitioner to have greater confidence in the medicines they are using.

THE NATURAL THERAPIST VOL 36 NO. 3 | SPRING 2021 | PAGE 13

ANTA Member Article Spring 2021

Bronwyn Campbell

ANTA Student Member BHSc (Nutritional & Dietetic Medicine) @synergynwb

In menopausal females, is supplementation with Vitamin E effective in reducing the frequency and severity of hot flashes: A literature review Abstract Menopause is a significant cause of stress, decreased self-esteem and discomfort for the majority of women. Declining oestrogen levels are frequently linked to the onset of symptoms including hot flashes, but physiological causes are poorly understood. A current and popular treatment option is hormone replacement therapy, however its long-term use is associated with increased risk of disease. Vitamin E is emerging as a suggested treatment option, whose possible efficacy may be linked to declining nitric oxide levels in menopause. The aim of this review is to systematically assess current evidence of Vitamin E supplementation on the reduction of frequency and severity of hot flashes in menopausal females. A systematic literature search was performed on PubMed and Proquest databases to source primary evidence published within the last 10 years and excluding samples of breast cancer patients. One 2007 trial was included as it addressed inclusion criteria due to the lack of evidence available. The four selected trials were appraised utilising the Cochrane Risk of Bias 2.0 tools for randomised and cross-over trials. One trial reported a statistically significant reduction in the frequency of hot flashes (p=0.029) following supplementation with Vitamin E following eight weeks of intervention compared to control. While the remaining three trials observed significant improvements in the frequency and severity of hot flashes and somatic menopausal symptoms, no significant difference in results were observed between treatment and control groups.

Limitations of this literature review included small size of sample groups and possibility of bias, particularly in two of the trials, due to poor reporting of methodology and outcome data. Further research into the efficacy of Vitamin E is recommended. Trials should have larger sample sizes, consider confounders such as dietary intake and explore the effect of Vitamin E on nitric oxide levels and resulting effect on hot flashes frequency and severity.

Keywords: Vitamin E, menopause, post-menopausal, peri-menopausal, oestrogen, nitric oxide, hot flashes THE NATURAL THERAPIST VOL 36 NO. 3 | SPRING 2021 | PAGE 15

ANTA Member Article Spring 2021

Introduction

The transition into menopause may be referred to as peri-menopause, defined as a time of irregular menses, hormonal changes and the final period of reproductivity1. Occurring at an average age of 51 years, menopause is the cessation of female reproductivity after a minimum 12 months of amenorrhea2. Post-menopause is the time following this cessation of menses3.

During menopause over 80% of females experience hot flashes causing significant stress and decreased self-esteem due to embarrassment and discomfort4,5.

Physiological causes are poorly understood, and often linked to declining oestrogen levels6. A diet including increased quantities of fruits and vegetables, and reduced fat intake, resulting in appropriate weight loss and body mass index (BMI) may reduce experience of vasomotor symptoms including hot flashes7. Common symptoms of menopause include: • Hot flashes • Metrorrhagia • Dysregulated sleep • Depression • Vaginal atrophy and dryness • Increased anxiety and stress Note: Adapted from “Perimenopause: From Research to Practice”, by N. Santoro, 2016, Journal of Women’s Health, 25(4), p. 332. Copyright 2016 by Mary Ann Liebert, Inc. During hot flashes increased levels of nitric oxide (NO) aids vasodilation increasing cutaneous blood flow, which alongside increased core body temperature results in excessive heat and sweating8.

As oestrogen acts on NO synthase, responsible for synthesis of NO, it’s declining levels in menopause are also linked to reduced protective effects from the increased risk of cardiovascular disease (CVD) that women utilising hormone replacement therapy (HRT) suffer9. Associations may also exist between oestrogen and neurotransmitter levels, dysregulating hypothalamic homeostasis of temperature10.

HRT is frequently utilised for menopausal symptoms including hot flashes11. Its popularity has lessened since long-term use is associated with increased risk of disease, including CVD and breast cancer12.

Alternative treatment options such as nutraceuticals with better safety profiles are being investigated, with Vitamin E (VE) emerging as a successful option13. VE’s safety has been established, with no links to increasing or reducing mortality14.

PAGE 16 | SPRING 2021 | THE NATURAL THERAPIST VOL 36 NO. 3

Benefits of the use of VE in the treatment of menopausal symptoms such as hot flashes may include the support of adrenal function and therefore production of sex hormones including oestrogen, increased NO levels reducing hot flashes, CVD risk and oxidative stress, and its antiinflammatory action6,15,16.

Limited evidence exists examining efficacy of VE for hot flashes in menopausal females and limited clinical trials where the population treated for hot flashes were not breast cancer sufferers. Therefore, this literature review assesses the current available research on the efficacy of VE supplementation on the frequency and severity of hot flashes in menopausal females.

Methods Literature Search

A systematic literature search was performed on PubMed and Proquest databases to source appropriate clinical trials. MeSH terms utilised included keywords “menopause” and “menopausal” for population, “vitamin E” (VE) or “α-tocopherol” for intervention, and “hot flashes” for outcome.

Eligibility Criteria

Clinical trials utilising VE supplementation versus a placebo control, with outcome measurements assessing frequency and/or severity of hot flashes were included. Initial search criteria included studies performed in the last 10 years, however an exception was made for a 2007 paper that addressed all other inclusion criteria due to the lack of eligible papers available17.

Trials were excluded that addressed hot flashes in cancer patients, were not primary sources or utilised interventions other than VE for the treatment of hot flashes.

Data Extraction

Data extracted for synthesis included authors, year of publication, design and duration of study, participants characteristics, drop-out rate, dosage of intervention and placebo, outcome measures, adverse effects and results.

Extracted outcome measurements relating to clinical question included change in mean frequency and severity scores based on completion of Visual Analogue Scale (VAS), somatic symptom score from Menopause Rating Scale (MRS), frequency and severity score of hot flashes/sweating item in Modified Kupperman Index (MKI). Ataei-

ANTA Member Article Spring 2021

Almanghadim et al. (2020)6 also utilised an adverse effects checklist designed by their research team.

Figure 2: PRISMA Flow Chart

Critical Appraisal Process

Trials were appraised utilising the Cochrane Risk of Bias 2.0 tools for randomised and cross-over trials to

Figure 1: Risk of Bias Summary

assess risk of bias and internal validity (see Figure 1).

Results

Pubmed and Proquest database searches performed 4th March, 2020 resulted in the identification of 38 papers which were uploaded to Mendeley to allow refinement of selection.

Studies that were not clinical trials including reviews and position statements, or with full-text unavailable, and those performed on incorrect populations or utilising other interventions were excluded. See Figure 2 for preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow chart.

Following screening of abstracts and assessment of eligibility three papers were selected6,18,15. An additional Google search was performed utilising the previous search terms providing a fourth paper for inclusion17. See Table 1 for details of studies considered eligible and appropriate for appraisal in this literature review.

Study Designs

Ahsan et al. (2017)18 was a prospective single-blinded randomised placebo-controlled trial conducted as pilot study due to the lack of available data in India.

Ataei-Almanghadim et al. (2020)6 was performed as a triple-blinded randomised placebo-controlled trial.

Ziaei et al. (2007)17 was performed as a single crossover double-blind controlled trial with a wash-out period of a week, while Rezasoltani et al. (2018)15

was a double cross-over double-blind randomised trial with an eight-day wash-out. Both cross-over studies compared VE with placebo for a period of four weeks in each phase17,15. Ahsan et al. (2017)18 was the longest study, being three months in duration.

Ataei-Almanghadim et al. (2020)6 was the only study of the four that was triple-blinded.

Ataei-Almanghadim et al. (2020)6 participants were randomly selected from eight health centres in Ahar City, Iran, and Rezasoltani et al. (2018)15 utilised volunteers suffering hot flashes who were referred to a teaching hospital in Iran associated with the author’s university.

Randomisation and Blinding

Ataei-Almanghadim et al. (2020)6 performed cluster sampling in eight health centres, followed by random stratified samples to select participants.

All studies were blinded, but none provided details of length of blinding. Rezasoltani et al. (2018)15 and Ataei-Almanghadim et al. (2020)6 specified use of packaging used, while the remaining studies did not report any details of blinding18,17.

Participant Characteristics

Mean ages of participants ranged from 41.2 years18 to 52.82 years (VE-PbO group)15. One study was performed in India18 and the remaining three in Iran15,17,6.

Rezasoltani et al. (2018)15 provided detailed characteristics of participants prior to intervention displaying homogeneity between groups. AtaeiAlmanghadim et al. (2020)6 also reported no statistical difference between participating groups, however Ziaei et al. (2007)17 and Ahsan et al. (2017)18 failed to provide detailed comparative baseline information of selected participants increasing risk of selection bias.

THE NATURAL THERAPIST VOL 36 NO. 3 | SPRING 2021 | PAGE 17

ANTA Member Article Spring 2021

Table 1: Details of Selected Clinical Trials Sourced from Database Search Title

Authors

Publication/Year

Pilot study to evaluate the effect of vitamin E supplementation on the Menopause Rating Scale scores among perimenopausal women

M. Ahsan, A. K. Mallick, & R. R. Prasad

International Journal of Contemporary Medical Research, 2017

The effect of oral capsule of curcumin and vitamin E on the hotflashes and anxiety in postmenopausal women: A triple blind randomised controlled trial

K. Ataei-Almanghadim, A. FarshbhafKhalili, A. R. Ostadrahimi, E. Shaseb, & M. Mirghavourvand

Complementary Therapies in Medicine, 2020

Effect of vitamin E supplementation on plasma nitricoxide in menopausal women with hot flashes: A cross-over, randomized clinical trial

P. Rezasoltani, N. Elliyoun, T. Ziaei, E. K. Leyli, S. K. Aski, & A. Sobhani

Iranian Red Crescent Medical Journal, 2018

The effect of vitamin E on hot flashes in menopausal women

S. Ziae, A. Kazemnejad, & M. Zareai

Gynecologic and Obstetric Investigation, 2007

Trials addressed both peri-menopausal18 and postmenopausal17,6 participants, while Rezasoltani et al. (2018)15 included eligible women in natural menopause. All studies required participants to not have undertaken any treatment for their menopausal symptoms. A minimum of 1-2 hot flashes per day was required as inclusion criteria by three studies17,15,6. Additional inclusion criteria included a minimum of 12 months of amenorrhea for menopausal and post-menopausal participants15,17,6.

Intervention

Different timings and dosage of VE were utilised to measure its efficacy, ranging from 200IU twice a day6, to 400IU once a day17,15, with the highest being Ahsan et al. (2017)18 at 400IU twice per day.

All interventions were given orally via capsules and Ziaei et al. (2007)17 specified use of dl-alphatocopheryl acetate.

Placebo

All studies administered placebo via identical capsules to VE intervention. Rezasoltani et al.

(2018)15 specified the inclusion of oral paraffin in the placebo capsule.

Outcome Measures

Hot flashes frequency was self-reported in diaries utilising a visual analogue scale (VAS) (0 = no hot flashes through to 10 = unbearable hot flashes)17, and by number per day on provided cards15. Ziaei et al.

(2007)17 also determined severity of hot flashes by the VAS. The MKI was utilised by Rezasoltani et al.

(2018)15 participants to record severity of hot flashes on a scale of 1-3 (1=<3/day, 2=3-9/day, 3=≥10/day).

A hot flashes checklist was the outcome measure for Ataei-Almanghadim et al. (2020)6 for frequency of hot flashes. Rezasoltani et al. (2018)15 reported PAGE 18 | SPRING 2021 | THE NATURAL THERAPIST VOL 36 NO. 3

on NO levels (mg/dL), via laboratory testing post 12 hours of intermittent fasting to determine the effect of VE on NO levels. Ahsan et al. (2017)18 interviewed participants utilising the MRS questionnaire, combining a score for somatic symptoms including hot flashes. They note a Cronbach’s alpha of 0.89 for reliability analysis of the questionnaire at baseline, giving it an acceptable/high rating, and possibility related to length of the test19.

A variety of outcome measures were reported over the studies, including mean ± standard deviation (SD), mean difference (MD), mean ranking (MR) or mean change (MC), p-values and/or % of reduction/ improvement. Only one study reported MD15, and only one reported confidence internal (CI)6.

Main Results

Outcome measures showed a similar trend over the trials of statistically similar results between intervention and control groups (see Table 2). AtaeiAlmanghadim et al. (2020)6 was the only trial to find a statistically significant reduction in the frequency of hot flashes in the intervention group compared to control (-8.7; 95% CI -15.0 to -0.6; p=0.029). This effect was not observed until eight weeks after intervention (p=0.025).

The remaining three studies produced similar results between intervention and control groups. Ziaei et al. (2007)17 found both intervention and control groups showed statistically significant reductions in the frequency and severity of hot flashes. However, there was a larger reduction in both severity score (SS) (MD 1.80 ± 0.87, p=<0.0001, 36.6%) and frequency (3.19 ± 2.94, p=<0.0001, 54.3%) of hot flashes in the VE group versus control (SS 2.37 ± 0.74, p=<0.0001, 16.5%; frequency 5.00 ± 3.34, p=<0.0001, 28.4%).

ANTA Member Article Spring 2021

Ahsan et al. (2017)18 also found VE (5.92 ± 1.68) demonstrated similar statistical and clinical results to control (5.73 ± 1.95) in the reduction of somatic symptoms (combined score from MRS questionnaire) including hot flashes in peri-menopausal women (<p=0.05, 20.54% improvement).

the remaining trial utilising 800IU18. Dosage for all four trials lays within the Australian recommended adequate intake of VE for women (aged 19-70 years) of 7mg/day22. Homogeneity of VE dosage across four of the trials allows for direct comparison17,15,6.

At the end of the second phase of cross-over Rezasoltani et al. (2018)15 observed a statistically significant downward trend in both VE (p=<0.001) and control groups (p=0.001) in the frequency of hot flashes, with little difference found between the groups (MD PbO-VE 3.03 ± 0.48 v VE-PbO 1.89 ± 0.32). The same was shown in similar trends for MR of severity of hot flashes between the groups (VE p=<0.001 v PbO p=<0.001). No statistical significance was reported on the efficacy of reducing hot flashes

by VE effect on plasma levels of NO (p=0.197). Over the two phases 48 participants in the VE group versus 23 in the PbO group stated they would continue use of the treatment, suggesting some clinical efficacy and higher external validity15.

Reported dropout rates were spread equally across groups and varied between 4%6 and 17.6%17. Ahsan et al. (2017)18 did not discuss attrition, presenting final data on 30 participants, as recruited. Reasons for drop-outs included no interest in co-operating in study6, not meeting inclusion criteria following baseline data collection or refusal to participate17.

While specific analysis protocols are not detailed, Ziaei et al. (2007)17 appeared to utilise per protocol analysis as they removed the dropout participant’s data from baseline for final analysis which may increase risk of outcome reporting bias.

Discussion

In this review only one of four trials, AtaeiAlmanghadim et al., (2020)6 found a statistically significance in the reduction of reported frequency and severity of hot flashes in menopausal women after eight weeks of intervention utilising the MKI (p=0.029). While statistical significance was also seen in VE groups in other studies, similar results were also observed in their control groups15,17,18.

Sample Size

All trials were small in size, ranging from 30 to 93 participants18,6 possibly compromising both external and internal validity and contributing to inaccurate and larger treatment effects20,21. Ahsan et al. (2017)18 acknowledged the limitations of their sample size due to the trial being run as a pilot study.

Outcome Measures

All trials reported outcome measures in accordance with their pre-specified outcomes18,6,17,15. Ahsan et al. (2017)18 utilised the MRS questionnaire by interviewing participants rather than selfadministration, which may they acknowledge may result in interview bias. Resazoltani et al. (2018)15 noted that a possible limitation of their study may be that the baseline frequency of hot flashes was recorded by a verbal report from the participant at the commencement of the study, rather than selfreporting over a period of time prior to the trial.

Duration and Dosage

For three trials VE daily dosage was 400IU17,15,6 with

Dropout Rates and Compliance

Rezasoltani et al. (2018)15 did not give reasons for dropouts, but discussed their low dropout rate of 16% as a strength of their study and were the only trial that noted use of the Intention To Treat (ITT) principle for data analysis minimising its risk of attrition bias23. Other authors failed to discuss how missing outcome data was managed presenting the possibility of reporting bias. Ataei-Almanghadim et al. (2020)6 utilised a medication checklist completed by participants to monitor compliance.

Washout Period

Waniek et al. (2017)24 state VE appears in plasma within two to four hours, peaking at 5-14 hours after ingestion. It has an elimination half-life of 48 hours, suggesting both cross-over trials have appropriate wash-out periods of 7-8 days17,15,24.

Adverse Effects

All studies reported adverse effects. Within intervention groups these included worsening of menopausal symptoms other than hot flashes, fatigue, numbness, bone pain, inflammation, itching.

Where adverse effects were reported Rezasoltani et al. (2018)15 noted that treatment was immediately discontinued, and patients were observed until recovery.

Confounders

None of the authors reported on current or previous dietary intake of participants, aside from intake of soy foods18,6 and alcohol15,6, and its possible impact on menopausal symptoms including hot flashes16.

Only Rezasoltani et al. (2018)15 considered BMI as an exclusion criterion7.

THE NATURAL THERAPIST VOL 36 NO. 3 | SPRING 2021 | PAGE 19

ANTA Member Article Spring 2021

Limitations

This literature review is limited by the small sample sizes of studies, and the lack of information provided in at least two of the trials18,17. Ahsan et al. (2017)18 was rated as high-risk following use of the Cochrane RoB 2 tool. Of particular concern was their failure to report a variety of information including selection, randomisation and allocation, blinding process and data analysis methodology suggesting high risk of bias and poor validity25.

Study

Study Design & Duration

Participants & Characteristics (sample size)

Ziaei et al.

(2007)

Placebo, double blindcontrolled, single crossover trial.

60 postmenopausal women: Mean age: 50.92 ± 40 YO Frequency of HF/ day: 2-3 : 11 4-9 : 30 10 : 10 Mean HF severity score: 2.84 Dropouts = 9.

8 weeks with 1 week baseline assessment and 1 week washout.

Conclusion

This literature review provides some evidence that supplementation with 400IU daily of VE for eight weeks may reduce both frequency and severity of hot flashes in menopausal women. While outcomes do reflect a positive trend for the effectiveness of VE, they are minimal and similar to control.

The trials included in this literature review provide insufficient quality evidence to justify the use and efficacy of VE for this purpose. All authors concur that further research is recommended18,6,17,15. Longer and larger high quality randomised controlled trials that incorporate confounding variables including dietary intake will benefit in confirming its mechanism of actions, efficacy and safety, and its establishment as a viable alternative to HRT. The inclusion of further investigations into the efficacy of VE via its effect on NO levels and resulting frequency and severity of hot flashes would also be beneficial26.

Ahsan et al.

(2017)

Rezasoltani et al. (2018)

Pilot study conducted as a prospective, single-blinded RCT.

30 peri-menopausal women.

3 months.

Mean age: 41.2 ± 1.51 YO.

Double-blind randomised double cross-over trial.

83 menopausal women.

8 weeks exposure, 8 day wash-out.

Dropouts = 13.

Table 2: Research Summary Table Abbreviations from the table: BD = twice a day. BMI = body mass index. CI = confidence interval. DM = diabetes mellitus. F = frequency. G = group. HF = hot flashes. HRT = Hormone Replacement Therapy.

Hx = history. VE = vitamin E. MC = mean change.

MD = mean difference. MR = mean rank. MRS = Menopause Rating Scale. NO = Nitric oxide. NR = not reported. PI = phase 1. PII = phase 2. PbO = placebo.

QD = once a day. RCT = randomised controlled trial.

SS = severity score. Tx = treatment. VAS = visual analogue scale. YO = years old.

AtaeiTriple-blind RCT. Almanghadim et al. (2020) 8 weeks exposure with 4 and 8 week follow-ups.

93 postmenopausal women.

Mean age = 51.7 ± 5.3 YO. Dropouts = 4.

For references log into your ANTA Member Centre > The Natural Therapist > Journal Articles PAGE 20 | SPRING 2021 | THE NATURAL THERAPIST VOL 36 NO. 3

ANTA Member Article Spring 2021 Inclusion Criteria

Exclusion Criteria

Intervention/ Exposure (sample size)

Control (sample size)

Main Outcomes

Results

Summary

Amenorrhoeic for at least 1 year, with HF for at least 4 months, at least 2/day.

No other current treatment for HF permitted including hormones, corticosteroids, multivitamins or other agents.

400IU VE (dI-alphatocopherylacetate) capsule QD (n=51).

PbO capsule QD (n=51).

F and SS of HF (measured by VAS), (mean ± SD, p-values and % of reduction).

SS: Baseline: 2.84 ± 0.37 After PbO: 2.37 ± 0.74, p=<0.0001, 16.5% SS: Baseline: 2.84 ± 0.37 After VE: 1.80 ± 0.87, p=<0.0001, 36.6% F: Baseline: 6.98 ± 4.48 After PbO: 5.00 ± 3.34, p=<0.0001, 28.4% F: Baseline: 6.98 ± 4.48 After VE: 3.19 ± 2.94, p=<0.0001, 54.3% MD and CI NR.

Statistically significant reductions in frequency and severity of hot flashes in postmenopausal women were observed in both placebo and VE intervention groups, with a larger reduction shown in the VE group.

Women who have declined HRT for menopausal complaints.

Hormonal Tx or consumption of soy-bean derived products in last 12 months.

GA: 800IU VE, BD for 3 months (n=15).

GB: PbO softgel capsule BD for 3 months (n=15).

MRS questionnaire combined scores for somatic symptoms (mean ± SD, p-values and % of improvement).

Before Tx: GA: 7.25 ± 1.81 GB: 7.45 ± 2.51 p=<0.05, 18.34%

VE showed similar improvements statistically and clinically to PbO in the reduction of somatic symptoms including HF in perimenopausal women.

- Natural menopause at 45-60 YO.

- Hx of diabetes, hypertension, dyslipidemia, cardiovascular, kidney or liver disease.

- Cancer.

- BMI ≥ 30.

- Consumption of medication or alcohol.

- Smoking.

- HRT.

400IU VE QD capsule for 4 weeks prior to crossover.

400IU PbO QD oral paraffin capsule for 4 weeks prior to cross-over.

Primary outcome: F and SS of HF: HFs/sweating item in Modified Kupperman Index (MD, MR and p-values).

MD of F of HF after PI: GA: 2.41 ± 0.50, p=0.002 GB: 1.64 ± 0.34, p=0.001

- Minimum 12 consecutive months since last menstruation.

- Minimum 1 HF/day.

- <6 years of normal menopause.

- 40-60 YO. - Minimum 2 HF/week.

PI: GA (PbO): n=41 GB (VE): n=42

Secondary outcome: Plasma NO levels: mg/ dL assessed by ELISA (mean ± SD, MR and p-value between groups).

PII: GA (VE): n=33 GB (PbO): n=38

- Use of herbal GA: 200IU oral remedies, capsule of VE BD medications for 8 weeks (n=31). affecting HF, thyroid disease, sexual response, antidepressants and anticoagulant drugs.

GB: PbO oral capsule BD for 8 weeks (n=31).

- Primary outcomes: HF checklist for F of HF (mean ± SD, p-value, MD (CI)).

After 3 months of Tx: GA: 5.92 ± 1.68 GB: 5.73 ± 1.95 p=<0.05, 20.54% MD and CI NR.

Use of VE and PbO resulted in a statistically significant MD of F of HF after PII: reduction in GA: 3.03 ± 0.48, p=0.001 frequency and GB: 1.89 ± 0.32, p=<0.001 severity of HF in menopausal MR of SS of HF after PI: women, with GA: 18 ± 1, p=<0.001 no difference GB: 22 ± 0, p=<0.001 between VE and PbO. MR of SS of HF after PII: GA: 20 ± 0, p=<0.001 VE had no effect GB: 19 ± 0, p=<0.001 on reducing HF via influence MC in NO levels: on plasma NO PbO: 0.004 levels.

VE: 1.34 p=0.197 (between groups) CI NR. F of HF: GA: Before: 31.8 ± 25.9 8 weeks after: 13.2 ± 16.7 GB: Before: 28.7 ± 23.9 8 weeks after: 20.3 ± 16.9

Intake of VE significantly reduced the frequency of HF in postmenopausal women after 8 weeks of intervention.

Comparison between groups: p=0.029; -8.7 (95%CI: -15.0 to -0.6) THE NATURAL THERAPIST VOL 36 NO. 3 | SPRING 2021 | PAGE 21

Add homeopathy to your practice!

A range of ready-made first aid kits for your clinic or your clients.

Common remedies, easy prescribing with remedy guidebook included in each kit.

Full catalogue and price list available.

Ring or email us for more information or to place an order.

(03) 9095 0909 lab@mandp.com.au martinandpleasance.com

Martin & Pleasance Homeopathic Lab

To subscribe with a 25% discount, use the code on our Members page!

•

Search, find and compare prescribing, technical and research information on ALL Practitioner Only products.

•

Use the Prescribing Guide to select the best products for your clients.

•

Use the Cumulative Total button to add ingredients across products.

•

Use the Prescribed button to print a list of products prescribed.

•

Find probiotic research, diagnostic tests, podcasts, webinars and educational information.

•

Claim CPE points for both a subscription and podcast listening (includes a printable record for ANTA)

Designed by Practitioners for Practitioners! www.npod.com.au PAGE 22 | SPRING 2021 | THE NATURAL THERAPIST VOL 36 NO. 3

Clinically Effective Solutions for Stress and Hormonal Support

• High dose 2 g Vitex agnus-castus per day to relieve premenstrual symptoms.

• Regulate menstrual cycle plus vitamin B6 for healthy hormone metabolism.

• One a day formula.

Order Code: PLFT (30 tablets)

• Supports healthy mood balance.

• Neuroprotective activity and may modulate neurotransmitters.

• Contains researched strength saffron and high dose BCM-95™ Turmeric.

Order Code: IFMD (60 VegeCaps)

• Patients feeling anxious and tense.

• Exert anxiolytic effects during times of stress.

• Modulate GABA and neurotransmitter pathways.

Order Code: AD (60 tablets) and AD120 (120 tablets)

• Supports a healthy stress response.

• Assists metabolism and synthesis of some neurotransmitters including the calming neurotransmitter GABA. • 350 mg Meta Mag® Magnesium for extra replenishment during times of stress.

Order Code: Raspberry: CALMR (241 g) and CALMRL (482 g) Tropical: CALMT (241 g) and CALMTL (482 g)

Not A Metagenics Account Holder?

Sign up today and you will receive a 10% discount on the entire Metagenics range.

To take advantage of this offer, simply call our friendly Customer Service Team on 1800 777 648 and mention it’s your first order.

To add these products to your clinic’s dispensary, call 1800 777 648, log on to the Metagenics Website, or speak to your Territory Manager today!

metagenics.com.au metagenicsinstitute.com.au orders@metagenics.com.au

MET7144 - 07/21

Always read the label. Follow the directions for use. If symptoms persist consult your healthcare professional.

ANTA Member Article Spring 2021

George Thouas, PhD

Head of R & D, Max BioCare Pty Ltd.

Effects of Fucoidans in Immune System Activity During Viral Infections Introduction

Marine plants such as brown seaweeds have historically been used in Asian countries as a source of dietary nutrients. Fucoidans are a complex family of sulfated polysaccharides extracted from brown seaweed, including mozuku and kombu species.

In more recent times, fucoidans have raised the awareness of health practitioners because of their immune modulating, anti-inflammatory, antioxidant and cardioprotective effects, with possible applications in many acute and chronic illnesses. This article provides an overview of selected evidence PAGE 24 | SPRING 2021 | THE NATURAL THERAPIST VOL 36 NO. 3

to support the therapeutic potential of fucoidans in viral infections.

Range of Mechanisms

Fucoidans provide a wide range of actions including antimicrobial and immunomodulating (both innate and adaptive) effects that, in combination, may protect the body before or during infections. This broad-spectrum activity not only interrupts the first stages of host-pathogen interaction and entry but influences immune system mechanisms to recognise and respond. In a similar capacity to the innate

ANTA Member Article Spring 2021

immune system, fucoidans can bind directly to the outer proteins of viruses and bacteria to block their entry into cells1. This has been shown for some respiratory viruses, including different strains of Influenza A2,3 and SARS4,5 virus. Fucoidans, among other mechanisms, bind to proteins such as Toll-like receptors (TLRs) and selectins6. These proteins are expressed on the surface of cells of the adaptive immune system, such as dendritic cells, natural killer (NK) cells, B- and T-lymphocytes, activating the production of antibodies, interferons and cytokines.

In studies of Influenza A infection, fucoidan ingestion has been shown to stimulate a 38% reduction in lung loads of Influenza A virus, a six-fold increase in IgA antibodies7 and a significant reduction in lung obstructions8. Oral fucoidan has also been shown to stimulate the mobilisation of bone marrow derived hematopoietic (CD34+) stem cells, which are precursors of all circulating immune cells9.

Support Roles

The anti-inflammatory, antioxidant and anticoagulant effects of fucoidans provide another angle of possible therapeutic effects that may help to alleviate the complications associated with infections. Fucoidan ingestion has been shown to reduce lipid peroxidation and the ingress of inflammatory cells, including macrophages, granulocytes, and CD4+ T lymphocytes, while preventing the over-production of interleukin 4 (IL-4), mucins, and mast cell activation during airway inflammation10. Fucoidans also provide anti-coagulant affects, owing to their ability to modulate different steps in the clotting process11, including binding to P-selectin on platelets5. Some forms of infection are associated with an increased occurrence of clotting problems12, so fucoidans have been proposed as a possible support supplement for this particular complication13. Fucoidan intake has been shown to significantly reduce the activity of platelets after Adenovirus exposure by 3-fold, while also improving signs of platelet activation14.

Clinical Studies

Several clinical studies of fucoidan usage have demonstrated multiple immune effects in humans, in the context of infection management. One study involved supplementation of healthy adults with a combination extract containing fucoidan and micronutrients15. A positive immune response was indicated by an increase in levels of cytotoxic T-lymphocytes, B-lymphocytes and NK cells, increased activity of phagocytes and reduced interleukin 6 (IL-6) production. Additionally, the subjects showed a 25% increase in their serum

Oxygen Radical Absorbance Capacity (ORAC) antioxidant capacity levels. A similar natural increase in NK cell activity has been observed by Timori et al (2021)16 in healthy adults who took fucoidan, with no changes in placebo subjects. Furthermore, in the randomised, placebo-controlled pilot study of Undaria fucoidan cited above that reported an increase in CD34+ progenitor cells proliferation8, investigators also found that fucoidan induced a dose-dependent increase in the anti-viral protein, interferon-gamma (IFN-Y). A clinical trial by Negishi et al. (2013)17 investigated the adjuvant effects of four weeks of fucoidan use in elderly immunocompromised adults, while they were given Influenza vaccines to (a) type A (H1N1), (b) type A (H3N2) or (c) type B (Brisbrane/60/2008) strains.

After five weeks, adults in the fucoidan group showed a significant improvement in their levels of anti-hemagglutinin antibodies, compared to the placebo group. This indicated a stronger antiviral immune response than without fucoidan, and this effect was nearly double for the Influenza B vaccine and sustained for 20 weeks. Furthermore, fucoidan helped to maintain their activity of NK immune cells after 24 weeks, compared to a lower NK activity in the control group. In relation to other less common forms of viral infection, such as Hepatitis C infection, sufferers who took fucoidan for up to 10-months revealed a progressive decline in viral load18. While in Herpes virus infections, Undaria fucoidan intake led to a promotion of healing rates, reduced skin eruptions and a stimulation of T-cell activity19. Taken together, these results suggest that fucoidans have potential to stimulate virus directed immune responses in both healthy and infected individuals.

Summary

Fucoidans from naturally occurring brown seaweed species show a range of biological effects that may counteract viral infection by preventing the initial steps of host infiltration, mounting a specific immune response and counteracting some associated symptoms. Since health protection in the context of acute infections is of high priority, understanding how fucoidans may be applied therapeutically as a part of new treatment or prevention approaches is worthy of further consideration.

For references log into your ANTA Member Centre > The Natural Therapist > Journal Articles

THE NATURAL THERAPIST VOL 36 NO. 3 | SPRING 2021 | PAGE 25

Elderberry Tablets

Traditionally used in Western herbal medicine to relieve cold & flu symptoms.

Order now at MyIntegria.com Always read the Label. Follow the directions of use.

mediherb.com.au

For practitioner dispensing only.

Customer Care or Clinical & Technical Support: 1300 654 336 Order Online: myintegria.com

PAGE 26 | SPRING 2021 | THE NATURAL THERAPIST VOL 36 NO. 3

Breaking the Cycle and Alleviating Hormonal Mood Disorders At some point during their reproductive years, most women* experience cyclical symptoms associated with hormonal mood disorders such as premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD). In fact, hormonal mood disorders are extremely common, with around 50% to 80% of females enduring PMS1,2, while 2% to 8% present with PMDD3. Although both conditions encompass overlapping physical and psychological symptoms, PMDD is considered a severe and disabling extension of PMS and a threat to mental wellbeing.

PMS includes a combination of somatic changes such as abdominal bloating, breast tenderness or swelling, headache, joint or muscle pain, and swelling of extremities, as well as psychological symptoms including mood swings, irritability, anxiety, and depression4, which may interfere with some day-today activities5. In contrast, PMDD is a severe mood disorder, characterised by disabling emotional and behavioural symptoms including affective lability, marked depressed mood, anxiety and irritability.

Additionally, poor concentration, decreased interest in usual activities, fatigue, hypersomnia or insomnia, changes in appetite, sense of overwhelm, and physical symptoms (breast tenderness, bloating or headaches) are hallmark features of PMDD6. Both presentations occur during the luteal phase (approximately two weeks before menstruation) and resolve within a few days of menstruation (Figure 1)7.

The Gravity of PMS and PMDD on Women’s Mental Health

PMS and PMDD have broad potential for negative impact on patient quality of life (QoL), particularly regarding school and work efficiency and productivity8, and interpersonal relationships9. Further, the monthly waxing and waning and magnitude of PMDD symptoms, ranging from mild to severe, can cause great distress and impairment totalling up to six months annually for some women10, significantly increasing the risk of suicide11. Despite being quite common, these conditions are often underdiagnosed or dismissed by both patients and Practitioners, with patients being left to navigate their monthly emotional highs and lows feeling invalidated and unsupported12. * For the purpose of this article, the term ‘woman’ or ‘women’ refers to an individual who has ovaries and therefore may experience PMS and PMDD. As such, the term includes individual who were assigned female at birth, but do not identify as a woman.

THE NATURAL THERAPIST VOL 36 NO. 3 | SPRING 2021 | PAGE 27

Shifting the Narrative: Hormonal Sensitivity Rather than Imbalance

It must be noted that alterations in the oestrogen (E2)-to-progesterone (P4) ratio and/or elevated prolactin release during the luteal phase may play a role in the somatic symptoms of PMS13. However, with respect to affective symptoms (particularly those associated with PMDD), current research has failed to demonstrate consistent abnormalities in E2, P4 or allopregnanolone (ALLO) levels between symptomatic and asymptomatic women14. Instead, an aberrant response to normal surges in reproductive steroid hormones throughout the menstrual cycle or during reproductive transitions (e.g. pregnancy, the peripartum period etc.) likely precipitates the psychological symptoms of PMS and PMDD15. Additionally, this heightened sensitivity appears to occur in susceptible women, with research demonstrating endocrinological, neural, psychosocial and genetic factors increase susceptibility to PMS and PMDD16.

Aetiological Contributions

Emerging evidence suggests that steroid hormone sensitivity is precipitated by altered functioning of the gamma-aminobutyric acid-A (GABAA) receptor in response to ALLO17,18. In asymptomatic women, this major progesterone metabolite binds to the GABAA receptor, potentiating the effect of GABA19 (seen in Figure 2) and boosting anxiolytic, analgesic and sedative actions20. However, in PMDD, dysfunctional GABAA receptor plasticity compromises adaptation to changing ALLO levels across the menstrual cycle, resulting in increasing sensitivity to ALLO and subsequent hallmark features of PMDD

PAGE 28 | SPRING 2021 | THE NATURAL THERAPIST VOL 36 NO. 3

including affective lability, anxiety, depression and irritability21.

Additionally, altered serotonergic function is apparent in premenstrual mood disorders22, including reduced blood serotonin and worsened symptoms during tryptophan depletion23; an amino acid essential to serotonin production. Selective serotonin reuptake inhibitors (SSRIs) are the gold standard conventional PMDD treatment, and their benefit may be partly due to their ability to stabilise ALLO24.

Evidence also suggests that periods of stress may result in greater premenstrual increases in mood symptoms25,26. Building on this, women with PMDD report additional perceived stress than those without the condition27, further exacerbating PMDD severity. While more research is required to determine the mechanism behind these responses, diminished GABAA receptor control of the hypothalamic-pituitary-adrenal (HPA) axis is proposed to increase sensitivity to stress in susceptible women28. Researchers suggest that early life adversity may contribute to dysregulation of the HPA and hypothalamic-pituitary-gonadal (HPG) axes and their modulation by neurosteroids29, evidenced by an association between adverse childhood events and PMDD/premenstrual symptoms30.

Further, brain imaging studies reveal structural and functional differences between individuals with and without PMDD, including altered grey matter density in the hippocampal cortex and parahippocampal cortex, and variations in blood flow and function in regions of the brain involved in affective regulation31.

Women with PMDD also show significantly increased expression of the the Extra Sex Combs/Enhancer of Zeste (ESC/E(Z) gene complex, which is proposed to alter steroid signalling responses within the central nervous system (CNS)32. Together, these observations suggest that PMDD pathophysiology is complex, requiring a multifaceted approach to address these underlying mechanisms.

Magnesium, B6 and Zinc: An Unbeatable Combination to Manage Reproductive Mood Disorders

Magnesium is often top-of-mind for patients with mood presentations such as anxiety and depression, due to its capacity to inhibit N-Methyl-D-aspartate receptor activation and increase GABAergic and serotonergic activity33. Additionally, research suggests that magnesium and vitamin B6 deficiency may contribute to PMS presentations, evidenced by improvement in affective symptoms (low mood and anxiety)34,35,36,37,38,39,40 and increased rate of PMS remission41 following supplementation. Highlighting these benefits, 250mg/d of magnesium and 40mg/d of vitamin B6 prescribed for two months were shown to significantly lower mean PMS scores including self-reported anxiety and depression42.

Involved in the synthesis of several neurotransmitters including GABA and serotonin, vitamin B6 deficiency may lead to neurotransmitter imbalances, increasing vulnerability to mood disorders43.

Therefore, use of this nutrient may ease mood-related PMS and PMDD symptoms that correspond with neurotransmitter deficiencies44. Illustrating this, supplementation with 80mg/d of vitamin B6 over two to three menstrual cycles has been shown to attenuate low mood and anxiety45,46,47,48.

Additionally, studies analysing serum zinc levels in women with PMS have recorded considerably lower levels when compared to women without PMS. Zinc plays a multitude of roles in the CNS including regulation and release of neurotransmitters that influence cognition and mood49,50. This mineral also supports hormone synthesis, as well as providing anti-inflammatory action51,52,53. Supplementing 30mg/d54,55 to 50mg/d56 of zinc over 12 weeks has been found to significantly improve both physical and psychological symptoms of PMS, sleep and QoL57,58,59, including notable reductions in PMS-related mood presentations such as anger/irritability, anxiety/tension, depressed mood, insomnia, and interference with work productivity60.

As such, multi-nutrient combinations including magnesium, vitamin B6 and zinc, which have been shown to diminish the negative effects of PMS and PMDD, provide a treatment alternative for hormonal mood disorders.

THE NATURAL THERAPIST VOL 36 NO. 3 | SPRING 2021 | PAGE 29

Reviving Premenstrual Mood with Vitex

Vitex agnus castus (vitex) has long been regarded a staple ingredient for management of hormonal mood disorders, with extensive evidence supporting its capacity to relieve affective symptoms in PMS. Specifically, vitex modulates stress-induced prolactin secretion and increases progesterone biosynthesis by up-regulating dopaminergic action61,62,63. Clinical trials demonstrate vitex, at doses between 20mg/d to 40mg/d daily from two to six menstrual cycles, provided significant decline in affective symptoms (mood swings, depressive-like symptoms, anxiety, irritability, anger, and crying spells) in women with moderate to severe PMS compared to placebo64,65,66,67,68. Furthermore, when measured against SSRI, fluoxetine, 20mg/d to 40mg/d of vitex administered for two months demonstrated comparable symptomatic improvement in women with PMDD, including premenstrual symptoms and depression rating scores69. Therefore, vitex is uniquely positioned to relieve affective symptoms associated with premenstrual conditions.

Turmeric and Saffron: The PMDD Dream Team

Studies have highlighted the benefits of Crocus sativa (saffron) and Curcuma longa (turmeric) in neuropsychiatric disorders, providing neurogenic and neuroprotective actions, as well as serotonergic modulation70,71,72,73. Several clinical trials have shown the benefits of 30mg/d of saffron in reducing PMS symptoms and low mood over two menstrual cycles74,75, largely owing to saffron’s ability to inhibit the reuptake of dopamine, noradrenaline and serotonin76. In support of this, efficacy of 30mg/d of saffron was compared to fluoxetine in a group of 120 females diagnosed with PMDD. After two menstrual cycles, participants in the saffron intervention, classified as having severe PMDD, reported a 78% reduction in depressive scores compared to a 61% reduction in the SSRI group. Additionally, the SSRI group encountered a remarkably higher rate of side effects compared to the saffron intervention77.

Curcumin from turmeric has similarly been found effective for PMS, with 100mg/d taken for seven days pre- and three days post-menstruation associated with significantly improved physical, behavioural and mood symptoms after three cycles78. Further, women with PMS provided with 100mg of curcumin twice daily for three consecutive cycles experienced a 53% reduction in the severity of affective symptoms compared with a 3% reduction in the placebo group79. This may be due to turmeric’s anti-inflammatory effects and ability to modulate dopamine, serotonin and noradrenaline in the brain80. Therefore, turmeric and saffron are essential considerations for PMDD.

Soothing Anxious Minds with GABA

Clinical trials have shown significant benefits from the use of Passiflora incarnata (passionflower) in anxiety, with effects equivalent to benzodiazepines81. The flavonoids in passionflower increase inhibitory GABAergic neurotransmission in the CNS, subsequently enhancing anxiolytic activity82 and improving subjective sleep quality83; commonly dysregulated during menstrual transition stages and during the premenstrual phase84. Highlighting this, supplementation with 1,020mg/d of passionflower has been shown to improve restlessness, anxiety, physical symptoms (poor concentration, sweating, nausea, tremors and palpitations), and sleep quality and maintenance in patients suffering from prolonged nervous tension85. Complementing these actions, Ziziphus jujuba (zizyphus) and Magnolia officinalis (magnolia) also enhance GABA neurotransmission, protecting against excessive glutamate activity that my exacerbate anxiety states86 common to PMS and PMDD.

Mental Wellbeing is Within Arm’s Reach

PMS and PMDD can be debilitating conditions, causing severe and prolonged psychological distress that significantly affect patient’s social relationships and QoL. Fortunately, Practitioners are uniquely positioned to empathetically support mental wellbeing, enabling patients to cope with hormonal mood disorders rather than incurring their detrimental effects. A holistic treatment plan combining evidencebased vitamins and minerals, such as magnesium, vitamin B6 and zinc, with therapeutic herbs including vitex, passionflower, ziziphus, magnolia, saffron and turmeric, can alleviate symptoms of PMS and PMDD and enable patients to regain true mental wellbeing.

For further technical data, visit metagenicsinstitute.com.au.

References available on request.

PAGE 30 | SPRING 2021 | THE NATURAL THERAPIST VOL 36 NO. 3

THE NATURAL THERAPIST VOL 36 NO. 3 | SPRING 2021 | PAGE 31

ANTA Member Article Spring 2021

Tony Reid

M.Ac (Acupuncture) M.TCM (Traditional Chinese Medicine)

Common Sources of Error in Clinical Trial Literature Part 2: Statistical and Other Issues in Clinical Research

Introduction

The application of statistical methodology in medical studies was first championed by Hill in the early 1960’s21,22. Better known by his full name, Sir Austin Bradford Hill introduced randomised controlled trials into clinical medicine, and also repeatedly warned of their limitations and their potential for misuse: problems that are still current some 50 years down the track23,24. Hill cautioned against the overemphasis of statistical significance as well as neglecting the possibility of undetected errors. Unfortunately, this advice continues to be pertinent today, when there are still too many unnecessary ‘false positive and non-replicable results’ in clinical research to date24.

A renowned professor of statistics published a seminal paper in 2005, entitled: ‘Why Most Published Research Findings are False’8. Ten years later, statistical errors are still all too common23,24,5.

Mills’ famous statement from 1993 still rings true: ‘If you torture the data long enough, they will tell you what you want to hear’ 25. You do not need to be well trained in the minutiae of statistics to spot the major problem areas, if you know where to look. The following is a summary of the important issues, for assessing the statistical accuracy, or otherwise, in a medical paper9,23,26.

Lack of Homogeneity Between Study Groups

In a clinical trial the effects seen in a group of subjects receiving a treatment are compared against those seen in a similar group who are given a placebo, and often also against a group receiving no treatment at all (i.e. on the waiting list). You should not trust the ‘random allocation’ of subjects, nor p values that appear to confirm that there are no significant differences in confounding factors between the study groups (e.g. age, severity of illness, previous treatments, etc.). The logic behind Null Hypothesis Significance Testing (NHST) dictates that this test is completely inappropriate for assessing whether or not there are significant PAGE 32 | SPRING 2021 | THE NATURAL THERAPIST VOL 36 NO. 3

differences between groups in a clinical trial5.

Therefore, if the study authors provide p values when comparing the characteristics of the two (or more) study groups, this is a meaningless measure – well intentioned or otherwise. Good reporting requires that all relevant characteristics of people within each group should be comparable, and the best way to show this is when the information is provided in the form of a table. You should check that these groups are, in fact, equal and homogenous, and that no important factors are omitted. As previously mentioned, factors that could potentially affect a trial’s outcomes include age, gender, severity of illness, duration of illness, previous treatments (and how long since stopping them before entering the trial), current medications, socio-economic factors, education level, patient expectations, attitudes to the illness (e.g. perceived benefits from being ill), and the validity of the diagnosis, i.e. do the subjects all have the same disease? The known potential confounding factors should be acknowledged, and other possible (i.e. ‘unknown’) confounders briefly explored.

A critical issue when assessing the homogeneity between groups is to look at how widely the pretrial measurements of the condition being treated (e.g. severity of depression) are spread out. Even when the mean values for each group at the beginning of the trial are exactly the same (or very close), if the spread of values on either side of the mean is markedly different for each group, this can have a profound influence on the trial outcomes.

A group with more subjects who are severely depressed and a few who are mildly depressed (i.e. when the measurements are very widely spread around the mean), may show markedly different responses to a treatment than a more homogenous group with scores that cluster very closely around the mean. Therefore, it is important to look at the standard deviations (SD) as well as mean values of the main outcome variable for all groups at the

ANTA Member Article Spring 2021

commencement of the trial. Both the mean and the SD values should be similar in each of the study groups.

Inappropriate Statistical Tests to Analyse the Data

While this is not an easy one for a non-statistician to spot, a study should at least report which particular statistical test was used to analyse the data and also provide reasons for the choice. You should be cautious in accepting the conclusions if this is not the case, and particularly when the size of the treatment effect is very small, and the statistical analyses appear to be very complex. A basic rule of thumb: if a treatment really works in clinical practice (i.e. provides clinically significant results), or if one treatment is really better than another, it should be obvious; the statistical analysis may then provide a likely range of values for the results and perhaps also provide comparison of results between different subgroups (e.g. older vs. younger patients, males vs females).

Placing Too Much Importance On the p Value

Following on from the discussion above, the p value lets us know whether or not we are on the right track, but on its own, doesn’t tell us what we really want to know. It only tells us the probability of obtaining results as (or more) extreme than the observed data if the null hypothesis was true.

Thus, it begins with the assumption that there is no significant difference in a particular factor (i.e. the expected outcome of an intervention) between the two groups being compared. When we examine the data at the end of the trial and calculate p, if it is below the accepted level (generally less than 0.05, i.e. below 5%) then we reject the null hypothesis and infer that the therapy is actually producing effects that are different to those occurring in the placebo group.

It is important to be aware that the p value is a function of, i.e. it is directly related to, three different factors: the size of the treatment effect, the sample size and the variability within the sample. Thus, the p value alone does not provide information about any one of these factors, and in particular, it does not give an indication of the size of the treatment effect.

As discussed above, the lower the p value, the more confident we can be that the treatment is not doing nothing. We may then infer that it is very likely that our treatment is largely responsible for the observed clinical effects (all else being equal), but we still need some way to quantify these effects. This information is provided by the confidence intervals.

At this stage we need to bear in mind the critical distinction between statistical significance (we strongly suspect that our treatment is having some sort of effect) and clinical significance (the effect is not trivial and will make a real difference to the health and well-being of patients and caregivers).

Here again, the p value does not provide the necessary information. The effects of the treatment need to be quantified, so that we can know that they are not trivial. This information should always accompany the p values in a trial report and is given in the form of confidence intervals.

Misinterpreting the Confidence Interval

The confidence interval (CI) relating to the effect size should always be given along with the p values in a trial report. We need to remember that the ‘effect size’ that we are talking about is actually the mean (or average) effect size. The individual effect sizes of the participants in the trial are generally clustered around this mean in a normal distribution pattern (see Figure 1, part 1). The CI, generally expressed as the ‘95% CI’, is the range of values within which there is a 95% possibility that the true mean of the treatment effect lies, when applied to the whole population of interest.

The 95% CI is generally a fairly narrow range.

However, the significance of the 95% CI is often misunderstood, as it is often described as the range in which the ‘true value’, is most likely to be.

Unfortunately, this ‘true value’ does not refer to the actual size of the treatment effect that we are most likely to see in this population. The ‘true value’ refers to the mean treatment effect size. This is a critical distinction: the CI does not signify that if we gave this treatment to 20 people, at least 19 of them will have a clinical response that lies within the CI range.

The CI only tells you the range, within which it is most likely that the population mean (or ‘true mean’) may occur - with most of the real values (i.e. the actual size of the treatment effect) falling on either side of this mean value.

This concept raises some important issues when applied to clinical practice. Say, for example, that we are reviewing a clinical trial in which the outcomes of a treatment (measured as ‘effect size’) above and including the mean were clinically significant, while outcomes below the mean were measurable but not clinically significant. If we based our clinical expectations on the mean effect size of the treatment group in the trial, we would be confident of achieving clinically significant outcomes in more than 50% of patients. However, when we take into consideration the 95% CI range, in which every value

THE NATURAL THERAPIST VOL 36 NO. 3 | SPRING 2021 | PAGE 33

ANTA Member Article Spring 2021

is equally likely, and look at the worst-case scenario (i.e. when the lowest value of the CI represents the true mean in the population), things don’t look quite so good. In this case, we would find considerably more than 50% of patients would fail to gain clinically meaningful results and that considerably less than 50% would have favourable outcomes.

These considerations may have a major influence on whether or not we choose to give this treatment to our patients. This information would have been concealed from us if we only relied on the mean treatment effect that was found in the clinical trial and misinterpreted the CI as the range of outcome measures that would be seen in 19 out of 20 patients in the general population. It may not be easy to make the necessary calculations, as studies in which the 95% CI shows the active treatment in a less favourable light, may not provide you with the relevant data, especially not in the abstract. Another rule of thumb: if the authors of a study do not clearly delineate the response level, above which you have clinically meaningful results, do not provide standard deviation values, or omit the confidence intervals they are probably trying to conceal something.

This is an area in which researchers and those who report research findings are often able to ‘creatively’ present the data. Obviously, if you choose to report the trial results as if the upper CI was the true mean for the population being studied, it looks much better than results based on the lower CI as the true mean. And we need to remember that all values within the CI range are equally likely.

Therefore, in a clinical trial where only the treatment outcomes (effect size) above and including the mean were clinically significant, as in the example two paragraphs above, the best that can be said is that ‘further research is warranted’.

Poor Handling of Dropouts and Outliers

Some subjects will inevitably fail to continue up until the end of the trial, for a variety of reasons (e.g. intolerable side effects of the active treatment or impatience for clinical results) – just as some patients that we see in clinic fail to continue with a course of treatment or never come back after the first consultation. Additionally, some subjects in a trial, as in our clinics, do not follow instructions and fail to take their medicine regularly. Subjects like this are referred to as ‘dropouts’ and researchers are often tempted to exclude them from the analysis of the trial results.

Another critical sub-group of subjects are those who experience effects that are considerably outside PAGE 34 | SPRING 2021 | THE NATURAL THERAPIST VOL 36 NO. 3

the usual responses, ranging from no effect at all to dramatic and rapid effectiveness – both in the treatment and placebo arms of the trial. How are these people to be treated in the trial results? Do they represent random ‘freak’ events that crop up from time to time within the general population?

Do they belong to the 5% of outliers that we would expect to find in any normally distributed variable?

If these subjects are part of that outlying 5%, we can expect that within the entire population there will be an equal balance of these results on either side of the mean, even if within our small-scale trial the results may be skewed one way or the other. Alternatively, extreme treatment effects may occur in considerably more than 5% of the general population for reasons related either to the intervention itself or the person receiving the treatment.

In light of these considerations, some researchers may be inclined to completely exclude the outliers from the final analysis of the trial results. However, in real world clinical scenarios, where practitioners see only a small proportion of the total population, the anomalous outcomes seen in a trial reflect the possible outcomes that may be seen in an individual clinical practice.

A good trial should include all of dropouts in the final analysis, as this reflects real-life, and helps provide an assessment of the overall clinical strategy related to the intervention being studied. This is referred to as Intention-To-Treat (ITT) analysis. Always check that the numbers of subjects analysed at the end are the same as the numbers enrolled at the beginning of the trial. Generally, dropouts should be counted as ‘treatment failed’. Additionally, large numbers of dropouts can give you some useful information: if they occur in the treatment arm, the treatment may be causing unpleasant side effects and/or is ineffective.

For the same reasons, subjects with effects that are extreme and unusual should also be included in the end of trial analysis, or the researchers should provide valid reasons why they were excluded.

Within Group Comparisons

This refers to researchers using comparisons between the baseline (at the beginning of the trial) measurements and end of trial measurements within the one group. This is called a ‘within-group paired test’. In spite of the fancy name, it is not valid. Even when this comparison shows a clinically significant improvement, it is completely irrelevant. There could have been other factors, both known and unknown,

ANTA Member Article Spring 2021

that caused a similar improvement within the placebo group, thus neutralising the apparent effects of the active treatment. The only valid comparison is between the placebo and the treatment groups, and only this comparison can provide a measure of the actual effect of the treatment. This is an essential principle of clinical trial methodology, which is often ignored when the researchers or sponsors want to hide the true facts and give a positive spin to the trial results.

p Value Hacking

This is the main way in which the data are ‘tortured until they tell you what you want to hear: using the same set of data to test out one or more new hypotheses’, especially when the one that was tested originally has failed to reach statistical significance. Let us suppose that we have a clinical trial on treatments for depression, in which the average response of the active treatment group is only marginally better than that of the placebo group. However, there are quite a few subjects in the active treatment group with very good clinical outcomes, far exceeding the best ones in the placebo group, but unfortunately there are also a number of subjects in the active group with minimal or no improvement. Hence, the low mean response within the active group. The logical next step would be to look for common characteristics in the subgroup with a good response and compare them with similar patients in the placebo group. This is a subgroup analysis and, strictly speaking, does not form part of the legitimate results of the original trial. In addition, every time you do a different subgroup analysis, the p value becomes further and further diluted, such that the ‘statistical significance’ of successive analyses becomes completely meaningless. The only valid use for this observation is to develop a new hypothesis and conduct a second trial to test it, e.g. that certain characteristics in patients with depression lead to consistently good outcomes, when using the same treatment protocol as in the original trial.

Therefore, any new hypotheses that are formulated after the trial data have been gathered and analysed should not be given much weight. The main reasons for this are as follows: • There are usually too few subjects with these specific characteristics in the treatment and placebo groups for a meaningful comparison • The placebo and active subjects may not be matched in terms of other important characteristics • Mathematically, the more hypotheses you try to prove with a single set of data, the more likely

you are to have erroneous findings Often used as a means to get a research paper published, ‘p value hacking’ is an attempt by researchers to find something that is statistically significant in the face of a non-significant finding in the main trial outcome. The data collected are analysed in different ways, looking at various subsets and (inevitably) finding one or more that provide a statistically significant result, often without any real clinical significance. Sadly, the bogus statistically significant result is then reported as if it were the main finding of the study, possibly appearing in the title or at least in the abstract. The converse may also occur, where a subgroup that was part of the initial trail protocol is conveniently omitted when the results do not suit the interests of the researchers. These practices (or rather malpractices) of post hoc hypothesizing are also known as ‘HARKing’ (Hypothesizing After Results are Known).

Of course, an important part of analysing the data at the end of a trial is too look for patterns, both in terms of the desired effects of a treatment as well as the unwanted effects. If this leads to a new hypothesis being developed (e.g. side effects are more common in subjects who are over 60) that is a good thing. However, this new hypothesis cannot be applied back to the original trial – it can only be used as the basis for future trials.

Mistakenly Inferring Effect Size From The p Value

As noted above, the p value is a function of the sample size; as you increase your sample size, the p value automatically decreases. This means that if the p value is too high to give statistical significance to your test results, you just have to continue the trial, adding more and more subjects until you get to the point where the p value is less than 0.05. In this way you can produce a ‘significant’ result, even when this result is exactly the same as that of the original smaller scale trial – with the same mean value, same spread of outcome measures around the mean and the same difference between the two groups27. Therefore, a very low p value should never be interpreted as an indication of a favourable effect size. Moreover, ‘statistical significance’ should not be taken to mean ‘clinical significance’. While different methods of measuring clinical outcomes may show a small difference in favour of the active treatment group, we always need to be sure that the net effect of the active treatment does, in fact, make an appreciable positive difference in the life of patients THE NATURAL THERAPIST VOL 36 NO. 3 | SPRING 2021 | PAGE 35

ANTA Member Article Spring 2021

and carers.

Hidden Sources of Bias and Scientific Errors

In addition to mishandling of statistical methodology, there are a number of other common sources of error in clinical trials. Although Consolidated Standards of Reporting Trials (CONSORT) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines have been widely promulgated, inadequate or improper reporting of clinical trials along with failures to adhere to best practice in methodology are still common. Additionally, there are several weaknesses within the accepted clinical trial methodology that critically impact the quality of the results. The following list outlines some of the more readily detectable ones9,23.

Use of Casual and Imprecise Language

The use of casual, imprecise or highly emotive language, especially in the abstract, should be a red flag for a ‘spin alert’. Authors should use precise language and clearly summarise the results of a trial, giving the key numerical findings.

Conclusions Drawn From Insufficient Data

Authors should provide sufficient data and the right kind of data to justify their conclusions. The actual values of p as well as SD and CI should be given. We should bear in mind that other comparative data, such as the odds ratio and relative risk have the potential to be misleading.

Poor Description of Methods and Results

the treatment are as well as the placebo arm of any trial. These should all be accurately described and recorded for comparison. Trials should always report both the benefits and the risks; the results of a trial should always include the frequency of all adverse events. Clinicians need to know the benefits as well as the risks of any treatment, so that these can be weighed against each other.

Publication Bias and Submission Bias

It is well known (but difficult to actually prove with evidence) that studies with negative findings rarely get published; in fact, researchers generally do not even bother to submit such studies for publication, and they are often stopped before completion. These statements have appeared in several peer reviewed papers, but, as far as I have seen, they are never supported by any hard data. This may appear to be useless information that cannot be proven. However, we can make use of it in the following ways. Firstly, when we are only able to find a single study (with a positive result) on a particular treatment that was published several years ago, with no other studies reported since then, this should raise suspicion.

Generally, we would expect that there will be other studies, perhaps larger or better designed, conducted subsequently, in the hope of gaining another positive result. If we cannot find any of these, we may be justified in presuming that ‘no news = no good news’, i.e., the treatment has not been found to work. Therefore, we should beware of treatments that are supported by only one study.

When you read through the description of the clinical trial, you should ensure that the methods and results are described accurately and in sufficient detail for a clear understanding of how the researchers conducted the trial and why they chose to adopt this methodology. Similarly, the results should be presented in a realistic way and include a discussion of the significance of the results and any possible limitations, cautions and caveats.

Generally, we should expect to find several studies that support a particular treatment, conducted a short time after publication of the initial positive result. Of course, this may not always be the case: if a treatment being tested is a non-pharmaceutical intervention that has the potential to supplant a widely used drug treatment, it may be difficult, if not impossible, for researchers to obtain the necessary funding for larger trials, e.g. lifestyle modification to manage gastric reflux28.

Specification of Main and Secondary Outcomes

Validity of the Diagnosis

The main outcomes should be described in sufficient detail to be unambiguous. There should also be a description of secondary outcomes (if any), which should be proposed at the beginning of the trial and included in the trial design, rather than being added in at the end after the results have been collected and analysed.

Description of Adverse Events

There will always be some adverse events – both in PAGE 36 | SPRING 2021 | THE NATURAL THERAPIST VOL 36 NO. 3

The elephant in the room, particularly in regard to trials on treatments for depression, is the validity of the diagnosis. Are we looking at a single disease with the same cause in each case? Or, as with so many conditions, are we taking several different disorders with different etiologies and lumping them together because they share one particular symptom, which all too often is only vaguely defined? In the case of ‘depression’, the definition of ‘major depressive disorder’ has become so

ANTA Member Article Spring 2021

elastic that it now includes many people who are experiencing sadness due to a loss of some kind, and who tend to get over it within a few months. This would explain the relatively high rates of ‘remission’ or improvement seen in the placebo groups in trials on treatments for depression.

This is an area that may readily be exploited by vested interests. To continue the above example, industry sponsored trials, in which the raw data have been sequestered (i.e. not published along with the trial report), may have a severe mismatch between subjects in the placebo and active treatment groups.

It is possible that subjects whose depressed mood is long term may predominate in the placebo group, while those with more recent onset depressive symptoms may predominate in the active treatment group. This type of placement would very likely give the advantage to drug treatment. Moreover, given the current definition of major depression, this arrangement is completely undetectable. Thus, even in the absence of any deliberate ‘stacking’ of the two groups, such a mismatch could also occur by chance.

The same kind of thing may happen in crossover trials when patients on active treatment are changed to placebo (inevitably suffering withdrawal symptoms, which are classed as ‘depression relapse’) and the placebo patients who remitted are excluded from this part of the trial29,30,31.

Measurement of the Effect Size: Accuracy and Validity

In many trials positive therapeutic outcomes include both complete remission as well as significant improvement. These are sometimes bundled up together and reported as a ‘positive result’. There are several issues here that require additional scrutiny. How is ‘clinical remission’ defined? What sort of follow up procedures are in place to provide information about whether or not the remission is maintained for a certain period of time, and whether or not ‘remission’ needs to be maintained by continuing with the therapeutic intervention, possibly indefinitely? Does the trial provide data about numbers of subjects experiencing complete remission as well as numbers of subjects with significant improvement? Is the level of ‘significant improvement’, as defined in the trial, the same as ‘clinical improvement’? How are these measured, and what is the margin for error in these measurements.

Let us take clinical trials on treatments for depression. Many of these trials use the Hamilton Depression Rating Scale (HDRS). However, serious issues regarding its validity have been raised and it has been described by critics as psychometrically and conceptually flawed32. Moreover, when it is

used, it should be administered and interpreted by a qualified and experienced psychiatrist, otherwise the margin for error is much greater. However, given these limitations, the appropriate definition of clinically significant improvement using the HDRS should be a 50% or more decrease from the baseline score, equivalent to a 7 – 11 points reduction33.

Unfortunately, the commonly accepted criterion in American and European trials is a reduction by 3 points from the baseline reading; and even then, most trials on Selective Serotonin Reuptake Inhibitors (SSRI) fail to achieve this15.

Relative Risk, Absolute Risk and Number Needed to Treat

When looking at new treatments or strategies that are aimed at avoiding bad health outcomes, the results of such a study may be expressed in three ways: the Relative Risk Reduction (RRR), the Absolute Risk Reduction (ARR) and Number Needed to Treat (NNT). Only the last two give a concrete and practical picture of the real-world application (or potential application) of the intervention in question.

The RRR is routinely used by government health authorities and agencies, as well as doctors, when they want to encourage the general public, or a patient, to take up a particular intervention that is aimed at reducing a particular bad health outcome34,35. As an example, the results of the same study are presented below, according to these three different ways of describing the outcome: • RRR: If you have this test every 2 years, it will reduce your chance of dying from this cancer by around one-third over the next 10 years • ARR: If you have this test every 2 years it will reduce your chance of dying from this cancer from around 3 in a 1000 to around 2 in a 1000 over the next 10 years • NNT: If around 1000 people have this test every 2 years, 1 person will be saved from dying from this cancer every 10 years Not surprisingly, it has been demonstrated that patients were more likely to take this test when it was presented in RRR terms and least likely to take it when presented in NNT terms34. In this way, the RRR, while being grossly misleading, but neverthe-less a statistically valid measurement, has become the figure of choice to use in the context of convincing a lay person to follow medical advice for that person’s purported benefit. This is justified by being regarded as a ‘win-win’ tactic by government agencies, pharmaceutical companies, as well as the medical profession. Driven by such factors, a statistical calculation, which is misleading to such THE NATURAL THERAPIST VOL 36 NO. 3 | SPRING 2021 | PAGE 37

ANTA Member Article Spring 2021

a high degree that it deserves to be described as ‘false’, or at the very least ‘inappropriate’ or ‘unsuitable’, has found its way into the front line of descriptors that are used in presenting the results of clinical studies34,35.

The Relative Risk Reduction (RRR) tells you how the results compare between the two groups in a trial.

The number of people receiving the intervention who had the bad outcome (e.g. contracting a COVID-19 infection), is looked at in comparison to the number of people who had the same outcome in the control group (i.e. those not receiving any treatment). The RRR is simply the two numbers divided and expressed as the percentage reduction in risk of obtaining the bad outcome when the treatment in question is applied (e.g. a new vaccine).

It is calculated by taking the fraction obtained by dividing the two results, subtracting it from one, and then expressing this number as a percentage. The RRR is therefore simply a way of comparing the two groups in a trial and does not tell you anything about how the trial results can be applied to the larger community. Referring to the above example, the original trial data compared two groups of women, 1000 in each group, over a 10-year period, in which one group underwent screening for breast cancer every two years and the other didn’t. There were two cancers in the screened group and three in the unscreened group within the 10 year study period.

From these results, the above values for RRR, ARR and NNT were obtained. In this case the RRR is calculated as follows: 1 - 2/3, which equals 1/3, which becomes 33.3%. As you can see, if a person is told that an intervention will reduce the risk of cancer by 33.3%, this is readily misinterpreted to mean that out of 100 women who would normally have got breast cancer, about 33 of them could have avoided it is they had undergone breast screening every two years. Unfortunately, this is not what the RRR is telling us. Moreover, in terms of the numerical values of the RRR, its inapplicability as a measure of clinical effectiveness stems from the fact that the same result is obtained every time you have 3 in one group and 2 in the other - regardless of how many subjects were in each of the two groups. You will get the same RRR value with groups of 100, 1000 or one million. With smaller numbers of subjects, the results become increasingly more compelling - and vice versa. This is indeed a seriously blunt instrument!

The Absolute Risk Reduction (ARR), on the other hand, while still being a mathematical expression, brings us much closer to a clear expression of what the results of a trial are really telling us. The ARR is meant to give an indication of the net effectiveness PAGE 38 | SPRING 2021 | THE NATURAL THERAPIST VOL 36 NO. 3

of an intervention compared to no intervention, and is the difference between the results of the no-treatment (i.e. control) group and the treatment group, all expressed as percentages. Thus, it is calculated according to the normal guiding principle of subtracting the placebo effect from the treatment effect; it is a valid and significant metric. In the above example of breast screening the 2 cancer deaths in the screened group (2/1000 = 0.2%) are subtracted from the 3 cancer deaths in the non-screened group (3/1000 = 0.3%) to give the real (or ‘absolute’) reduction in risk that is associated with bi-annual breast screening over a 10-year period (0.1%).

The Number Needed to Treat (NNT) spells out the data in the clearest fashion and tells you how many people need to receive a treatment, undergo screening, modify their lifestyle, etc. in order to enable one person to avoid a specific bad health outcome34,35,36.

A current example of the way in which the RRR is used to sway public opinion and encourage people to receive a treatment relates to the newly developed gene-modifying agents to combat COVID-19 infection. Although they are still in the experimental stage, without adequate risk assessment, the efficacy of these agents has been universally expressed and promoted using the RRR. The ‘best’ one having an RRR of 95%. In reality, according to the trial results of this particular agent, the NNT is 119 (with ARR of 0.84%)37. In a real-world scenario, with a large portion of the population having received this ‘vaccine’ in Israel, an analysis of the outcomes gives an RRR of 94% and NNT of 21737.

This latest analysis of vaccine effectiveness from academics in the UK and Luxemburg, has the fact checkers, even those from reputable news sources, scrambling to reassure their readers that somehow the RRR is much more valid and meaningful than the ARR38. None of them mentions the NNT.

Epilogue

The opening paragraph of Leo Tolstoy’s novel, Anna Karenina, begins with a bold statement that has spawned several iterations of the ‘Anna Karenina Principle’. This glorious generalisation, laying claim to universal truth and placing Murphy’s law into its proper context, speaks to the notion that there are only a few ways to get something right – and a seemingly unlimited number of ways to get it wrong: ‘Happy families are all alike. Every unhappy family is unhappy in its own way.’ On reflection, it appears that the number of ways to ‘get it right’ or ‘achieve the desired outcome’ are strictly limited, while the number of different ways to err is several orders of

ANTA Member Article Spring 2021

magnitude greater. The comforting fact being that, as we are living in a finite world, the number of possible mistakes that can be made should also be finite.

This review and summary of the ‘popular’ errors in contemporary medical research is current at the time of writing. Optimistically, the scientific community will correct them where possible or learn to make

allowances for them where unavoidable; realistically, however, we should expect to find more new ones cropping up on a regular basis; and hopefully, we will come to the end of our finite number of mistakes sometime in the not-too-distant future.

For references log into your ANTA Member Centre > The Natural Therapist > Journal Articles

Table 1: Checklist for Assessing a Randomised Controlled Trial (RCT) The Abstract

The main content is clearly described.

Purpose of the research outlined.

The relevance or importance of the work clearly stated.

Main outcomes given with sufficient data to support the conclusions.

Methodology

Methods described in sufficient detail. Rationale behind the choice of methodology is given.

Homogeneity between study groups

In terms of age, gender, severity of illness, duration of illness, previous treatments (and how long since stopping them before entering the trial), current medications, socio-economic factors and education level; if p values are given, you should ignore them.

How widely are the pre-trial measurements (especially severity of the illness) are spread out reflected in the SD for each group.

Both the mean and the SD values should be similar between the study groups.

Assessing the unknown confounding factors

Are there any potential confounding factors that have not been acknowledged by the researchers?

Statistical tests - appropriate or not

Is the reason for applying a particular test clearly given?

Is the raw data self-explanatory (i.e., the treatment is obviously more effective than placebo or other treatment) or do the data need to be put through a complex series of statistical tests to reveal the ‘true’ results of the trial? This should raise suspicion.

Null hypothesis significance testing: p values and confidence intervals

Confidence intervals should always be given along with p values. Is the minimum effective size for clinical significance clearly stated?

Dropouts and outliers

Does the study provide an intention-to-treat (ITT) analysis? Always check that the numbers of subjects analysed at the end are the same as the numbers enrolled at the beginning of the trial.

Generally, dropouts should be counted as ‘treatment failed’.

Subjects with effects that are extreme and unusual should also be included in the end of trial anaylsis, or the researchers should provide valid reasons why they were excluded.

Large numbers of dropouts in the treatment arm may mean that the treatment causes unpleasant side effects and/or is ineffective.

If a study does not clearly delineate the response level, above which you have clinically meaningful results, does not provide standard deviation values, or omits the confidence intervals - they are probably trying to conceal something.

THE NATURAL THERAPIST VOL 36 NO. 3 | SPRING 2021 | PAGE 39

ANTA Member Article Spring 2021 Within group comparisons

If the study gives ‘within-group paired test’, this is invalid and generally reflects a bias or vested interest.

Specification of main and secondary outcomes

Are the main and secondary outcomes specified at the beginning of the trial.

p value hacking

Post hoc hypothesizing is only useful as a rationale for having future trials involving the subgroup in question, not for generating additional results.

Mistakenly inferring effect size from the p value

p value is a function of the sample size; as you increase your sample size, the p value automatically decreases.

‘Statistical significance’ should not be taken to mean ‘clinical significance’.

If the trial was deliberately continued with additional subjects so that the results could reach statistical significance, the treatment is most likely ineffective.

Use of casual and imprecise language

Methods and results should be reported in percise and scientific language.

The methods should be described clearly and in sufficient detail to be critically evaluated.

Conclusions drawn from insufficient data

Does the data collected during the trial actually support the conclusions given in the report?

Sometimes additional unjustifiable conclusions are given along with the correct ones.

Description of adverse events

Are the adverse events in all of the groups described clearly?

Publication bias and submission bias

Are there any other studies that confirm the results of a particular trial? If you can’t find any, what are the possible reasons for this?

Validity of the diagnosis.

Are there any issues with daignosis and how the severity is measured?

Is there a possibility that the diagnosis is not valid? (e.g. depression, irritable bowel syndrome) How accurate and how valid is the measurement or grading system for the disease being studied? (e.g., the Hamilton rating scale for depression, especially when not administered by a psychiatrist)

Are the results clearly expressed in terms of Number Needed to Treat (NNT) and Absolute Risk Reduction (ARR)

If the results are only expressed in terms of the Relative Risk Reduction (RRR), you will need to review the data and do your own calculations of Absolute Risk Reduction (ARR) and Number Needed to Treat (NNT) to get a clear picture of the effectiveness of an intervention.

Are there any secondary outcomes that have been added after the trial results have been collected?

These should not be taken as definite results; they are a new hypothesis that is yet to be verified.

PAGE 40 | SPRING 2021 | THE NATURAL THERAPIST VOL 36 NO. 3

SUNHERBAL.COM

1300 797 668

MediMag

Calm

NEW 240g Size Available

Contains Withania traditionally used in Ayurvedic medicine as a nerve tonic and Magnesium to support muscle relaxation.

Order now at MyIntegria.com Always read the Label. Follow the directions of use.

mediherb.com.au

For practitioner dispensing only.

Customer Care or Clinical & Technical Support: 1300 654 336 Order Online: myintegria.com

PAGE 42 | SPRING 2021 | THE NATURAL THERAPIST VOL 36 NO. 3

THE NATURAL THERAPIST VOL 36 NO. 3 | SPRING 2021 | PAGE 43

Key nutrients and phytomedicines to reduce the risk of cancer recurrence Curcumin

Inhibits all stages of tumour progression: initiation, promotion, proliferation, angiogenesis and metastasis

Green tea

Mushrooms

Induces beneficial innate and adaptive immune responses, modulating inflammatory and anti-tumour activities

Modulates immunity and enhances DNA repair

Retinoids directly target neoplastic cells by inducing differentiation, inhibiting cell growth and promoting apoptosis

Vitamin E Inhibits signalling molecules involved in the proliferation and differentiation of cancer cells

Modulates multiple signalling pathways, regulating growth, survival and metastasis of cancer cells

Vitamin D

A

Vitamin A

D

Se

E

Selenium

selectively induces apoptosis of cancer cells

Zinc

Deficiency is associated with a variety of cancers

Zn

To learn more, review our Lunch and Learn series, ‘Supporting Cancer Survivors’ at biomedica.com.au/lunch BioMedica Nutraceuticals P 1300 884 702 | www.biomedica.com.au

BioMedica International Oncology Summit 2021

Making a difference in the life of a person with cancer REPLAY NOW AVAILABLE #BOS2021 The BioMedica International Oncology Summit 2021 brings together pre-eminent International and National speakers in the fields of oncology and natural medicine.

As the incidence of cancer continues to rise, there is an urgent need to ensure that patients are not only surviving cancer, but living well. Holistic and natural medicine practitioners are well placed to offer significant support to patients at every stage of their cancer journey.

The Summit is designed to equip practitioners with the knowledge and confidence to make a difference in the life of a person with cancer.

View program and secure your replay today at biomedica.com.au/BOS2021

PAGE 44 | SPRING 2021 | THE NATURAL THERAPIST VOL 36 NO. 3

ANTA Member Article Spring 2021

Shiki Coppola

ANTA Member BHSc (Naturopathy)

Efficacy of N-acetylcysteine as an adjunctive therapy in improving the clinical outcomes of Obsessive-Compulsive Disorder in adult patients: A literature review Abstract Background: Obsessive-Compulsive Disorder is a chronic and debilitating neuropsychiatric illness, and a leading cause of morbidity worldwide. Symptoms result in significant anxiety, distress, and functional impairment that decreases quality of life. Although the exact aetiology is unclear, several factors are involved in its pathogenesis, including neurotransmitter dysfunction, neuro-inflammation and oxidative stress. Currently, the first-line pharmacotherapy for obsessive-compulsive disorder includes selective serotine reuptake inhibitors. However, 40-60% of patients are non-responsive to treatment. There is a growing interest in the use of N-acetylcysteine as an adjunctive therapy for the treatment of obsessivecompulsive disorder due to its potential to modulate glutamatergic transmission, oxidative stress and neuroinflammation. This systematic review aims to explore the current evidence available concerning the efficacy of N-acetylcysteine as an adjunctive therapy for the treatment of obsessive-compulsive disorder in an adult population.

Methods: The databases PubMed and CINHAL Complete were searched are articles published up until 31st August 2019. The inclusion criteria were original studies investigating the efficacy of N-acetylcysteine as an adjunctive therapy in the treatment of obsessive-compulsive disorder in adult patients. Non-human studies, systemic reviews and articles published in a language other than English were all excluded.

THE NATURAL THERAPIST VOL 36 NO. 3 | SPRING 2021 | PAGE 45

ANTA Member Article Spring 2021

Results: A total of four articles met the eligibility criteria, and included two double-blind, randomised placebo-controlled trials, and two case reports. Study duration and sample size for the randomised placebocontrolled trials were 10 weeks (n=44) and 12 weeks (n=48). Both case reports involved one subject, and closely followed treatment for 12 weeks, with additional follow ups ranging from two months to one year.

All four studies showed positive results for the use of N-acetylcysteine in conjunction with serotonin reuptake inhibitors for the treatment of obsessive-compulsive disorder.

Conclusions and Recommendations: The use of N-acetylcysteine as an adjunctive therapy shows promising preliminary results for the reduction of symptoms in moderate to extreme, or treatment-resistance, obsessive-compulsive disorder in adults. However, due to some methodological limitations and the low level of evidence of the case reports, further clinical trials are required to strengthen these findings and provide a more definitive answer regarding the role of N-acetylcysteine in obsessive-compulsive disorder. Considering current treatment options are limited for patients with moderate-severe and/or refractory obsessivecompulsive disorder, and due to its good safety profile and acceptable tolerability, N-acetylcysteine should be considered as an add-on treatment to standard serotonin reuptake inhibitor treatment, on an ad hoc basis in a clinical setting.

Keywords: N-acetylcysteine; obsessive-compulsive disorder; augmentative disorder; literature review; Y-BOCS; adult

Introduction

Obsessive-Compulsive Disorder (OCD) is a chronic and debilitating neuropsychiatric illness, characterised by intrusive, unwanted, and persistent thoughts, as well as repetitive behaviours in response to the obsessive thoughts1. With a high prevalence of 2-3%, it is the fourth most common mental disorder, and a leading cause of morbidity worldwide2. Symptoms result in significant anxiety, distress, and functional impairment that decreases quality of life3. Furthermore, comorbidity occurs in up to 90% of patients and includes depression, panic disorder, phobias, bipolar disorder, substance use and impulse control disorders4. Although the exact aetiology is unclear, several factors are involved in its pathogenesis, including neurotransmitter dysfunction, neuroinflammation and oxidative stress5.

Currently, the first-line pharmacotherapy for OCD includes selective serotonin reuptake inhibitors (SSRIs). However, 40-60% of patients are nonresponsive to treatment5. There is growing evidence of the use of N-acetylcysteine (NAC), a precursor to the antioxidant glutathione, as an adjunctive therapy for many psychiatric conditions, due to its potential to modulate glutamatergic transmission, oxidative stress and neuro-inflammation6.

Current pharmacotherapy remains inadequate for many OCD patients, with a high percentage of treatment-resistant OCD in the adult patients, requiring an urgent need for alternative strategies.

Therefore, this systemic review aims to explore the current evidence available concerning the efficacy of PAGE 46 | SPRING 2021 | THE NATURAL THERAPIST VOL 36 NO. 3

NAC as an adjunctive therapy for the treatment of OCD in an adult population.

Methods

The PICO framework was used to develop literature search strategies. The research question was ‘In N-acetylcysteine as an adjunctive therapy effective at improving the clinical outcomes of obsessivecompulsive disorder in adult patients?’.

Search Strategy

The databases PubMed and CINHAL Complete were searched for articles published up until 31st August 2019. PubMed MeSH terms and CINHAL Complete subject heading terms for “ObsessiveCompulsive Disorder” and “Acetylcysteine’ were utilised to conduct a two-arm search of the literature (Appendix A and B – See article within ANTA Member Centre). Articles were entered into Mendeley software before the screening process.

Eligibility Criteria

The inclusion criteria were original studies investigating the efficacy of NAC as an adjunctive therapy in the treatment of OCD in adult patients.

Adjunctive therapy refers to NAC being taken in conjunction with first-line pharmacotherapy for OCD. Articles were excluded if subjects were under the age of 18, or if NAC was taken as a stand-alone therapy. Non-human studies, systemic reviews and articles published in a language other than English were all excluded. There was no exclusion based on geographical location or publication date.

ANTA Member Article Spring 2021

Data Extraction

Data extracted for synthesis included: author’s; year of publication; study location; study design and duration; sample size; inclusion/exclusion criteria (for clinical trials); participant characteristics and comorbidities; type, doses and duration of pharmacotherapy and adjunctive NAC treatment; outcome measures and results.

Results Search and Study Selection

A total of 32 articles were identified through the key database searches, of which eight duplicates were removed. After title and abstract screening, six articles were considered for full-text review, of which three articles were considered eligible.

Excluded articles were due to being an irrelevant intervention (n=6), literature reviews (n=9), animal study (n=2) or incorrect demographic (n=4). Hand searching was also conducted on reference lists during the screening process which identified one additional article for inclusion. Therefore, a total of four articles met the eligibility criteria, which includes two double-blind, randomised placebo-controlled trials (RCT’s), and two case reports7,8,9,10.

Overview of Study Design

Time of publication for the four studies ranged from 2005 to 2019. The two RCT’s were based in Iran, and the two case reports were based in North America. Study duration and sample size for the RCT’s were 10 weeks (n=44) and 12 weeks (n=48).

Both case reports involved one subject, and closely followed treatment for 12 weeks, with additional

follow-ups ranging from two months to one year.

All four studies examined the effects of NAC in conjunction with serotonin reuptake inhibitors (SRIs) for the treatment of diagnosed OCD. The two RCT’s compared adjunctive NAC therapy vs standard therapy alone, while the case reports only observed the effect of adjunctive NAC therapy, without a comparison. The daily dose for NAC supplementation was 2000mg/day in one RCT, while the other RCT ranged from 600mg-2400mg, depending on individual symptom severity and patient tolerance. Both case reports used 3000mg/ day.

Participant Characteristics

The combined age range for all studies was 1860 years. All studies except for one case report mentioned the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnostic criteria for their diagnoses of OCD. One RCT selected patients with moderate-to-severe OCD (Y-BOCS≥21), while the other RCT selected patients with treatmentresistant OCD (Y-BOCS≥16) who experienced a failed response after 12 weeks of conventional treatment.

Once case report observed a patient with extreme OCD (Y-BOCS=34) with substantial impairment to daily functioning. The other case report observed a patient with persistent and severe OCD symptoms with stable but partial response to conventional treatment.

Outcome Measures

All four studies utilised the Yale-Brown ObsessiveCompulsive Scale (Y-BOCS) scoring system to quantify the severity of OCD symptoms and measure treatment response. One RCT also utilised the Y-BOCS obsession subscale score and Y-BOCS compulsion subscale score, while the other utilised the Clinical Global Impression-Severity Scale (CGI-S) and Clinical Global ImpressionImprovement Scale (CGI-I), to further assess treatment outcomes. Furthermore, both RCT’s quantitatively measured the rate of response based on a percentage of Y-BOCS score reduction at the end of the trial. Case reports included qualitative clinical observation to further highlight the treatment progress.

Efficacy Results: Randomised Placebo-Controlled Trials

Paydary et al. (2016)10 reported a significant effect for time x treatment interaction in the Y-BOCS total score (p=0.012) and THE NATURAL THERAPIST VOL 36 NO. 3 | SPRING 2021 | PAGE 47

ANTA Member Article Spring 2021

Y-BOCS obsession subscale score (p=0.011) between groups (NAC vs placebo), but not in the Y-BOCS compulsion subscale score (p=0.095). There were non-significant results for the difference between mean scores of Y-BOCS total score (p=0.16), Y-BOCS obsession subscale score (p=0.11) and Y-BOCS compulsion subscale score (p=0.52), between two groups at the end of the trial. Twelve patients in the NAC group, compared to five patients in the placebo group, achieved remission (≤16 Y-BOCS score) at the end of the trial that was borderline significant (p=0.062). However, the combined result for partial or complete response rate between the two groups was insignificant (p=0.54).

experienced OCD symptoms that significantly affected her daily functioning, with difficulty completing basic life tasks and maintaining interpersonal relationships. Over the course of treatment with adjunctive NAC therapy, she was better able to resist her compulsive rituals and was able to confront her obsessional triggers better than she has been able to over the many years.

After a 2-month follow up, her symptoms remained improved. Prior to the intervention, she reported a stable but partial response to fluvoxamine in the preceding 12 years. Previous attempts at psychotherapy saw failed responses.

Afsher et al (2012)7 reported a significant effect for time x treatment interaction compared to placebo in the Y-BOCS total score (p=0.001) and CGI-S scale score (p=0.027) between groups (NAC vs placebo), but not in the CGI-I scale score (p=0.39). At the study endpoint, significant improvement was also seen for mean score reduction in Y-BOCS total score (p=0.003) and CGI-S scale score (p=0.01), but not in the CGI-I scale score (p=0.14). Moreover, there was a significantly higher ‘full response’ rate in NAC groups (52.6%) compared to placebo (15%) (p=0.013).

Recent evidence supports the role of glutamatergic hyperactivity and oxidative stress in the pathogenesis of OCD. Thus, NAC has been proposed as a potential therapy for OCD due to its glutamatemodulating and antioxidant properties in the central nervous system11. This review explored the available evidence for the efficacy of NAC as an augmentation strategy in the treatment of OCD in adults – all four studies in this review showed a positive response, despite some limitations.

Efficacy Results: Case Reports

Bhaskara (2019) reported a Y-BOCS score reduction from 34 at the start of the intervention, to 28 after 12 weeks of treatment. It was further reduced to a score of 18 at the sixth month follow up. Prior to the intervention, the 25-year-old male patient was taking 150mg/day clomipramine and spent 8-10 hours each day on obsessive and compulsive rituals and routines. His daily functioning was substantially impaired – he was unemployed and living with his parents and was for the most part house-bound with no social life. At 12 weeks, he was able to limit his rituals to less than three hours, and his clomipramine was reduced to 75mg/day, with no worsening of symptoms. At six months, he began a part-time job and obtained his driver’s license.

A one-year follow up saw sustained results with substantial improvement in his functioning – he was employed full-time and expressed his intention to start a university degree. Past conventional treatments prior to the intervention included SSRI’s and cognitive behavioural therapy (CBT), which showed limited or partial response that was not sustained.

8

Lafleur et al. (2005)9 reported a dramatic reduction in Y-BOCS score from around 32 at the start of the intervention, to just under 10 at 12 weeks. Prior to the intervention, the 58-year-old female patient PAGE 48 | SPRING 2021 | THE NATURAL THERAPIST VOL 36 NO. 3

Discussion

Study Duration

Both Paydary et al. (2016)10 and Afsher et al. (2012)7 – whose study duration was 10 and 12 weeks respectively – reported a significant effect for time x treatment improvement in the Y-BOCS total scores. Despite some statistically insignificant values for difference in mean score reduction in certain effect measures in both studies, they all revealed the greatest score difference at the end-point of the trial, compared to earlier progress points. This prompts future clinical trials to include a longer study duration to gain further insights into the latency period of NAC efficacy as well as its long-term effects. Neither Paydary et al. (2016)10 nor Afsher et al. (2012)7 included follow-ups after their initial treatment period – which limits our understanding on maintenance and relapse incidence. In contrast, both case studies of Lafleur et al. (2005)9 and Bhaskara (2019)8 included follow-ups, which revealed further improvements at two months and six months, respectively. Bhaskara et al. (2019)8 saw sustained response at a one year follow up, making it less likely to be a placebo response or spontaneous recovery.

Treatment-Resistant ObsessiveCompulsive Disorder

The current standard therapy for OCD is SRI’s due to the serotonergic dysfunction hypothesis. However,

ANTA Member Article Spring 2021

there is a substantial rate of treatment-resistant OCD, necessitating research into other mechanisms, such as glutamate signalling pathways12. Three out of four studies7,8,9 specifically studied subjects experiencing refractory OCD. Afsher et al. (2012)7 used clinical instruments to evaluate the degree of response to previous SSRI monotherapy before the intervention period, further strengthening the validity of their positive results. The case studies provided qualitative insight into the severity of the patient’s refractory OCD. In Lafleur et al. (2005)9, there was a dramatic reduction in Y-BOCS score in just 12 weeks of intervention, compared to 12 years of partial response with standard SRI therapy.

Although we cannot generalise from a single case, this response is consistent with the hypothesis that glutamatergic dysfunction is implicated in the pathogenies of OCD, at least for a subset of patients who have not benefited from SRI’s alone.

However, the exact mechanism of action cannot be inferred from these studies, and future studies may benefit from including other tools such as magnetic resonance imaging (MRI) to increase our understanding of the disease pathogenesis.

Optimal Dosage

The optimal dose of NAC augmentation therapy is still not established and requires further research to determine therapeutic dose with a consideration for safety and tolerance. A possible limitation for the clinical trials7,10 is the dose used, as it is not the highest conceivable dose. The case studies8,9 did utilise a higher dose of 3000mg/day, which Saw dramatic improvements and was well tolerated.

However, these patients were diagnosed with severe to extreme OCD symptoms, and we cannot infer from these case reports that higher doses lead to better outcomes. Future dose-finding studies are required to determine whether greater efficacy is correlated with higher doses.

significantly higher rates of gastrointestinal adverse effects were seen in the intervention group in Afsher et al. (2012)7. A total of four subjects discontinued the study. The reason for drop-out was omitted for the one patient in Paydary et al. (2016)10, and the other three were due to adverse effects of medication in Afsher et al. (2012)7 – however, no further details were provided, increasing the risk of reporting bias.

From the evidence gathered in this review, a daily NAC dosage range between 2000mg-3000mg shows acceptable tolerability, but gastrointestinal side effects may be expected in some patients. It would be useful to investigate whether different administration methods – such as taking it with meals – can reduce the incidence of gastrointestinal side effects, along with bioavailability measures.

Other Limitations and Risk of Bias

Other limitations in the studies include a notable drop-out rate in Afsher et al. (2012)7, and a relatively small sample size in both clinical trial studies, affecting validity and reliability. Comorbidities were also not discussed in the evaluations and analyses in all four studies, which may have affected the efficacy of treatment. An overestimation for the effect of NAC in Lafleur et al. (2006)9 is possible, due to the fact that the patient was hospitalised and was offered supporting psychotherapy – although it was not a formal or manual driven CBT treatment, it has the potential to influence the results positively.

Application of the Cochrane Risk of Bias tool14 highlights some risk of bias. In Afsher et al. (2012)7, a risk of performance bias is noted, due to the sulphur smell of NAC effervescent tablets, and Paydary et al. (2016)10 presents an unclear risk of attrition bias due to omission of confidence interval (CI) values for the Greenhouse-Geisser corrected rules. Due to the high risk of bias associated with case report study designs, the level of evidence is low for the two

Safety and Tolerance

Paydary et al. (2016)10 and Afsher et al.

(2012)7 reported on the frequency and nature of adverse events during the intervention.

Adverse effects were mostly gastrointestinal in nature, such as diarrhoea, nausea, vomiting and constipation, and no serious or unusual adverse events were reported. As NAC is known to have a mucolytic activity which can reduce mucous viscosity, this may be contributing to these gastrointestinal side effects13. In Paydary et al. (2016)10, the frequency of adverse events did not significantly differ between the groups, but THE NATURAL THERAPIST VOL 36 NO. 3 | SPRING 2021 | PAGE 49

ANTA Member Article Spring 2021

included case reports and cannot be generalised to the broader population.

Conclusion

OCD can cause significant functional impairment, and due to its high prevalence and poor response rate with standard SRI treatment, alternative methods need to be researched. The use of NAC as an adjunctive therapy shows promising preliminary results for the reduction of symptoms in moderate to extreme, or treatment-resistant, OCD in adults.

All four studies in this literature review have shown significant positive results. However, due to some methodological limitations and the low level of evidence of the case reports, further clinical trials are required to strengthen these findings and provide a more definitive answer regarding the role of NAC in OCD. Future studies should involve a larger sample size and a better characterisation of participants, such as mean duration of disease, symptom dimensions, and analysis of any comorbidities in their evaluations. A longer duration of study with long-term follow-ups is required to determine NAC latency time, how improvements are maintained over time, and the incidence of

PAGE 50 | SPRING 2021 | THE NATURAL THERAPIST VOL 36 NO. 3

relapse after discontinuation. Study designs that address optimum dosage and duration, absorption and bioavailability and NAC will also be helpful in improving our understanding for its potential clinical use. Additionally, using MRI in future studies as a tool to observe the specific neurological effects of NAC in the brain will help strengthen and expand our knowledge of OCD pathophysiology. Overall, the results in this literature review have shown that NAC augmentation therapy is a potentially useful treatment option for OCD, and warrants further research. Considering current treatment options are limited for patients with moderate-severe and/or refractory OCD, and due to its good safety profile and acceptable tolerability, NAC should be considered as an add-on treatment to standard SRI treatment, on an ad hoc basis in a clinical setting.

For references log into your ANTA Member Centre > The Natural Therapist > Journal Articles

INTRODUCING

The next level Vitamin E

Research indicates that tocotrienols exhibit antioxidant, free radical scavenging, anti inflammatory and cholesterol lowering properties.

Tocotrienols are better absorbed than traditional Vitamin E.

This medicine may not be right for you. Read the label before purchase.

If symptoms persist, talk to your health professional.

Available in Go Vita and selected health food stores Australia wide.

SUPPORTING YOU TO ACHIEVE OUTSTANDING RESULTS FOR YOUR PATIENTS.

A UPD

TED

• CLINICAL GUIDES (reference manuals) • CLINICAL PROTOCOLS • EQUIVALENT FORMULAS • CASE STUDIES • CAUTIONS & CONTRAINDICATIONS • JOURNAL ARTICLES • FORMULA COMPARISONS • CPD EVENTS

SUNHERBAL.COM

INN_15737

NEW COMPREHENSIVE ONLINE PRACTITIONER SUPPORT