On 2016 Nov 22, Alex Vasquez commented:

Correspondence on this article has been published but as of 22 Nov 2016 (more than a month after publication on 19 Oct 2016) has not been appropriately linked; the citation is as follows: Vasquez A. Correspondence regarding Cutshall, Bergstrom, Kalish's "Evaluation of a functional medicine approach to treating fatigue, stress, and digestive issues in women.” Complement Ther Clin Pract. 2016 Oct 19 doi: 10.1016/j.ctcp.2016.10.001 http://www.ctcpjournal.com/article/S1744-3881(16)30107-4/abstract

Critiques of this article are described in the following paragraphs.

1. Description of treatments: The authors state that treatments were “personalized” but provide little data on how or why the treatment was allocated other than to divide patients into two groups for the “adrenal protocols” which are faintly outlined in the footnotes; no dosages are provided as all of the product formulations appear to be proprietary. Table 1 which outlines the “adrenal protocols” shows the treatments to be remarkably similar between the high and low salivary cortisol groups. The authors administered “DHEA drops” and “pregnenolone drops” but the varying dosages of the hormones, administered three times each per day, are not provided. Authors need to provide the actual dosages of all treatments, including hormones.

2. Use of hormonal therapy: The authors need to have described the laboratory methodology. Salivary DHEA levels were found to increase, decrease, and change unreliably, thus rendering these results worthless. Table 5 of the results shows that Cortisol/DHEA ratio started at 5.2 and resulted at 12 at the end of the study. Consistently throughout the medical literature, respectively higher levels of cortisol and lower levels of DHEA are causatively associated with insulin resistance, intra-abdominal obesity, hippocampal atrophy, and bone loss[1,2]; to the contrary of the bulk of the peer-reviewed literature, these authors present these results as beneficial changes. The “DHEA drops” and “pregnenolone drops” are not described either in dosage or formulation. Pregnenolone and DHEA are mood-elevating neurosteroids[3-5]. DHEA administration raises androgens and estrogens[6] which promote cancers[7,8]. The authors should have described appropriate serologic and clinical follow-up, risk considerations, and limits to duration of treatment. By failing to describe the dose of the steroid hormones used, the authors present that these hormones can be used without regard to dosage or duration; this presents a potential hazard by modeling unsafe use.

3. Accurate description of functional medicine: The authors define functional medicine as “The functional medicine model is focused on restoring optimal functioning of 3 body systems: hormonal, digestive, and detoxification.” The authors’ sweeping statement “Restoring these 3 body systems has positive effects on stress, energy, fatigue, digestive issues, and quality of life” has no citations. The definition of functional medicine provided by these authors is discordant with more authoritative descriptions published by the Institute for Functional Medicine[9] and International College of Human Nutrition and Functional Medicine.[10] The authors use the terminology “adrenal and digestive cleanse protocols” without definition, justification, or citation. In scientific publications, unique statements require substantiation and citation.

4. Controlling for external influences: The authors describe the dates of the study as “September 2014 through April 2015” but did not control for vitamin D levels and sunlight exposure which are known to affect mood and cognition[11,12]. The severity of depression, pain, and “functional disorders” has been reported to vary seasonally with exacerbations in fall and winter and alleviation in spring and summer.[13,14] The “lifestyle and nutritional counseling” included a 1-hour in-person coaching session at the start of the study, followed by various telephone contacts and “online group sessions” including “nutrition coaching and follow-up with diet compliance.” Patients may have felt better simply as a result of season change or social contact.

5. Disclosure of commercial interests: The authors deny conflict of interest and that “The study sponsors had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.” However, the authors do not disclose the identity of the sponsors. One of the authors (Kalish) is a consultant/speaker for a large distributor of nutritional supplements[15] and also a consultant/speaker/endorser of the laboratory used in this study[16]; these relationships are not disclosed in the article. According to the authors' interview[17] and press release[18] regarding their publication, they provide "training in functional medicine" and seminars related to the treatments used in this study. The authors fail to provide the identity of the study sponsors and the nature of the conflict(s) of interest.

6. Fecal microbiologic testing; antimicrobial treatments: The authors fail to detail the laboratory methodology for the microbiologic testing. Per the footnote describing the mastic product, the authors do not clearly describe the identity nor the ingredients of this treatment.

7. This clinical trial was not registered: The authors make no mention of having registered this clinical trial, and no record of the trial is available at https://clinicaltrials.gov/.

While the functional medicine approach to healthcare is science-based, eclectic, and effective[19], the field is not benefited by poorly conducted research, especially that which does not accurately reflect the practice, which employs poor methodology, and/or which uses steroid hormones without appropriate risk/benefit considerations. This publication is not an accurate representation of the clinical practice of functional medicine. The study design and description present several errors, the methods are not reproducible, the treatments were not sufficiency described, and the study cannot be either validated or refuted scientifically due to design flaws and/or inadequate description of treatments.

[1] Brown et al. Biol Psychiatry. 2004 Jan 1;55:1-9 [2] Ferrari et al. Eur J Endocrinol. 2001 Apr;144:319-29 [3] Brown et al. Neuropsychopharmacology. 2014 Nov;39:2867-73 [4] Fung et al. J Autism Dev Disord. 2014 Nov;44:2971-7 [5] Gaby AR. Alt Med Rev 1996;1:60-69 [6] Arlt et al. J Clin Endocrinol Metab. 1999 Jun;84:2170-6 [7] Folkerd E, Dowsett M. Breast. 2013 Aug;22 Suppl 2:S38-43 [8] Stoll BA. Eur J Clin Nutr. 1999 Oct;53:771-5 [9] Vasquez A. Reprint from Textbook of Functional Medicine: Web-like interconnections of physiological factors. Integrative Medicine 2006 April;5:32-37 [10] Vasquez A. Textbook of Clinical Nutrition and Functional Medicine. ICHNFM.ORG; 2016:134-146 [11] Kent et al. Environ Health. 2009 Jul 28;8:34 [12] Vieth et al. Nutr J. 2004 Jul 19;3:8 [13] Schlager et al. Compr Psychiatry. 1995 Jan-Feb;36:18-24 [14] Schlager et al. Br J Psychiatry. 1993 Sep;163:322-6 [15] emersonecologics.com/drkalish and emersonecologics.com/Webinars-DrKalish. June 10, 2016 [16] "BioHealth Adrenal Testing – Dan Kalish", "Premenopause Hormone Profiles: In Brief – Dan Kalish", and "Functional Lab Testing – Dan Kalish". biohealthlab.com/multimedia-archive/. June 17, 2016. [17] Functional Medicine Plan Treats Fatigue, Stress and Digestive Issues in Women. medicalresearch.com/author-interviews/functional-medicine-plan-treats-fatigue-stress-and-digestive-issues-in-women/25012. June 23, 2016. [18] Research Conducted with Mayo Clinic Practitioners and Kalish Institute Confirms Efficacy of Functional Medicine. businesswire.com/news/home/20160524005553/en/ June 23, 2016. [19] Vasquez A. Inflammation Mastery, 4th Edition. http://www.ICHNFM.ORG 2016 Dr Vasquez, Director ICHNFM and Consultant to Biotics Research

On 2016 Nov 22, Alex Vasquez commented:

Correspondence on this article has been published but as of 22 Nov 2016 (more than a month after publication on 19 Oct 2016) has not been appropriately linked; the citation is as follows: Vasquez A. Correspondence regarding Cutshall, Bergstrom, Kalish's "Evaluation of a functional medicine approach to treating fatigue, stress, and digestive issues in women.” Complement Ther Clin Pract. 2016 Oct 19 doi: 10.1016/j.ctcp.2016.10.001 http://www.ctcpjournal.com/article/S1744-3881(16)30107-4/abstract

Critiques of this article are described in the following paragraphs.

1. Description of treatments: The authors state that treatments were “personalized” but provide little data on how or why the treatment was allocated other than to divide patients into two groups for the “adrenal protocols” which are faintly outlined in the footnotes; no dosages are provided as all of the product formulations appear to be proprietary. Table 1 which outlines the “adrenal protocols” shows the treatments to be remarkably similar between the high and low salivary cortisol groups. The authors administered “DHEA drops” and “pregnenolone drops” but the varying dosages of the hormones, administered three times each per day, are not provided. Authors need to provide the actual dosages of all treatments, including hormones.

2. Use of hormonal therapy: The authors need to have described the laboratory methodology. Salivary DHEA levels were found to increase, decrease, and change unreliably, thus rendering these results worthless. Table 5 of the results shows that Cortisol/DHEA ratio started at 5.2 and resulted at 12 at the end of the study. Consistently throughout the medical literature, respectively higher levels of cortisol and lower levels of DHEA are causatively associated with insulin resistance, intra-abdominal obesity, hippocampal atrophy, and bone loss[1,2]; to the contrary of the bulk of the peer-reviewed literature, these authors present these results as beneficial changes. The “DHEA drops” and “pregnenolone drops” are not described either in dosage or formulation. Pregnenolone and DHEA are mood-elevating neurosteroids[3-5]. DHEA administration raises androgens and estrogens[6] which promote cancers[7,8]. The authors should have described appropriate serologic and clinical follow-up, risk considerations, and limits to duration of treatment. By failing to describe the dose of the steroid hormones used, the authors present that these hormones can be used without regard to dosage or duration; this presents a potential hazard by modeling unsafe use.

3. Accurate description of functional medicine: The authors define functional medicine as “The functional medicine model is focused on restoring optimal functioning of 3 body systems: hormonal, digestive, and detoxification.” The authors’ sweeping statement “Restoring these 3 body systems has positive effects on stress, energy, fatigue, digestive issues, and quality of life” has no citations. The definition of functional medicine provided by these authors is discordant with more authoritative descriptions published by the Institute for Functional Medicine[9] and International College of Human Nutrition and Functional Medicine.[10] The authors use the terminology “adrenal and digestive cleanse protocols” without definition, justification, or citation. In scientific publications, unique statements require substantiation and citation.

4. Controlling for external influences: The authors describe the dates of the study as “September 2014 through April 2015” but did not control for vitamin D levels and sunlight exposure which are known to affect mood and cognition[11,12]. The severity of depression, pain, and “functional disorders” has been reported to vary seasonally with exacerbations in fall and winter and alleviation in spring and summer.[13,14] The “lifestyle and nutritional counseling” included a 1-hour in-person coaching session at the start of the study, followed by various telephone contacts and “online group sessions” including “nutrition coaching and follow-up with diet compliance.” Patients may have felt better simply as a result of season change or social contact.

5. Disclosure of commercial interests: The authors deny conflict of interest and that “The study sponsors had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.” However, the authors do not disclose the identity of the sponsors. One of the authors (Kalish) is a consultant/speaker for a large distributor of nutritional supplements[15] and also a consultant/speaker/endorser of the laboratory used in this study[16]; these relationships are not disclosed in the article. According to the authors' interview[17] and press release[18] regarding their publication, they provide "training in functional medicine" and seminars related to the treatments used in this study. The authors fail to provide the identity of the study sponsors and the nature of the conflict(s) of interest.

6. Fecal microbiologic testing; antimicrobial treatments: The authors fail to detail the laboratory methodology for the microbiologic testing. Per the footnote describing the mastic product, the authors do not clearly describe the identity nor the ingredients of this treatment.

7. This clinical trial was not registered: The authors make no mention of having registered this clinical trial, and no record of the trial is available at https://clinicaltrials.gov/.

While the functional medicine approach to healthcare is science-based, eclectic, and effective[19], the field is not benefited by poorly conducted research, especially that which does not accurately reflect the practice, which employs poor methodology, and/or which uses steroid hormones without appropriate risk/benefit considerations. This publication is not an accurate representation of the clinical practice of functional medicine. The study design and description present several errors, the methods are not reproducible, the treatments were not sufficiency described, and the study cannot be either validated or refuted scientifically due to design flaws and/or inadequate description of treatments.

[1] Brown et al. Biol Psychiatry. 2004 Jan 1;55:1-9 [2] Ferrari et al. Eur J Endocrinol. 2001 Apr;144:319-29 [3] Brown et al. Neuropsychopharmacology. 2014 Nov;39:2867-73 [4] Fung et al. J Autism Dev Disord. 2014 Nov;44:2971-7 [5] Gaby AR. Alt Med Rev 1996;1:60-69 [6] Arlt et al. J Clin Endocrinol Metab. 1999 Jun;84:2170-6 [7] Folkerd E, Dowsett M. Breast. 2013 Aug;22 Suppl 2:S38-43 [8] Stoll BA. Eur J Clin Nutr. 1999 Oct;53:771-5 [9] Vasquez A. Reprint from Textbook of Functional Medicine: Web-like interconnections of physiological factors. Integrative Medicine 2006 April;5:32-37 [10] Vasquez A. Textbook of Clinical Nutrition and Functional Medicine. ICHNFM.ORG; 2016:134-146 [11] Kent et al. Environ Health. 2009 Jul 28;8:34 [12] Vieth et al. Nutr J. 2004 Jul 19;3:8 [13] Schlager et al. Compr Psychiatry. 1995 Jan-Feb;36:18-24 [14] Schlager et al. Br J Psychiatry. 1993 Sep;163:322-6 [15] emersonecologics.com/drkalish and emersonecologics.com/Webinars-DrKalish. June 10, 2016 [16] "BioHealth Adrenal Testing – Dan Kalish", "Premenopause Hormone Profiles: In Brief – Dan Kalish", and "Functional Lab Testing – Dan Kalish". biohealthlab.com/multimedia-archive/. June 17, 2016. [17] Functional Medicine Plan Treats Fatigue, Stress and Digestive Issues in Women. medicalresearch.com/author-interviews/functional-medicine-plan-treats-fatigue-stress-and-digestive-issues-in-women/25012. June 23, 2016. [18] Research Conducted with Mayo Clinic Practitioners and Kalish Institute Confirms Efficacy of Functional Medicine. businesswire.com/news/home/20160524005553/en/ June 23, 2016. [19] Vasquez A. Inflammation Mastery, 4th Edition. http://www.ICHNFM.ORG 2016 Dr Vasquez, Director ICHNFM and Consultant to Biotics Research