Research on Nutraceuticals A guide for designing high-quality clinical trials

Adrian L. Lopresti, PhD

Copyright © Clinical Research Australia 2020

www.clinicalresearch.com.au

Interest in nutraceuticals and dietary supplements is increasing with a report indicating worldwide sales of USD 140 billion in 2018. This number is predicted to increase to USD 216 billion in 20261. In a survey conducted in 2017, it was revealed that over the previous twelve months, 76 per cent of U.S. adults took dietary supplements2. Vitamins and minerals are the largest selling category, while sales of omega-3 fatty acids and probiotics are also high. There is also increasing popularity of herbal ingredients, and according to the HerbalGram Herb Market Report, the 5 top-selling herbal ingredients in the U.S. included horehound, echinacea, turmeric, elderberry, and green tea3.

Growth in the sales and intake of dietary supplements are believed to result from the increasing awareness of the importance of nutrition on general health. Lifestyle changes including the increased intake of unhealthy foods and reduced physical activity, increased time constraints to engage in healthy lifestyle and dietary practices, a worsening chronic disease burden, and a large older-age population are also believed to be associated with the increasing popularity of dietary supplements. Dissatisfaction with the limited efficacy of pharmaceutical medications, particularly for the treatment and prevention of chronic diseases, adverse effects associated with pharmaceutical use, and the perception of greater safety and tolerability of dietary supplements are also reasons for the high interest in and popularity of dietary supplements.

A common criticism associated with nutraceuticals is their lack of stringent regulation and limited research supporting their efficacy to advance health and wellbeing and treat disease. Unlike pharmaceutical medications, which are highly regulated by relevant government organisations such as the Food and Drug Administration (FDA) in the USA, the European Medicines Agency (EMA) in Europe, and the Therapeutic Goods Administration (TGA) in Australia, sales of dietary supplements are associated with far less regulation. However, given the increasing sales and popularity of dietary supplements, this landscape is changing and likely to become increasingly more stringent over time4. This makes research into the safety, tolerability, and efficacy of nutraceuticals increasingly important. Summarised on the following page are the types of evidence that are used to support the safety and efficacy of nutraceuticals, with greater weight associated with the latter forms of evidence:

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1. Traditional evidence – this is where the use of medicinal plants by our ancestors are used to demonstrate safety and efficacy.

2. In vitro studies – these cell-based trials are used to demonstrate how a nutraceutical works, and conditions/diseases that a nutraceutical may be potentially helpful in preventing and/or treating.

3. Animal studies – these studies, most-commonly conducted on rats and mice, are used to provide preliminary evidence about potential safety and efficacy in humans. They can also help clarify how a nutraceutical works.

4. Open-label, non-blinded, and/or non-randomised trials – these human trials provide preliminary evidence about safety and efficacy. However, given their absence of a comparison group (e.g., a placebo or other treatment) and lack of treatment blinding (of participants and/or researchers), the strength of conclusions from these studies are often considered weak.

5. Randomised, controlled, double-blind clinical trials – these trials are considered ‘gold-standard’ study designs and are perceived to provide a strong level of clinical evidence. However, as will be covered in the following section, the robustness of the findings may be compromised by several variables.

6. Meta-analyses and systematic reviews – when there are a sufficient number of studies conducted, combined data from these studies can be used to complete systematic reviews and meta-analyses. Because conclusions are formed based on the results from multiple studies rather than single trials, they are considered the strongest levels of evidence for an intervention. However, the strength of conclusions from systematic reviews and meta-analyses will be influenced by the quality of studies reviewed, characteristics of the populations evaluated, and comparability in the quality and dosage of the nutraceutical evaluated.

Nutraceutical companies are becoming increasingly aware of the importance of conducting clinical trials on their ingredients. Consequently, the number of clinical trials that are being conducted on nutraceuticals is increasing. However, to maximise the strength of evidence associated with nutraceutical clinical trials, they must be of high quality and ideally, published in reputable, peer-reviewed journals. In the following section, recommendations are provided on how nutraceutical research should be conducted. This will strengthen the evidence of the efficacy and safety of nutraceuticals.

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Definition of terms

Between-group statistical analysis

Statistical analyses that examine differences ‘between’ two or more groups. For example, did depressive symptoms change more in people receiving the nutraceutical compared to the placebo?

Clinical significance

A measure of whether a treatment is ‘clinically meaningful.’ Did it result in noticeable changes to the participants, and/or did it result in changes that will have a therapeutic effect on the investigated condition/disease?

Double-blind study A study where both the researchers and participants do not know what treatment is being received.

Effect size

A measure of the magnitude of the intervention on the measured outcome. Effects sizes can be calculated compared to a placebo and/or compared to the comparison intervention (e.g., pharmaceutical drug). An effect size of 0.2 is considered small, 0.5 is considered medium, and 0.8 and higher is considered large.

Eligibility criteriaThe criteria used in a study to determine who is eligible or not for a study. Eligibility criteria include both ‘inclusion’ and ‘exclusion’ criteria.

Impact factorA measure of the frequency with which the average article in a journal has been cited in a particular year. It is used to measure the importance or rank of a journal.

Mechanism of action A mechanism through which treatment works.

Nutraceutical

A hybrid term linking the words nutrition and pharmaceutical. However, despite its use, there is no universally accepted definition. Its use covers a wide range of different naturally-occurring products which are believed to positively influence human health. In this article, the term nutraceutical refers to dietary supplements (e.g., vitamins, minerals, proteins, and amino acids), plants/herbs and their extracts, probiotics, and prebiotics.

Open-label study A study where both researchers and participants in a research study know the treatment the participant is receiving.

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Outcome measure

The outcome measures used to examine the effect of a treatment. Outcome measures could involve questionnaires, blood markers, salivary markers, cognitive tests, and other performance measures.

Placebo

An inert substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar or fibre pills), inert injections (like saline), sham surgery, and other procedures.

Placebo effect

A beneficial effect produced by a placebo treatment which cannot be attributed to the properties of the placebo itself. In most placebo-controlled trials, placebo treatments are associated with improvements over time. The placebo effect may be due to a person’s belief or expectation associated with the treatment, positive interactions with investigators, and/or the reduction of symptoms associated with time.

Probability value (p-value)

The probability that the ‘null hypothesis’ is true (e.g., there is no difference between the two conditions). In most trials, a p-value of less than 0.05 is used. This means that if a result is less than 0.05, there is less than a 5 per cent chance the treatment had no effect. Therefore, a p-value of less than 0.05 increases our confidence that the treatment effect is real (i.e., we are more than 95% confident in the finding).

Randomised, controlled, double-blind design

A study where participants are randomly allocated to a treatment group or a comparison/ control group (e.g., placebo and/or pharmaceutical), and both the participants and researchers do not know which treatment the participants are receiving.

Statistical significance

A p-value of less than 0.05 is considered statistically significant. However, this does not necessarily mean that the treatment was ‘clinically meaningful’

Study power

This is influenced by the effect size, the sample size recruited for the study, and the desired level of statistical significance. If an effect size is small, a large sample size is required. If the effect size is large, a smaller sample size is required. If the sample size is too small based on the anticipated effect size, then the study is considered ‘underpowered.’

Within-group statistical analysis

Statistical analyses that examine changes within a group. For example, did the participants receiving the nutraceutical experience changes in depressive symptoms compared to their baseline scores?

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CLINICAL TRIAL RECOMMENDATIONS

Use gold-standard trial designsClinical trials should comprise ‘gold-standard,’ randomised, controlled, double-blind designs. Open-label and non-randomised trials can provide preliminary evidence about the safety and tolerability of a nutraceutical; however, their flawed impairs the ability to makes definitive conclusions about treatment efficacy. The placebo effect is a well-established phenomenon, so without an appropriate comparison group, identifying treatment effects associated with nutraceutical administration is impossible. Unfortunately, some studies published in the nutraceutical field utilise these inferior study designs.

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Ensure trials are adequately poweredAn essential component in the planning of clinical trials is to ensure the sample size is large enough to identify treatment effects. This involves reviewing similar, previously-conducted trials to estimate the potential magnitude of change a treatment will have on the outcome measures that will be used in the study. If a placebo-controlled trial is being conducted, an effect size compared to a placebo needs to be predicted. In nutraceutical research, it is common to find underpowered studies. For example, it is common to find placebo-controlled trials involving 40 participants or less. In a study with 40 people, a large effect size of 0.8 is required to get an 80 per cent chance of finding a statistically-significant effect at a p-value of less than 0.05 (this is assuming there are no dropouts in the study). If we review effect sizes in pharmaceutical studies, we regularly do not see effect sizes this large, so it is unreasonable to expect this effect size from nutraceutical interventions.

There are also many studies where the efficacy of a nutraceutical is compared to an established pharmacological intervention. Non-significant differences in treatment outcomes are then purported to confirm similar treatment efficacy between the nutraceutical and pharmaceutical. However, this finding can be easily established by ensuring the study is underpowered. Therefore, when comparing a nutraceutical to a proven efficacious pharmaceutical, large sample sizes are required. This is because if there is a difference in treatment efficacy, the effect size is likely to be small-to-

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medium. If a small effect size of 0.2 is predicted, the sample size should comprise over 600 people. If a medium effect size of 0.5 is predicted, the sample size should consist of over 100 people. In many published studies where a nutraceutical was compared to a drug, sample sizes of less than 50 were often recruited. Predictability, no statistical difference between the drug and nutraceutical was identified and it was incorrectly concluded that the two treatments had similar efficacy. However, the more appropriate conclusion should be that the study was underpowered so no meaningful conclusion could be made.

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Choose appropriate populations and eligibility criteriaWhen conducting a clinical trial, the specific population to be investigated needs to be identified and eligibility criteria established. This should be based on the aims of the study, how the nutraceutical is believed to work, practicalities associated with recruitment, the potential costs and benefits associated with participating in the study, and other ethical considerations. Based on the study results, conclusions about the effects of a nutraceutical on the recruited population can then be made. For example, if a nutraceutical is found to be effective at lowering stress levels in students experiencing academic stress, it can be concluded that it may be an effective agent for individuals experiencing high academic stress. However, efficacy should not be generalised to people experiencing other types of stress or stress that is different in nature (e.g., physical stress), severity, or chronicity. Moreover, the results should not be generalised to individuals with a diagnosed anxiety disorder. Conclusions about the efficacy of a nutraceutical in a specific population should only be made if investigations have been conducted on the relevant population. The same criteria apply when making conclusions based on gender, age, severity or chronicity of symptoms, people with co-morbid medical conditions, efficacy as an adjunct treatment, etc. If investigations have not been conducted on a specific population, then conclusions about efficacy for that population should be made cautiously.

____________________________________________________________________Control for the limitations associated with conducting trials on healthy populationsOne of the drawbacks of nutraceutical research is that it needs to be conducted on ‘healthy’ populations. Despite the potential of nutraceuticals in preventing or treating disease, claims associated with the treatment of disease require high levels of evidence to support the claims. This is usually

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the arena of pharmaceutical medications. Because a significant body of evidence is required to make health claims about diseased populations, costs of clinical trials are in the millions. Therefore, to allow nutraceutical health claims, research needs to be conducted on healthy populations. However, the problem in conducting trials on healthy populations is that there is often little room for improvement, making the benefits of treatment difficult to identify. As a result, careful consideration about the recruited population must be undertaken to ensure the greatest chance of the benefits of treatments being identified.

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Use appropriate outcome measuresTo examine the efficacy of an intervention, choosing appropriate outcome measures is imperative. Decisions on outcome measures should be based on the aims of the investigation and should involve the selection of both reliable and valid instruments. For example, if the goal of an intervention is to identify whether a nutraceutical intervention is effective for the treatment of depression, reliable and valid self-report and clinician-rated instruments must be used. If the goal is to examine the effect of an intervention on cortisol levels, appropriate collection and measurement procedures must be in place. However, if a treatment is associated with reduced cortisol, we cannot infer that because cortisol is often dysregulated in people with depression, it must, therefore, be an effective treatment for depression. All that can be concluded is that the intervention lowers cortisol, and this may be a potential mechanism of action associated with the nutraceutical. Without an adequate assessment of depressive symptoms, we cannot conclude that it is an effective treatment for depression. The same applies to cardiovascular drug research where statins are regularly shown to lower cholesterol levels. While it can be concluded that the statin reduced cholesterol, we cannot then confidently infer that it lowers cardiovascular disease risk unless cardiovascular mortality and morbidity were included as an outcome measure.

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Use appropriate statistical analysesWhen examining treatment outcomes, appropriate statistical analyses must be conducted. In trials involving a control group, between-group comparisons must be conducted. It is not uncommon in nutraceutical trials to see statistical analyses of within-group changes over time. That is, statistical analyses are conducted to see if there were improvements over time in each

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treatment group. Given the established placebo effects, this analysis is flawed as we know that even a placebo will likely result in improvements over time. Therefore, to examine the efficacy of an intervention, analyses must be conducted to determine if the magnitude of changes in outcome measures differed between the two groups. Moreover, appropriate statistical tests must be used to examine these between-group differences. This involves choosing the most appropriate parametric or non-parametric tests. If multiple statistical comparisons are conducted, significance values should also be modified to account for the increasing likelihood of finding a statistically-significant effect by chance. For example, at a p-value of 0.05, there remains a 5 per cent chance of finding a statistically-significant effect by chance. If two analyses are conducted and the p-value remains at 0.05, then there is a 10 per cent (0.05 x 2) chance of finding a statistically-significant effect. This likelihood of finding an effect by chance continues to increase as more analyses are conducted.

____________________________________________________________________Examine clinically-meaningful versus statistically-significant resultsA common criticism associated with all interventional studies is the over-emphasis on ‘statistically-significant’ results compared to ‘clinically-meaningful’ results. In a study, a statistically-significant change in an outcome measure may be identified; however, the change is so small that it is not clinically meaningful. For example, there may be a 5 per cent larger reduction in a self-report measure compared to the placebo and this may be statistically-significant. However, it may not be that meaningful. That is, people don’t even notice this 5 per cent change in terms of its symptomatic relief. One way to overcome this problem is to calculate treatment effect sizes. An effect size indicates how strong the effect of treatment was compared to the placebo. A small effect size is 0.2, a medium effect size is 0.5, and a large effect size is 0.8 and above. Therefore, calculating effect sizes in clinical trials is important as it provides information about the magnitude of treatment effects. However, there is a cautionary note associated with effect size calculations. Even though an effect size may be large, which is considered a good thing, it does not tell us how much effort, financial costs, and other resources were needed to obtain this treatment effect. For example, a 12-month intervention that involves regular visits to a practitioner, costs thousands of dollars, and is associated with several adverse effects may have a large treatment effect. However, taking a nutraceutical twice daily, which costs $30 a month, may have a small treatment effect, but the resources required are minimal. If you simply compare the effect sizes you

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will conclude that one treatment was better than the other. But there is no consideration of the costs, financially or otherwise, to the individual and the community. This requires consideration when interpreting the results of a study.

____________________________________________________________________Examine treatment dosage responsesWhen evaluating the efficacy of an intervention, it is important to determine the most effective and tolerable treatment dosage. This includes decisions about the amount, frequency, and length of treatment. Decisions about dosage and safety can be informed by animal trials, however, human trials are required to establish definitive conclusions. Dosage may also vary based on the recruited population, treatment length (i.e., acute versus chronic), the condition being treated, and the composition of nutraceutical extract used. Unfortunately, in many nutraceutical trials, the same dosage is regularly used across trials. Even though there may be efficacy at the evaluated dosage, greater treatment effects may be realised at different dosages. It is also possible in some studies that a negative finding may not result from the nutraceutical being ineffective, but rather the dosage delivered being sub-therapeutic.

____________________________________________________________________Ensure appropriate randomisation and treatment blindingThe most robust investigations are randomised, controlled, double-blind designs where group randomisation and blinding of both participants and investigators are appropriately conducted. As many nutraceuticals have a distinct colour, taste, and/or odour, placebos must be matched based on these characteristics. The dose, treatment delivery (e.g., tablet, powder, liquid), and frequency of intake must also be identical between conditions. This increases the likelihood of ensuring effective blinding. Checks must also be in place to determine if blinding has been maintained throughout the study. In addition to participant blinding, adequate measures must be in place to ensure the investigators are blinded. Details about the randomisation and blinding procedures should be provided in the publication.

____________________________________________________________________Include treatment follow-upsIdeally, data collection in clinical trials should occur during treatment plus a follow-up period. The length of the follow up will vary based on treatments goals, potential mechanisms of action associated with the nutraceutical, and

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the population being examined. Having a follow up allows conclusions to be made about the extended benefits, safety, and tolerability of a nutraceutical. If there are benefits in taking a nutraceutical, do the gains continue after the treatment is ceased? Unfortunately, follow-up is not commonplace in either nutraceutical or drug-based clinical trials. This is likely due to the extra costs and difficulties associated with participant retention.

____________________________________________________________________Use caution when generalising study findings to other plant extractsUnlike drug-based studies where the efficacy of an isolated, replicable compound may be investigated, the quality and composition of plant extracts can vary substantially. This can significantly influence safety, tolerability, and treatment efficacy. Even though two herb, plant, fruit, or vegetable extracts may share the same name (e.g., St John’s Wort, saffron, turmeric, cranberry, etc.), there may be significant differences in their amounts of active ingredients. For example, it would be unrealistic to expect two oranges grown in two different countries to have an identical concentration of vitamin C. The same applies to herbal or plant extracts. This is because they may be grown in two different countries with very different climates, soil quality, cultivation practices, time of harvesting, storage practices, etc. The extraction processes may also vary significantly which can greatly influence the composition, quality, and contaminants contained in the final product. Therefore, generalising findings from a study conducted on a specific, uniquely-formulated extract to every other extract should be done cautiously. To ameliorate this, many manufacturers are producing standardised, patented plant extracts. The processes associated with manufacturing these extracts remain uniform over time to increase the likelihood of replicable extracts being produced. These extracts may also be standardised for certain active ingredients to ensure replicability. Even though there are criticisms associated with standardisation, mainly due to the potential of excessively focusing on a single active ingredient to the detriment of others in the plant, it does help ensure reproducibility in plant extracts.

This means that due to differences in plant extracts, conclusions based on a study should only apply to the specific extract that was investigated in the study and not to the plant as a whole. Manufacturers who wish to make claims on their extract should, therefore, conduct studies on their unique extract and not simply use evidence from other studies to claim efficacy for their extract.

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____________________________________________________________________Multi-ingredient formulas should have studies conducted to support their safety and efficacyIt is now common for supplement companies to produce products that contain several ingredients. A driving hypothesis is that consuming a combination of ingredients is associated with a greater therapeutic potency compared to taking a single ingredient. Even though decisions around creating multi-ingredient products may be based on sound theoretical principles, thereby potentially increasing treatment efficacy, evidence from clinical trials are required to validate safety and efficacy. Claims about a product should not be based on research conducted on a single ingredient contained in the formula as we do not know about interaction effects, the stability of ingredients when used in combination, or doses required when used in combination.

____________________________________________________________________Conduct studies with real-world applicability

In some clinical trials, eligibility criteria is so strict that the results have little relevance for the general population. For example, participants may need to be of a healthy weight, have no medical conditions, be medication-free, take no supplements, be non-smokers, and consume little-to-no alcohol. The restrictiveness of this eligibility criteria means that the recruited participants do not represent the people that are likely to take the nutraceutical in the real world. Even though some restrictions are necessary in clinical trials, it is important that the recruited cohort accurately represents the target audience.____________________________________________________________________To validate nutraceutical efficacy, research on mechanisms of action should be conducted

In addition to research on treatment efficacy, trials should also be conducted to help understand how a nutraceutical works. This should be based on in vitro, animal, and human trials. Demonstrating that a nutraceutical influences physiological mechanisms that may be associated with the pathophysiology of a disease helps validate the efficacy of a treatment. While determining potential mechanisms of action can be difficult to decipher (for many pharmaceutical drugs we still don’t know how they work), developing studies that include appropriate biological outcome measures to examine processes of change should be considered.

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____________________________________________________________________Clinical trials should be conducted in multiple countriesDue to the costs associated with conducting a clinical trial, many nutraceutical intervention studies are conducted in countries where it is cheapest to implement. Initial trials in these countries are encouraged as it can provide preliminary evidence of safety and efficacy. However, to increase robustness and confidence in findings, trials should be conducted on multiple populations. This is particularly pertinent if the ingredient will be sold internationally. By conducting studies in multiple sites around the world, we can establish a product’s efficacy and tolerability in diverse populations. Moreover, because many herbal treatments are based on traditional practices, exposure to a plant may be commonplace in a specific country/culture but not another. This can potentially influence tolerability and efficacy in different populations.

____________________________________________________________________Use independent clinical trial sitesIn-house studies can help manufacturers to understand the potential efficacy and safety of their ingredient/product. This is encouraged before the increased commercialisation of the ingredient/product. However, larger-scale studies must be conducted by independent clinical trial organisations. This can include universities or independent contract research organisations (CROs). Having an independent organisation conduct a clinical trial decreases the potential risk of bias and increases the perceived credibility of study findings. When choosing a research organisation, factors that need to be considered include the level of expertise and publication history of the researchers, costs of conducting the study (which should be fixed and agreed before the commencement of the study), level of adherence to good clinical practice, ethics approval and trial registry processes, ease of communication with research staff, recruitment processes used, intellectual property agreements, trial site accessibility for relevant populations, and the speed in conducting the study and submitting the results for publication.

____________________________________________________________________Publish in reputable, peer-reviewed journalsAfter a study is conducted, the results should be published in a high-quality, reputable, peer-reviewed journal. Even though in-house reports can help provide evidence of safety and efficacy, greater credibility in the findings occurs when an article is published in a journal after undergoing peer review by experts in the field. Unfortunately, many nutraceutical trials are either unpublished or published in low-quality journals. Moreover,

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decisions need to made about the most appropriate journal to publish in as this can have a significant impact on the level of awareness and publicity a research study receives. The number of available journals in the market is increasing, but unfortunately, many of them have a poor reputation and/or are low impact (i.e., no-one reads them). Some journal publishers also deceptively cite exaggerated impact factors (a measure of the popularity of a journal).

It is important to note that even if the findings of a trial are negative, studies should still be published. It is simply impossible for every trial on a nutraceutical to be positive. If trial results are negative this can help in developing a plan on future directions for the nutraceutical. Demonstrating that a company publishes all trials, irrespective of the results, can increase consumer confidence and trust in a company/brand.

____________________________________________________________________If possible, avoid sponsor-funded trialsWhere possible, sponsor-funded trials should be avoided as this can adversely influence community perception associated with the independence of findings. However, it is acknowledged that obtaining independently-sourced funds for a trial is extremely difficult for nutraceutical research. If manufacturers do not sponsor a trial it is unlikely one will ever be conducted. However, where possible, other avenues should be explored.

CONCLUSIONSDespite the increasing global interest and sales of nutraceuticals, government authorities and consumers alike, now have greater expectations of nutraceutical companies to prove the safety and efficacy of their products. The expanding availability and competition associated with nutraceuticals also mean that there is a greater need for companies to invest in clinical trials. However, even though companies are increasingly aware of the importance of, and are willing to invest in clinical trials, the quality of studies continue to be variable. Based on the recommendations that have been outlined, it is hoped that the nutraceutical industry will collectively improve research quality as well as the safety and efficacy associated with nutraceutical use.

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References1. Dietary Supplements Market Analysis, By Ingredient (Botanicals, Vitamins, and

others) By Product (Tablets, Capsules, and others), By Application (Medicinal, Sports, and others), By Distribution Channel (Online, Pharmacies and others), Forecasts to 2026. (accessed 21st March 2020) https://www.reportsanddata.com/report-detail/dietary-supplements-market

2. Council for responsible nutrition. 2017 CRN Consumer Survey on Dietary Supplements. (accessed 21st March 2020) https://www.crnusa.org/resources/2017-crn-consumer-survey-dietary-supplements

3. HerbalGram Herb Market Report - American Botanical Council (accessed 21st March 2020) http://cms.herbalgram.org/herbalgram/issue123/files/HG123-HMR.pdf

4. The Lancet. Dietary supplement regulation: FDA's bitter pill. Lancet. 2019 Feb 23;393(10173):718.

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About the authorDr Adrian Lopresti is a Clinical Psychologist in private practice, managing director at Clinical Research Australia (CRA), and adjunct senior lecturer at Murdoch University, Western Australia. He has over 20 years of clinical experience working with children and adults experiencing a range of mental-health conditions. Dr Lopresti has experience in several psychological therapies and has received extensive training in nutritional and lifestyle treatments for mental health disorders. Dr Lopresti regularly publishes in peer-reviewed, high-impact journals on the effects of diet, nutraceuticals, sleep, and exercise for the treatment of mental-health problems such as depression, anxiety, attention deficit hyperactivity disorder (ADHD), and bipolar disorder. He also publishes research on the effects of nutraceuticals on gastrointestinal health, the endocrine system, quality of life, and physical performance. Dr Lopresti is the founder of Personalised Integrative Therapy (PI Therapy), and regularly conducts workshops and seminars both nationally and internationally.