Synephrine

Synephrine

Systematic (IUPAC) name
4-[1-hydroxy-2-(methylamino)ethyl]phenol
Clinical data
Pregnancy cat.	?
Legal status	?
Identifiers
CAS number	94-07-5 Y
ATC code	C01CA08 S01GA06
PubChem	CID 7172
ChemSpider	6904 Y
UNII	PEG5DP7434 N
KEGG	D07148 Y
ChEBI	CHEBI:29081 N
ChEMBL	CHEMBL33720 Y
Chemical data
Formula	C9H13NO2
Mol. mass	167.205 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C9H13NO2/c1-10-6-9(12)7-2-4-8(11)5-3-7/h2-5,9-12H,6H2,1H3 Y Key:YRCWQPVGYLYSOX-UHFFFAOYSA-N Y
N(what is this?)  (verify)

Synephrine (or oxedrine) is a drug commonly used for weight loss. While its effectiveness is widely debated, synephrine has gained significant popularity as an alternative to ephedrine, a related substance which has been made illegal or restricted in many countries due to health risks and its use as a precursor in the illicit manufacturing of methamphetamine. There is however no occurrence of diverted synephrine for the manufacture of amphetamines, and the naturally occurring synephrine is, due to its phenolic group, unsuitable for such diversion. Products containing bitter orange or synephrine are suspected of causing adverse cardiovascular reactions.^[1] Synephrine is derived primarily from the immature fruit of Citrus aurantium, a relatively small citrus tree, of which several of its more common names include Bitter Orange, Sour Orange, and Zhi shi. Dietary supplements generally supply single oral doses of 3–30 mg, while as a pharmaceutical agent it is given orally or by parenteral injection in 20–100 mg doses as a vasoconstrictor to hypotensive patients.^[2]

Claims

• Decreases appetite
• Burns fat
• Increases energy
• Increases metabolism
• Promotes weight loss
• Increases body heat

Synephrine and neosynephrine

There has been some confusion surrounding synephrine and phenylephrine (neosynephrine), one of its positional isomers. The chemicals are similar in structure; the only difference is the location of the aromatic hydroxyl group. In synephrine, the hydroxyl is at the para position, whereas in neosynephrine it is at the meta position. Each compound has differing biological properties.

• Phenylephrine acts primarily on alpha₁ adrenergic receptors, so it has mainly vasoconstricting actions.
• Synephrine's pharmacology has not been thoroughly studied. Some comparisons with octopamine have been performed.^[3] There is some evidence that it may act at β₃ adrenergic receptors.^[4]

Associated risks

Many diet products such as "Stacker 2", "Xenadrine-EFX", etc. contain a "stack" of synephrine along with caffeine, sometimes with an NSAID. Some reports have indicated that such diet pills cause numerous harmful effects.^{[citation needed]} The Mayo Clinic published a report that suggested a link between Stacker 2 pills and increased risk of ischemic stroke, increased blood pressure, and myocardial infarction (heart attack).^[5]

Due to the aromatic hydroxyl group, the pharmacological profile is different to ephedrine; synephrine as a catecholamine analog is acting predominantly on peripheral adrenergic receptors and does not have a pronounced effect on the CNS.^{[citation needed]}

Synephrine can also cause arrhythmias.^[6] It is similar to ephedrine ^[6] and can therefore show similar symptoms (see ephedrine adverse effects).

Following the presentation of a healthy young man with a myocardial infarction, a case study and subsequent literature review found that the makers of "nutritional supplements" who replaced ephedrine with its analogs p-synephrine and/or p-octopamine from "bitter orange" had in effect simply found a loophole in the FDA's April 2004 regulation banning ephedra in those supplements by substituting a similar substance the regulation did not address, while permitting them to label the products as "ephedra-free".^[7]

Natural occurrence

It is reported as naturally occurring in the following species: Coryphanta cornifera, C. durangensis, C. elephantides, C. greenwoodii, C. ottonis, C. pectinata, C. poselgeriana, C ramillosa, C. runyonii, Dolichothele sphaerica, D. surculosa, D. uberiformis.^[8]

Unripe, dried fruits from Asian cultivars of Citrus aurantium (TCM: Zhi shi) contain phenylethylamines, mostly synephrine (to about 0.2%). Extracts thereof are today the main source of naturally occurring synephrine.^[9]

Synephrine and related alkaloids occur in in citrus fruit juices, particularly in bitter orange products and certain mandarin cultivars. Concentrations ranged from 55 to 160 mg/L in juice products obtained from the Satsuma mandarin variety.^[10] It can be assumed that trace amounts of synephrine also occur in regular juice products obtained from Citrus aurantium.

References

1. ^ Jordan S, Murty M, Pilon K (October 2004). "Products containing bitter orange or synephrine: suspected cardiovascular adverse reactions". Canadian Medical Association Journal 171 (8): 993–4. PMID 15497209. 
2. ^ Baselt RC (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, California: Biomedical Publications. pp. 1471–2. ISBN 9780962652370. 
3. ^ Brown CM, McGrath JC, Midgley JM et al. (February 1988). "Activities of octopamine and synephrine stereoisomers on alpha-adrenoceptors". Br. J. Pharmacol. 93 (2): 417–29. PMC 1853804. PMID 2833972. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1853804. 
4. ^ Carpéné C, Galitzky J, Fontana E, Atgié C, Lafontan M, Berlan M (April 1999). "Selective activation of beta3-adrenoceptors by octopamine: comparative studies in mammalian fat cells". Naunyn Schmiedebergs Arch. Pharmacol. 359 (4): 310–21. doi:10.1007/PL00005357. PMID 10344530. http://link.springer.de/link/service/journals/00210/bibs/9359004/93590310.htm. 
5. ^ 1: Mayo Clin Proc. 2006 Dec;81(12):1630-1.Links Ischemic colitis associated with use of a bitter orange-containing dietary weight-loss supplement. Sultan S, Spector J, Mitchell RM. Department of Medicine, University of Florida Medical Center and Malcolm Randall Veterans Affairs Medical Center, Gainesville, Fla 32605, USA. Since the US Food and Drug Administration banned the use of dietary supplements containing ephedra in February 2004, numerous "ephedra-free" weight-loss products have appeared on the market. Many of these supplements contain compounds such as bitter orange that are similar in structure and action to ephedra. We describe a patient in whom ischemic colitis developed 1 week after initiation of a bitter orange-containing weight-loss supplement. The patient had no other predisposing factors, and discontinuation of the supplement led to immediate improvement and ultimate resolution of her symptoms. Both consumers and health care professionals should be aware of the potential harm that bitter orange-containing dietary supplements can cause and report such adverse events to the US Food and Drug Administration.
6. ^ ^{a b} Livsmedelsverket (Swedish FDA)
7. ^ Thomas JE, Munir JA, McIntyre PZ, Ferguson MA (2009). "STEMI in a 24-Year-Old Man after Use of a Synephrine-Containing Dietary Supplement: A Case Report and Review of the Literature". Tex Heart Inst J. 36 (6): 586–90. PMC 2801940. PMID 20069086. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2801940. 
8. ^ Shulgin, Alexander & Shulgin, Ann (1997). Page 671. Tihkal: The Continuation. Berkeley: Transform Press. ISBN 0963009699 .
9. ^ X.G. He, L.Z. Lian, L. Lin and M. Bernart. (1997) J. Chromatogr. A 791, 127-134
10. ^ Dragull K, Breksa AP 3rd, Cain B. (2008) J Agric Food Chem. 8 ; 56 (19) : 8874-8 doi:10.1021/jf801225n

External links

• Ischemic Stroke Associated With Use of an Ephedra-Free Dietary Supplement Containing Synephrine (Mayo Clinic)
• Slim Pickings: Looking Beyond Ephedra (New York Times)
• SYNEPHRINE: Is Chih-shih (Zhishi) Toxic?