Natural Sympathomimetic Drugs: From Pharmacology to Toxicology
Abstract
:1. Introduction
2. Trace Amines
2.1. Sources
2.2. Pharmacology
2.2.1. TAAR1 and Its Agonists
2.2.2. TAAR1 Localization
2.2.3. Trace Amines as Indirect Sympathomimetic Agents
2.2.4. Trace Amines Pharmacokinetics
2.3. Toxic Effects of Trace Amines
3. Synephrine
3.1. Sources and Amounts Found in Natural Sources
3.2. Pharmacological Effects
3.3. In Vitro and In Vivo Toxicological Effects
3.4. Toxicology and Clinical Cases
Reference | Route of Administration | Toxidrome | Clinical History |
---|---|---|---|
[100] | Oral—Edita’s Skinny Pill 1 capsule daily containing 300 mg of C. aurantium, for one year. Other components: carnitine 250 mg, chromium 400 μg, chitosan 250 mg, herbal diuretic complex 200 mg, guarananine 30 mg, green tea 30 mg, calcium 150 mg. | Acute lateral-wall myocardial infarction. | The 55-year-old woman presented dull aching shoulder and chest pain after eating a Chinese food. An arteriogram revealed a lesion in the left main coronary artery (previously unknown), she reported smoking 1 ½ pack per day and high ingestion of caffeine. |
[101] | Oral—Stacker 2 Ephedra Free 1 or 2 capsules daily, labelled as having 6 mg of synephrine and 200 mg of caffeine. Treatment underwent for 1 week. | Acute and subacute infarctions in the left thalamus and multiple infarctions in the left cerebellum. | The 38-year-old man presented recent onset of dizziness, difficulty in concentrating, memory loss, and unsteady gait. He had no major risk factors for cardiovascular disease, and had not been taking long-term medications. |
[102] | Oral—CortiSlim 1 tablet twice daily. It contains: Leptiplex 125 mg (C. aurantium extract with 5% synephrine and Green tea leaf extract with 50% epigallocatechin. Other components: vitamin C 100 mg, calcium 100 mg, chromium 50 mg, insutrol 16.5 mg (Banaba leaf extract and vanadyl sulfate). | Variant angina involving the right coronary artery. | The 57-year-old man presented left-sided chest pressure with radiation to the jaw, shortness of breath, and diaphoresis while at rest. He had history of hypertriglyceridemia and gastroesophageal reflux disease. He had quit smoking 7 years yearlier and reported drinking 3 to 4 alcoholic beverages at night. Long-term medications used: fenofibrate, omeprazole, aspirin, a multivitamin, vitamin B complex, and vitamin E. |
[103] | Oral—Lipo 6 twice daily for 3 months. The supplement contains: synephrine, caffeine, and yohimbine (concentrations were not available). | Severe rhabdomyolysis, complicated by acute renal failure and bilateral compartment syndrome. | The 22-year-old, previously healthy, obese (body mass index 31), man, with sickle cell trait presented fatigue, light-headedness, and myalgia that started while running. He was diagnosed with rhabdomyolysis and heat exhaustion, and was discharged after brief hospitalization. Several weeks later, he had another episode of rhabdomyolysis and heat exhaustion, in this case severe. He presented hypotension, tachycardia, tachypnea, and myalgias. Initial evaluation revealed combined lactic and respiratory acidosis with metabolic alkalosis stemming from muscle hypoxia and ischemia with imminent respiratory failure. He developed hypovolemic shock, respiratory failure, acute renal failure, and disseminated intravascular coagulation. The patient had no history of exercise-associated rhabdomyolysis when performing physical activities without dietary supplements. |
[104] | Oral—Xenadrine-EFX was used for a few months. Posology was not detailed. | Left middle cerebral artery vasospasm and stroke. | The 36-year-old woman presented weakness in the right upper extremity, difficulty in speaking, right facial droop and severe headache. Exams revealed cerebral infarctions in the left frontal and opercular regions and decreased diameter of the left middle cerebral artery. She was previously healthy, with no history of migraine, tobacco use, thrombophilia, hyperlipidemia, or oral contraceptive use. |
[105] | Oral—Hi-Tech Lipodrene 1 tablet twice a day in the first week and then 2 tablets twice a day for two weeks. | Ventricular fibrillation. | The 27-year-old active duty Air Force female was performing the routine physical training when suddenly stopped and lied inactive. She presented thread pulse and agonal breathing, and cardiopulmonary resuscitation was required. The electrocardiogram showed a right bundle branch block and a QTc prolongation. She had a five pack-per-year smoking history and was previously healthy. |
[106] | Oral—Nutrex Lipo-6x 1 capsule twice a week for 3 weeks. The supplement contains synephrine, yohimbe, and phenylethylamine. He also reported the use of caffeine energy drinks. | ST-segment-elevation myocardial infarction (STEMI). | A previously healthy 24-year-old man presented acute-onset, “crushing,” mid-sternal chest pain that was accompanied by shortness of breath, ansiety, diaphoresis, and emesis. Emergent coronary angiography revealed extensive, diffuse thrombi in the left anterior descending coronary artery. The patient had no risk factors for coronary artery disease, and denied the use of drugs and alcohol. |
[107] | Oral—Jillian Michaels’ Fat Burner (two pills every morning) and Calorie Control (two pills three times a day). She increased the dosages 4 days prior to the episode. | Severe psychosis. | The 52-year-old woman with a history of anxiety, depression, and hypothyroidism, presented a change in mental status, tachycardia, high blood pressure, and unsteady gait. She had abused phenylpropanolamine and over-the-counter diet pills 28 months prior, which led to a previous episode with similar symptoms. She was previously taking buspirone and levothyroxine regularly. She denied drug and alcohol abuse, but her urine drug screen was positive for amphetamines >1000 ng/mL. |
[108] | Oral—She had been taking dietary supplements containing caffeine and synephrine during one week. Posology and product were not detailed. | Apical ballooning syndrome. | The 21-year-old female presented disturbed consciousness and seizure. Admission exams evidenced apical ballooning of the left ventricle due to akinesis from the apical to mid ventricular segments, hyperkinesis of the basal segments, with reduced left ventricular ejection fraction. She had no prior relevant medical history. |
[109] | Oral—two doses of C4 pre-workout supplement (contains synephrine and caffeine) within one hour of symptom onset. He consumed the supplement and energy drinks chronically. | Ascending aortic dissection. | The 38-year-old male presented syncopal episode and hypotension. Exams revealed ascending aortic dissection extending to the left subclavian artery, tricuspid aortic valve with severe aortic regurgitation, moderate left ventricular dilatation with a mildly depressed ejection fraction, and severe pulmonary hypertension. He had no prior significant medical history. |
[110] | Oral—Performix stim-free 1 capsule up to three times a day for one year. He drank 3 scoops of Performix SST for the first time on the afternoon of symptoms. | ST-segment-elevation myocardial infarction (STEMI) | The 22-year-old male presented acute onset of “pressure-like” substernal, non-radiating chest pain associated with shortness of breath and nausea while playing basketball. Angiography revealed acute dissection with thrombosis of the distal left main coronary artery leading into the proximal left anterior descending artery. He had no significant prior medical history and denied excessive caffeine use, smoking, and alcohol intake. |
4. Ephedrine
4.1. Sources and Amounts Found in Natural Sources
4.2. Pharmacological Effects
4.2.1. Activation of α1- and α2-Receptors
4.2.2. Activation of β1-, β2- and β3-Receptors
4.2.3. Hypoglycemic Effects
4.2.4. Nasal Vasoconstrictor Effects
4.3. Toxicological Effects
4.3.1. Cardiovascular Toxicity
4.3.2. Amphetamine-like Effects and CNS Toxicity
4.3.3. Hepatotoxicity
5. Cathinone
5.1. Definition and Sources
5.2. Pharmacology of Cathinone and Its Natural Derivatives
5.3. Toxicology of Cathinone and Its Natural Derivatives
6. Cocaine
6.1. Sources
6.2. Pharmacology of Cocaine and Its Metabolites
6.3. Toxicity of Cocaine
7. Caffeine and Other Anti-Thermogenic Drugs
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AADC | L- amino acid decarboxylase |
CNS | Central nervous system |
DAT | dopamine active transporter |
GPCR | G protein-coupled receptors |
EFSA | European Food Safety Authority |
FDA | The U.S. Food and Drug Administration |
MAO | monoamine oxidase |
MAOI | monoamine oxidases inhibitor |
TAARs | trace amine—associated receptors |
VMAT 2 | vesicular monoamine transporter 2 |
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Sample | Trace Amines (mg/kg) | Reference | ||
---|---|---|---|---|
TYR | PEA | TRYP | ||
Soppresata | 8.12–511.44 | 10.56–19.90 | ND | [22] |
Sausages | 10.33–338.85 | ND | ND | [22] |
Salami | 77.14 | 3.2 | 1.63 | [23] |
Hamburger | 1.5–27.0 | ND | 9.3–13.5 | [24] |
Chocolate | 3.11 | 2.67 | 1.43 | [23] |
Coffee | 1.26–16.41 | / | / | [9,25] |
Fermented cabbage | 60.66 | 0.73 | 0.18 | [23] |
Azeitão cheese 30 days of ripening | 122 | / | ≅ 65 | [20] |
Parmigiano cheese | 3.75 | 0.2 | 0.07 | [23] |
Yogurt | ND | 0.001 | ND | [23] |
Leerdamer | ND | 0.005 | 0.04 | [23] |
Red wine | 1.93 | 0.61 | 0.03 | [23] |
Red wine Abruzzo (Chieti, Italy) | 11.94 ± 7.79 mg L−1, mean ± s.d | ND | / | [26] |
Rosé wine Abruzzo (Chieti, Italy) | 0.27 ± 0.23 mg L−1, mean ± s.d. | 0.16 | / | [26] |
White wine Abruzzo (Chieti, Italy) | ND | ND | / | [26] |
Fiore Sardo Sheep Cheese (Sardinia, Italy) | 350 ± 300 mg/kg, mean ± s.d | / | / | [27] |
Lupin Luteus Spontaneously fermented | 32.6 | 128.8 | / | [28] |
Lupin Albus Spontaneously fermented | 69.1 | 144.1 | / | [28] |
Soybean Rudoji Spontaneously fermented | 30.1 ± 3.1 | 230.1 ± 8.6 | / | [28] |
Soybean Progress Spontaneously fermented | 27.8 ± 3.2 | 234.5 ± 12.3 | / | [28] |
Feta cheese | 0–246 | 0.77–4.94 | 2.18–6.24 | [29] |
Reference | Sample | Synephrine Content |
---|---|---|
[75] | Seville orange (C. aurantium) juice | 56.9 ± 0.52 μg/mL |
[66] | Dried fruits of Citrus species | 0.11–2.0 mg/g dry weight |
[68] | Unripe fruits and leaves of Citrus species | Fruits: 0.037–0.197% Leaves: 0.006–0.087% |
[77] | C. aurantium fruits and peels | Fruits: 0.99 ± 0.05 mg/g Peels: 1.14 ± 0.02 mg/g |
[64] | Juices of peeled Citrus unshiu fruits | 73.3–158.1 mg/L |
[78] | C. aurantium fruit extracts and fruit parts | Whole fruit extract: 600 µg/g |
Exocarp: 1100 µg/g | ||
Mesocarp: 580 µg/g | ||
Endocarp + juice: 94 µg/g | ||
[79] | Citrus reticulata ‘Chachi’ pericarp harvested at different stages | Early harvest: 1.90 ± 0.26 g/kg |
Middle harvest: 1.77 ± 0.27 g/kg | ||
Late harvest: 1.50 ± 0.20 g/kg | ||
[65] | C. aurantium fruits, leaves, stems, and roots in different harvest periods (June–September) | Fruits |
June: 3.36 ± 0.64 g/kg | ||
September: 0.41 ± 0.04 g/kg | ||
Leaves | ||
June: 1.86 ± 0.31 g/kg | ||
September: 1.08 ± 0.15 g/kg | ||
Stems | ||
June: 0.10 ± 0.00 g/kg | ||
September: 0.49 ± 0.23 g/kg | ||
Roots | ||
June: 0.03 ± 0.01 g/kg | ||
September: ≤ 0.01 g/kg |
Reference | Route of Administration | Concentrations | Toxidrome | Clinical History |
---|---|---|---|---|
[130] | Oral—cough mixture containing ephedrine. | Consumption of more than 400 mg of ephedrine a day. Ephedrine plasma concentration was not evaluated. | Cardiomiopathy | The 35-year-old man presented with general fatigue and shortness of breath. An electrocardiogram showed sinus tachycardia of 110 beats per min and left ventricular hypertrophy. Chest radiographs showed generalised cardiomegaly. Depressed left ventricular function with a corrected left ventricular ejection time of 65%. The man had had exercise-induced and hyperventilation asthma since the age of 14. In 1972 and 1973 he was treated for cardiac failure. |
[131] | Oral—Tablets containing 10 mg ephedrine and 100 mg caffeine. Morning of the presentation day: 20 mg ephedrine 200 mg caffeine Afternoon of the presentation day: 30 mg ephedrine 300 mg caffeine The day before presentation (2 pills morning and afternoon): 40 mg ephedrine 400 mg caffeine | Ephedrine plasma concentration of 150 ng/mL. | Cardiac Ischemia | The 22-year old woman presented with palpitations, nausea, tremulousness, abdominal pain, and vomiting. The initial electrocardiogram revealed a ST segment depression of 1 mm in leads V3 and V4, along with inverted T waves in leads V1–V4. |
[132] | Oral—Two tablets (one in the morning and one at lunch) making up a daily ingestion of 24 mg ephedrine and 80 mg caffeine for one month. | Ephedrine plasma concentration was not evaluated. | Myocardial infarction | The 45-year-old woman presented complaining of a 2-h substernal chest pressure with the pain radiating down into both forearms. An electrocardiogram showed a T-wave inversion and nonspecific ST changes suggestive of possible ischemia. The patient smoked 30 packs of cigarettes/year. Her family history was positive for premature coronary artery disease (her father underwent coronary artery bypass grafting at age of 63). Cardiac enzyme measurements revealed an elevated troponin level of 9.6 ng/mL. Cardiac catheterization was performed and no atherosclerotic disease was found in the coronary vessels, thus leading to the conclusion that vasospasm induced by ephedrine alkaloids was the cause of the patient’s acute myocardial infarction. |
[133] | Oral— ephedrine 30 mg, as well as aspirin 30 mg, caffeine 120 mg and narnegin 80 mg. | Ephedrine plasma concentration was not evaluated | Collapse | Male with collapse after running a half-marathon. On hospital arrival, a Glasgow coma score fluctuating between 12 and 13, hypoxic, and a temperature of 39 °C. Tachycardia and bilateral mydriasis. After being resuscitated, became hypoglycaemic and suffered two seizures. After intubation, he was admitted to the critical care unit. |
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Costa, V.M.; Grando, L.G.R.; Milandri, E.; Nardi, J.; Teixeira, P.; Mladěnka, P.; Remião, F.; on behalf of The OEMONOM. Natural Sympathomimetic Drugs: From Pharmacology to Toxicology. Biomolecules 2022, 12, 1793. https://doi.org/10.3390/biom12121793
Costa VM, Grando LGR, Milandri E, Nardi J, Teixeira P, Mladěnka P, Remião F, on behalf of The OEMONOM. Natural Sympathomimetic Drugs: From Pharmacology to Toxicology. Biomolecules. 2022; 12(12):1793. https://doi.org/10.3390/biom12121793
Chicago/Turabian StyleCosta, Vera Marisa, Luciana Grazziotin Rossato Grando, Elisa Milandri, Jessica Nardi, Patrícia Teixeira, Přemysl Mladěnka, Fernando Remião, and on behalf of The OEMONOM. 2022. "Natural Sympathomimetic Drugs: From Pharmacology to Toxicology" Biomolecules 12, no. 12: 1793. https://doi.org/10.3390/biom12121793