The Natural Health Products Directorate (NHPD) of Health Canada recently released a Health Risk Assessment (HRA) report on p-synephrine, p-octopamine, and caffeine¹ that markedly relaxes the previous guidelines for Canadian government compliance enforcement against unlicensed products containing these 3 natural ingredients. p-Synephrine is the primary protoalkaloid in bitter orange extract (Citrus aurantium, Rutaceae)² and is frequently combined with caffeine in weight loss and sports performance products. p-Octopamine, a protoalkaloid that is structurally and pharmacologically related to p-synephrine, exists in Citrus species such as lemons (C. limon, Rutaceae), but is present in trace amounts or absent in bitter orange extract.²

The HRA report,1 approved and issued in May of 2011, indicates that up to 50 mg per day of p-synephrine use in healthy adults is now classified as a Type III health risk, which by definition is “a situation in which the use of, or exposure to, a product is not likely [emphasis added] to cause any adverse health consequences.”³ The report further notes that products providing 40 mg per day or less of p-synephrine with 320 mg per day or less of caffeine are also classified as a Type III health risk. Products containing greater amounts of these ingredients are classified as a Type II health risk, which by definition is “a situation in which use of, or exposure to, a product may cause temporary adverse consequences or where the possibility of serious adverse health consequences is remote.”³ The daily dose-based health risk classifications for p-octopamine are identical to p-synephrine.

The previous “Guidelines for the Use of Synephrine in Natural Health Products,” published by Health Canada in January of 2010,⁴ had adopted a limit of 30 mg per day as the maximum allowable dose for total synephrine and octopamine, and prohibited the addition of any caffeine to a synephrine-containing product without submission of sufficient clinical evidence in human subjects.

The new report also requires the following cautionary statements (or words to this effect) on product labels “at doses higher than 50 mg p-synephrine or in combination with caffeine or other ingredients in vulnerable subpopulations, to mitigate the risk of potentially serious adverse events:”

• “Contraindicated in children, pregnancy, and breast feeding;”
• “Do not use if you are taking blood pressure medications (either hypertensives or antihypertensives), thyroid medications, sympathomimetics, or monoamine oxidase inhibitors (MAOIs).”

If these cautionary statements are lacking from a product containing 40 mg or less of p-synephrine and 320 mg or less of caffeine per day,¹ the product is classified as a Type II health risk as defined above.³

Health Canada has functions similar to the US Food and Drug Administration. The p-synephrine compliance guidelines were reviewed and the report was written because of information brought to the attention of NHPD in the form of new research and review publications:

• human clinical trials,^5,6
• animal studies,^7,8
• clinical case study reviews,^9,10
• recent in-depth review articles on the safety and efficacy of p-synephrine alone and in combination with caffeine,^11-13
• a review of comparative adrenergic receptor binding studies of the isomers and enantiomers of p-synephrine and related protoalkaloids,¹⁴ and
• the occurrence of up to 20-25 mg or more of p-synephrine per 8 oz glass of various citrus juices.²,

The conclusions of these various articles were not consistent with existing Health Canada guidelines for the use of p-synephrine.⁴

The new HRA report on p-synephrine, p-octopamine, and caffeine is a detailed and well-researched document that reviews the chemistry, receptor binding and in vitro studies, animal studies, human studies, summaries of clinical case reports, and Canadian clinical case reports. The report concluded that although p-synephrine-containing products had been implicated in adverse event case reports, “causality is not likely due to the p-synephrine content on its own, but rather due to other ingredients.” The report addresses misconceptions and misinformation concerning the safety of p-synephrine, and establishes more appropriate dosing guidelines for p-synephrine based on new clinical studies and published reviews of safety information. It does not address efficacy of p-synephrine-containing products.

All Health Canada reports must be made available in both English and French before they can be placed on the public website (www.healthcanada.gc.ca). The new report is 49 pages in length and has not been translated into French. Therefore, it has been available only upon request since its approval in May. Permission has been requested to make the report available through the American Botanical Council website (www.herbalgram.org).

Health Canada Clarification

According to Robin J. Marles, PhD, director of the Bureau of Clinical Trials and Health Sciences at NHPD, “This is not new regulatory approach; it is guidance to inspectors recommending that they don’t give priority for compliance enforcement to unlicensed products with lower doses of caffeine and synephrine that don’t pose a significant risk to health” (oral communication and e-mail, to M. Blumenthal, August 1, 2011).

“It is not Health Canada’s position as to how these products can be regulated,” he continued. “This is not a guideline to manufacturers as to what they can put into their products. They can actually include more of these ingredients if they can justify their approach with appropriate scientific and clinical evidence in an application for a natural health product license. A key difference from the US regulatory framework is that in Canada, dietary supplements can have therapeutic claims on the label but must be licensed before they can be sold legally.”

Dr. Marles, who is also a member of the ABC Advisory Board, further clarified his agency’s position on this issue: “Most of the products containing p-synephrine, sold as dietary supplements in the United States, are not licensed as Natural Health Products in Canada (which require government pre-approval). One of the biggest problems for NHPD/Health Canada is correlating the actual claims for the weight loss products with the actual clinical trials that have been conducted on weight loss, e.g., duration of the trial compared to label recommendations for duration of use of the product, dose, clinical endpoints tested, etc. So far there is little evidence to support these products helping people to lose enough body weight, over a long enough time, to be a real benefit to their health. Consuming fewer calories and getting more exercise remains the only proven weight loss approach.”

“Health Canada continues to work with industry stakeholders, healthcare practitioners, academia, regulatory agencies and consumers on how best to regulate weight loss and weight management products” (S. Sawler, director general of NHPD, September 1, 2011).

Summary

The Health Canada NHPD has reviewed and revised its guidelines to inspectors on the prioritization of compliance enforcement against unlicensed health products with respect to the amount of p-synephrine that can be contained in a product for daily use, as well as the amount of caffeine that may also be present. Cautionary label statements are required under some conditions. More appropriate dose-based guidelines have been established based on recent clinical studies, as well as published reviews of safety information.

Conflict of Interest Disclosure

The author has served as a consultant for Nutratech Inc., a company that markets bitter orange extracts.

References

1. Marles R. Synephrine, octopamine and caffeine health risk assessment (HRA) report. Health Canada Natural Health Products Directorate, File No. 172091. May 2011;1-49.
2. Uckoo RM, Jayaprakasha GK, Nelson DS, Patil BS. Rapid simultaneous determinations of amines and organic acids in citrus using high‐performance liquid chromatography. Talanta. 2010;83: 948–954.
3. Anon. Health Canada Health Products and Foods Branch Inspectorate-Recall Policy (POL-0016), 2006. Available at: www.hc-sc.gc.ca/dhp-mps/compli-conform/info-prod/drugs-drogues/pol_0016_recall_policy-politique_retrait_ltr-doc-eng.php. Accessed August 29, 2011.
4. Anon. Guidelines for the use of synephrine in Natural Health Products. Health Canada Natural Health Products Regulations, January 2010. Available at: www.hc-sc.gc.ca/dhp-mps/prodnatur/legislation/docs/notice-avis-synephrine-eng.php. Accessed August 29, 2011)
5. Seifert JG, Nelson A, Devonish J, Burke ER, Stohs SJ. The effects of acute administration of an herbal preparation in humans. Int J Med Sci. 2011; 8:192-197.
6. Stohs SJ, Preuss HG, Keith SC, Keith PL, Miller H, Kaats GR. Effects of p-synephrine in the presence and absence of selected flavonoids on resting metabolic rate, heart rate, blood pressure and self-reported mood changes. Int J Med Sci. 2011; 8: 295-301.
7. Arbo MD, Schmitt GC, Limberger MF, Charao MF, Moro AM, et al. Subchronic toxicity of Citrus aurantium L. (Rutaceae) extract and p-synephrine in mice. Reg Toxicol Pharmacol. 2009; 54: 114-117.
8. Hansen DK, Juliar BE, White GE, Pellicore LS. Developmental toxicity of Citrus aurantium in rats. Birth Defects Res Part B Devel Reprod Toxicol. 2011; 92: 216-223.
9. McGuffin M. Media spins numbers on bitter orange AERs based on erroneous information from FDA. HerbalGram. 2006; 69: 52-55.
10. Stohs SJ. Assessment of the adverse event reports associated with Citrus aurantium (bitter orange) from April 2004 to October 2009. J Funct Foods. 2011; 2: 235-238.
11. Stohs SJ, Preuss HG. The safety of bitter orange (Citrus aurantium) and its primary protoalkaloid p-synephrine. HerbalGram. 2011; 89: 34-39.
12. Stohs SJ, Preuss HG, Shara M. The safety of Citrus aurantium (bitter orange) and its primary protoalkaloid p-synephrine. Phytother Res. 2011. doi: 10.1002/ptr.3490.
13. Stohs SJ, Shara M. A review of the safety and efficacy of bitter orange (Citrus aurantium) and its primary protoalkaloid p‐synephrine in weight management. In: Obesity: Epidemiology, Pathophysiology and Prevention (2nd Ed.). Bagchi D,Preuss H (eds). CRC Press: Boca Raton, FL, 2011. (in press).
14. Stohs SJ, Preuss HG, Shara M. Review of the receptor binding properties of p-synephrine as related to its pharmacological effects. Oxid Med Cell Long. 2011; doi: 10.1155/2011/482973.
15. Dragull K, Breksa AP, Cain B. Synephrine content of juice from Satsuma mandarins (Citrus unshiu Marcovitch). J Agric Food Chem. 2008; 56: 8874–8878.