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DIMETHYLAMYLAMINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Dimethylamylamine (1,3-dimethylamylamine or DMAA) is an amphetamine derivative (often referred to as a "natural" stimulant) that can induce transient sympathomimetic effects.
    B) It is a straight chain aliphatic amine found in geranium flowers. It has been found in nutritional and body-building supplements under product names such as forthane, methylhexaneamine, geranium extract, and geranamine. As of April 2013, the US FDA has banned the sale of dietary supplements containing DMAA; companies are required to remove the products from the market or reformulate the products.

Specific Substances

    A) DIMETHYLAMYLAMINE SYNONYMS
    1) DMAA
    2) 1,3-DMAA
    3) 1,3-dimethylamylamine
    4) 1,3-dimethylpentylamine
    5) 2-amino-4-methylhexane
    6) 2-methyl-2-hexylamine
    7) 4-methyl- (9CI)
    8) Forthane
    9) Floradrene
    10) Geranamine
    11) Geranium
    12) Geranium Oil
    13) Geranium Extract
    14) Methylhexaneamine

Available Forms Sources

    A) FORMS
    1) It was originally produced in 1948 as a nasal inhaler and used as a nasal decongestant due to its vasoconstrictive action, but was withdrawn from the market in the 1970s. Today, it is used as an ingredient in numerous (over 200) sports supplements and weight loss products and sold in many health stores in the US (Cohen, 2013).
    2) In Europe and New Zealand, DMAA had been used as a party drug in place of 1-benzylpiperazine when the latter became a scheduled drug (Cohen, 2013; Vorce et al, 2011).
    3) Products containing dimethylamylamine may be listed as forthane, mehtylhexaneamine, 1,3-dimethyl-pentylamine and geranamine. A supplement may also use the terms geranium oil extract or geranium to describe DMAA (Vorce et al, 2011).
    B) SOURCES
    1) SUMMARY
    a) It has long been purported that DMAA can be isolated from the geranium plant (Vorce et al, 2011). However, variation in plant species and geographic and regional differences in the plant may account for the difference observed in DMAA concentration (Fleming et al, 2012).
    2) REMOVAL FROM MARKET
    a) FDA WARNING: As of April 2013, the FDA has banned the sale of dietary supplements that contain DMAA. Warning letters have been sent to companies producing these products to remove them from the market (U.S. Food and Drug Administration (FDA), 2013).
    b) PRODUCT BANNED: In Canada and the US Military, products (ie, dietary supplements) containing dimethylamylamine have been banned (Cohen, 2013; Forrester, 2013). It has also been banned in numerous other European countries including: Britain, Sweden, Denmark, Finland, Canada, New Zealand and Australia. In New Zealand, DMAA was previously sold as a party pill over-the-counter after the restricted sale of 1-benzypiperazine (BZP); measures to remove its sale began in 2009 (Vorce et al, 2011).
    3) COMMERCIAL PRODUCTS REPORTEDLY CONTAINING DIMETHYLAMYLAMINE
    1) Adrena G
    2) Allmax
    3) Biorhythm SSIN Juice
    4) Body Octane GAME DAY
    5) C4 (TM)
    6) Cellucor M5 Extreme
    7) Code Red
    8) Cryoshock
    9) D Stunner
    10) Flashover
    11) Freak n Muscle
    12) Hemo Rage Black
    13) Jack3d
    14) Lean Efx
    15) Lipo-6 Black Ultra
    16) Lipo-6 Black
    17) Lipo-6 Black Hers Ultra
    18) Lipo-6 Black Hers
    19) Mesomorph
    20) Methyl Fire
    21) MethylHex 4,2
    22) Methyldrene
    23) Muscle Spike
    24) Muscle Warfare
    25) Napalm
    26) Nitric Blast
    27) OxyElite Pro
    28) PWR (Pre Workout Revolution)
    29) Pressurge
    30) PumpFixx
    31) Razor8
    32) Spirodex
    33) Tiger Claw
    34) Unleashed
    35) Vyperize
    a) NOTE: The list of products below was derived prior to the recent ban of dietary supplements containing DMAA by the US FDA (April 2013); products may have been withdrawn or reformulated.
    b) REFERENCES: (Forrester, 2013; Vorce et al, 2011)
    4) BAN OF DMAA CONTAINING SUPPLEMENTS
    a) The following DMAA containing products have been withdrawn from all US Military Exchanges as of December 2011 (Cohen, 2012) following the death of 2 soldiers (Forrester, 2013):
    1) Jack3d (tropical fruit and lemon lime)
    2) OxyELITE Pro
    3) Lipo 6 Ultra
    4) Lipo 6 Black Ultra
    5) Hemo Rage Black
    6) PWR Ultra Concentrated Pre Workout Revolution
    7) Neuocore Powder
    8) HydroxyStim
    9) Lean EFX
    10) Napalm
    11) Nitric Blast
    12) Biorhythm SSIN Juice
    13) Code Red
    14) MethylHex4,2
    15) Arson Fat Burner Capsule
    16) Spirodex
    C) USES
    1) Dimethylamylamine (1,3-dimethylamylamine or DMAA) is an amphetamine derivative (often referred to as a "natural" stimulant) (U.S. Food and Drug Administration (FDA), 2013; Fleming et al, 2012) that has been sold commercially as both a bodybuilding supplement and a legal stimulant (Gee et al, 2010). It is a straight chain aliphatic amine found naturally in geranium flowers. Dimethylamylamine has sympathomimetic physiological effects, that acts as a norepinephrine reuptake inhibitor and/or a norepinephrine releasing agent (Forrester, 2013).
    2) At present, there is limited information on the safety of DMAA-containing products (Forrester, 2013).
    3) Individuals taking dimethylamylamine-containing products have reported sleeplessness, shakiness, anxiety, chills, sweating, nausea, tingling, fatigue and headaches (Forrester, 2013).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Dimethylamylamine (1,3-dimethylamylamine or DMAA) is used alone or often combined with caffeine as a dietary supplement, weight loss aid, and body building energy supplement. It is found in herbal products and is sometimes listed as "geranamine" or geranium oil extract. Two of the most common supplements containing DMAA are "Jack3d" and "OxyELITE Pro. However, as of April 2013, the FDA has banned the sale of dietary supplements containing DMAA and requested companies producing these products to remove them from the market. It has also been used as a "party" drug in Europe and New Zealand.
    B) PHARMACOLOGY: Dimethylamylamine has been naturally found in low concentrations in geranium plants (Pelargonium graveolens), and reportedly an indirect sympathomimetic amine. It is a central nervous system stimulant and can induce transient sympathomimetic effects.
    C) TOXICOLOGY: It may have amphetamine-like effects. Similar to amphetamines, overdose or chronic excessive use can cause a sympathomimetic toxidrome (eg, tachycardia, hypertension, agitation, and, in severe cases, psychosis).
    D) EPIDEMIOLOGY: Exposure is more likely to occur in young adult males; however, exposure has occurred in children.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Limited data. Nausea, vomiting, and tachycardia are the most frequently reported adverse events reported with dimethylamylamine use. Other events have included agitation, headache and dizziness. DMAA-containing supplements have also been implicated in panic attacks and seizures.
    2) SEVERE TOXICITY: There have been several reports of cerebral hemorrhage following the use of dimethylamylamine containing products. Fatalities have been reported secondary to a hyperthermia-like syndrome (severe hyperthermia in a setting of mild environmental temperatures and physical exertion, hypotension, cardiac arrest, metabolic acidosis, renal failure, liver injury and acute lung injury) in healthy young adults.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Hyperthermia was reported following physical exertion in 2 soldiers taking a dietary supplement containing DMAA.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Plasma levels are not clinically useful or readily available.
    C) Monitor serum electrolytes and renal function. Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (agitation, delirium, seizures, coma, hypotension, hyperthermia).
    D) Monitor liver enzymes and coagulation studies in patients who develop severe toxicity.
    E) Monitor creatinine phosphokinase in patients with prolonged agitation, seizures, hyperthermia or coma; monitor renal function and urine output in patients with rhabdomyolysis.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Limited data. Treatment is symptomatic and supportive. Monitor vital signs and mental status. Hypertension and tachycardia have been reported with exposure and were well tolerated; treat with benzodiazepines as necessary.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. The goal of treatment is to manage agitation and prevent end-organ damage. Consider activated charcoal in recent, large overdoses (GI decontamination should be performed only in patients who are cooperative and can protect their airway or who are intubated). Treat agitation with benzodiazepines. Seizures may require aggressive use of benzodiazepines, propofol and/or barbiturates. Monitor and treat for dysrhythmias. Monitor core temperature and treat hyperthermia with aggressive benzodiazepine sedation to control agitation, external cooling. Neuromuscular paralysis and endotracheal intubation may be necessary in patients with severe hyperthermia. Monitor patient closely until symptoms resolve; the half-life of dimethylamylamine is unknown.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended because so little is known about the toxicity of dimethylamylamine. Agitation and seizure have occurred in a limited number of cases.
    2) HOSPITAL: Activated charcoal if recent, substantial oral ingestion, and the patient is cooperative and able to protect their airway or is intubated.
    D) AIRWAY MANAGEMENT
    1) Perform early in a patient with severe intoxication (i.e., seizures, dysrhythmias, severe agitation or hyperthermia).
    E) ANTIDOTE
    1) None.
    F) SEIZURES
    1) Treat with IV benzodiazepines, add propofol or barbiturates if seizures persist or recur. Correct hyponatremia, if present.
    G) HYPERTHERMIA
    1) Control agitation with benzodiazepines, initiate aggressive external cooling measures. Undress patients, keep skin moist and use fans to enhance evaporative cooling. Ice water immersion should be considered in severe cases but can make access to the patient for resuscitation more difficult. If needed, intubate, sedate and paralyze.
    H) PSYCHOMOTOR AGITATION
    1) Sedate patient with benzodiazepines as necessary; large doses may be required. Minimize external stimuli; place in quiet, dark room.
    I) FLUID ELECTROLYTE DISORDER
    1) Monitor fluids status and serum electrolytes if significant vomiting occurs, and replete as necessary.
    J) ENHANCED ELIMINATION
    1) Hemodialysis and hemoperfusion are not of known value.
    K) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic or minimally symptomatic (nausea, self limited vomiting, mild tachycardia or headache) adults may be monitored at home following a minor exposure that was not a self-harm attempt. Asymptomatic children can be monitored at home following a minor (1 tablet of a dietary supplement containing DMAA) exposure, if a responsible adult is present.
    2) OBSERVATION CRITERIA: Patients with deliberate self-harm ingestions and symptomatic patients should be sent to a healthcare facility for evaluation and observation for 6 to 8 hours.
    3) ADMISSION CRITERIA: Patients with significant persistent central nervous system toxicity (i.e., somnolence, coma, severe headache) or persistent tachycardia should be admitted. Patients with coma, seizures, dysrhythmias, or cerebral hemorrhage should be admitted to an intensive care setting.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (i.e., seizures, dysrhythmias, cerebral hemorrhage, coma), or in whom the diagnosis is not clear.
    L) PITFALLS
    1) Failure to control agitation and manage hyperthermia and seizures can result in death and irreversible end-organ damage. Patients with altered mentation should be evaluated for intracranial hemorrhage, infection, metabolic disturbance and hyponatremia.
    M) PHARMACOKINETICS
    1) Dimethylamylamine is an amphetamine derivative (also referred to as a "natural" stimulant). It is a straight chain aliphatic amine found naturally at low concentrations in geranium flowers. Dimethylamylamine is an indirect sympathomimetic amine and has sympathomimetic physiological effects (both vasoconstrictive and cardiovascular effects), that acts as a norepinephrine reuptake inhibitor and/or a norepinephrine releasing agent. In a small study of healthy volunteers, the pharmacokinetic effects of oral dimethylamylamine (a single 25 mg oral dose) were analyzed and the results are as follows: mean Tmax of 3.57 hours (range, 2 to 6 hours), Cmax had a mean of 76.54 ng/mL with a mean oral clearance of 20.02 +/- 5 L/hr; the volume of distribution was 236 +/- 38 L; and terminal half-life was 8.45 +/- 1.9 hours.
    N) DIFFERENTIAL DIAGNOSIS
    1) Hypoglycemia, central nervous system infection, other sympathomimetic poisoning (such as cocaine), anticholinergic toxicity, or ethanol/benzodiazepine/barbiturate withdrawal.

Range Of Toxicity

    A) TOXIC DOSE: Limited data. Two fatalities from a heat stroke like syndrome have been associated with the use of dietary supplements containing dimethylamylamine; the first case died within hours of exposure and the second case died several weeks later from complications due to sepsis. Cerebral hemorrhage was reported in a young adult after ingesting 2 dimethylamylamine (278 mg/capsule) capsules at a party; severe impairment of memory and abstract reasoning and mild impairment of speech and right hand coordination occurred.
    B) DIETARY SUPPLEMENTS: Dimethylamylamine can be found in some dietary and body-building supplements.

Clinical Effects

Summary Of Exposure

    A) USES: Dimethylamylamine (1,3-dimethylamylamine or DMAA) is used alone or often combined with caffeine as a dietary supplement, weight loss aid, and body building energy supplement. It is found in herbal products and is sometimes listed as "geranamine" or geranium oil extract. Two of the most common supplements containing DMAA are "Jack3d" and "OxyELITE Pro. However, as of April 2013, the FDA has banned the sale of dietary supplements containing DMAA and requested companies producing these products to remove them from the market. It has also been used as a "party" drug in Europe and New Zealand.
    B) PHARMACOLOGY: Dimethylamylamine has been naturally found in low concentrations in geranium plants (Pelargonium graveolens), and reportedly an indirect sympathomimetic amine. It is a central nervous system stimulant and can induce transient sympathomimetic effects.
    C) TOXICOLOGY: It may have amphetamine-like effects. Similar to amphetamines, overdose or chronic excessive use can cause a sympathomimetic toxidrome (eg, tachycardia, hypertension, agitation, and, in severe cases, psychosis).
    D) EPIDEMIOLOGY: Exposure is more likely to occur in young adult males; however, exposure has occurred in children.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Limited data. Nausea, vomiting, and tachycardia are the most frequently reported adverse events reported with dimethylamylamine use. Other events have included agitation, headache and dizziness. DMAA-containing supplements have also been implicated in panic attacks and seizures.
    2) SEVERE TOXICITY: There have been several reports of cerebral hemorrhage following the use of dimethylamylamine containing products. Fatalities have been reported secondary to a hyperthermia-like syndrome (severe hyperthermia in a setting of mild environmental temperatures and physical exertion, hypotension, cardiac arrest, metabolic acidosis, renal failure, liver injury and acute lung injury) in healthy young adults.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Hyperthermia was reported following physical exertion in 2 soldiers taking a dietary supplement containing DMAA.
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) Severe hyperthermia (core temperatures of 105 degrees F and 105.5 degrees F) despite mild ambient temperatures was noted in 2 soldiers that collapsed following moderate physical activity while taking a dietary supplement containing DMAA (the substance was confirmed by laboratory confirmation). One patient died shortly after admission due to refractory asystole and the second patient died 5 weeks later of complications due to sepsis (Eliason et al, 2012).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) In a retrospective review of 39 oral exposures to DMAA-containing products only reported to the Texas Poison Control Network during 2010 to 2011, tachycardia was one of the most frequently reported adverse clinical events. All patients recovered and most patients were managed at home (Forrester, 2013).
    b) In retrospective review of 50 calls received to the New South Wales Poison Information Center reporting adverse events among adults from use of DMAA-containing products (recreational or therapeutic), tachycardia (n=21) was frequently reported (Brown & Buckley, 2013).
    c) CASE REPORT: A 32-year-old female soldier with mild obesity and sickle cell trait collapsed after almost completing a 2-mile physical fitness test. She was found asystolic and CPR was initiated. Upon admission, the patient was unresponsive with severe hypotension (77/36 mmHg), tachycardia (109 beats/min) and hyperthermia (105 degrees F). Ambient temperature was 23 degrees C. She developed anion gap metabolic acidosis, renal and liver insufficiency and evidence of disseminated intravascular coagulation (prolonged PT, PTT and INR). The patient remained comatose and developed multiple organ failure (rhabdomyolysis, renal and liver failure, pancreatitis, DIC and pulmonary edema). A toxicology analysis performed 4 days after admission was positive for DMAA (0.04 mg/L) and caffeine (1.9 mg/L) only. Two supplements containing DMAA were found in her car; it was uncertain how long she had been taking the supplement or the amount. The patient improved briefly, but ultimately developed sepsis and died 5 weeks after admission (Eliason et al, 2012).
    d) CASE REPORT: A 2-year-old child inadvertently ingested a DMAA-containing product (amount not reported) and required hospitalization overnight and benzodiazepine therapy for agitation and tachycardia (Brown & Buckley, 2013).
    B) HYPERTENSIVE DISORDER
    1) WITH POISONING/EXPOSURE
    a) SUMMARY: In one study, systolic increases in blood pressure following DMAA use appeared to be dose-dependent (ie, 75 mg dose compared to 50 mg dose) (Bloomer et al, 2013).
    b) In a retrospective review of 56 oral exposures to DMAA-containing products only reported to the Texas Poison Control Network during 2010 to 2011, hypertension occurred infrequently. All patients recovered and most patients were managed at home (Forrester, 2013).
    c) In retrospective review of 50 calls received to the New South Wales Poison Information Center reporting adverse events among adults from use of DMAA-containing products (recreational or therapeutic), hypertension was reported in 4 cases (Brown & Buckley, 2013).
    C) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 32-year-old female soldier with mild obesity and sickle cell trait collapsed after almost completing a 2-mile physical fitness test. She was found asystolic and CPR was initiated. Upon admission, the patient was unresponsive with severe hypotension (77/36 mmHg), tachycardia (109 beats/min) and hyperthermia (105 degrees F). Ambient temperature was 23 degrees C. She developed anion gap metabolic acidosis, renal and liver insufficiency and evidence of disseminated intravascular coagulation (prolonged PT, PTT and INR). The patient remained comatose and developed multiple organ failure (rhabdomyolysis, renal and liver failure, pancreatitis, DIC and pulmonary edema). A toxicology analysis performed 4 days after admission was positive for DMAA (0.04 mg/L) and caffeine (1.9 mg/L) only. Two supplements containing DMAA were found in her car; it was uncertain how long she had been taking the supplement or the amount. The patient improved briefly, but ultimately developed sepsis and died 5 weeks after admission (Eliason et al, 2012).
    D) CARDIAC ARREST
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 21-year-old man developed cardiac arrest while exercising at a gym. Spontaneous circulation returned following cardiopulmonary resuscitation and defibrillation. An ECG revealed ST segment elevation without QT prolongation. Laboratory data indicated elevated troponin T (1.09 ng/mL), creatine kinase (1868 units/L), and CK-MB (58.6 ng/mL) concentrations. The patient experienced blurry vision, and a head CT scan and a subsequent MRI indicated evidence of symmetric hypoxic-ischemic brain injury. There was no evidence of anabolic steroid use, and urinalysis via gas chromatography/mass spectrometry was negative for phentermine, ephedrine, pseudoephedrine, methamphetamine, MDA, and MDMA. Further investigation of the patient revealed that he had taken a dietary supplement containing 1,3-dimethylamylamine and a protein powder prior to his workout. An echocardiogram on hospital day 2 revealed reduction in the biventricular systolic function with a left ventricular ejection fraction (LVEF) of 35%. The next day, measurement of the LVEF was 52% (at the lower end of normal) and, by hospital day 4, systolic function normalized to 65%. A cardioverter defibrillator was implanted and the patient was discharged with continued outpatient rehabilitation. Prior to discharge, a repeat ECG showed normalization of ST segment changes. At his 4-month follow-up visit, there was no evidence of neurologic deficits (Karnatovskaia et al, 2015).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CEREBRAL HEMORRHAGE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 21-year-old man experienced a cerebral hemorrhage after ingesting 2 dimethylamylamine (278 mg/capsule) capsules at a party. Thirty minutes after exposure he complained of a severe global headache followed by confusion, urinary incontinence and vomiting for several hours prior to falling to sleep. The following day he awoke with slurred speech and was admitted with confusion and right facial droop and right-sided weakness. A head CT showed a large hemorrhage in the left basal ganglia region causing a 5 mm midline shift. Following acute care he was transferred to a brain injury rehabilitation center. A multidisciplinary assessment indicated that patient had severe impairment of memory and abstract reasoning, along with mild impairment of speech and right hand coordination. Laboratory analysis confirmed the presence of dimethylamylamine only (Gee et al, 2010).
    b) CASE REPORT: A 26-year-old male solider stationed in Afghanistan developed a severe headache after taking a weight lifting supplement called "Jack3d" (3 scoops/day; maximum recommended amount for approximately 3 weeks) which was found to contain geranamine, caffeine, creatine, and amino acids. He continued to have severe pain behind the right eye and awoke later with left hemidysesthesia, weakness and lack of coordination. A CT scan confirmed a right midbrain-thalamic hemorrhage; repeat images showed that lesion was medically stable. The patient was returned to the US and diagnosed with Dejerine-Roussy syndrome (a thalamic hemorrhagic stroke). Other screening tests were negative and a small patent foramen ovale was considered noncontributory. He had a slight improvement of his left hemidysesthesia and was transferred for further rehabilitation (Young et al, 2012).
    B) PSYCHOMOTOR AGITATION
    1) WITH POISONING/EXPOSURE
    a) In a retrospective review of 56 oral exposures to DMAA-containing products only reported to the Texas Poison Control Network during 2010 to 2011, agitation and/or irritability occurred infrequently. All patients recovered and most patients were managed at home (Forrester, 2013).
    b) In retrospective review of 50 calls received to the New South Wales Poison Information Center reporting adverse events among adults from use of DMAA-containing products (recreational or therapeutic), anxiety or agitation was reported in 7 cases (Brown & Buckley, 2013).
    c) CASE REPORT: A 2-year-old child inadvertently ingested a DMAA-containing product (amount not reported) and required hospitalization overnight and benzodiazepine therapy for agitation and tachycardia (Brown & Buckley, 2013).
    C) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) In retrospective review of 50 calls received to the New South Wales Poison Information Center reporting adverse events among adults from use of DMAA-containing products (recreational or therapeutic), headache occurred in 8 cases (Brown & Buckley, 2013).
    D) DIZZINESS
    1) WITH POISONING/EXPOSURE
    a) In retrospective review of 50 calls received to the New South Wales Poison Information Center reporting adverse events among adults from use of DMAA-containing products (recreational or therapeutic), dizziness was reported in 4 cases (Brown & Buckley, 2013).
    E) SEIZURE
    1) WITH THERAPEUTIC USE
    a) DMAA-containing supplements have been implicated in seizures and panic attacks. An exact cause and effect has not been determined (Cohen, 2013).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) In a retrospective review of 39 exposures to DMAA-containing products only reported to the Texas Poison Control Network during 2010 to 2011, nausea and vomiting were the most frequently reported adverse clinical events. All patients recovered and most patients were managed at home (Forrester, 2013).
    b) In retrospective review of 50 calls received to the New South Wales Poison Information Center reporting adverse events among adults from use of DMAA-containing products (recreational or therapeutic), nausea and/or vomiting were the most commonly reported adverse events (Brown & Buckley, 2013).
    c) CASE REPORT: 21-year-old man ingested 2 tablets of DMAA (278 mg capsule) and developed a severe global headache within 30 minutes and then he began vomiting for 2 to 3 hours. The patient was taken to the hospital 19 hours after ingestion with confusion and slurred speech and was diagnosed with a cerebral hemorrhage. The patient gradually improved over a few weeks following rehabilitation (Gee et al, 2010).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) METABOLIC ACIDOSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 32-year-old female soldier with mild obesity and sickle cell trait collapsed after almost completing a 2-mile physical fitness test. She was found asystolic and CPR was initiated. Upon admission, the patient was unresponsive with severe hypotension (77/36 mmHg), tachycardia (109 beats/min) and hyperthermia (105 degrees F). Ambient temperature was 23 degrees C. She developed anion gap metabolic acidosis, renal and liver insufficiency and evidence of disseminated intravascular coagulation (prolonged PT, PTT and INR). The patient remained comatose and developed multiple organ failure (rhabdomyolysis, renal and liver failure, pancreatitis, DIC and pulmonary edema). A toxicology analysis performed 4 days after admission was positive for DMAA (0.04 mg/L) and caffeine (1.9 mg/L) only. Two supplements containing DMAA were found in her car; it was uncertain how long she had been taking the supplement or the amount. The patient improved briefly, but ultimately developed sepsis and died 5 weeks after admission (Eliason et al, 2012).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Plasma levels are not clinically useful or readily available.
    C) Monitor serum electrolytes and renal function. Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (agitation, delirium, seizures, coma, hypotension, hyperthermia).
    D) Monitor liver enzymes and coagulation studies in patients who develop severe toxicity.
    E) Monitor creatinine phosphokinase in patients with prolonged agitation, seizures, hyperthermia or coma; monitor renal function and urine output in patients with rhabdomyolysis.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor sodium and renal function.
    2) Monitor creatinine phosphokinase in patients with prolonged agitation, seizures, hyperthermia, or coma; monitor renal function and urine output in patients with rhabdomyolysis.
    3) Monitor liver enzymes and coagulation studies in patients who develop severe toxicity.
    4) Monitor fluid status, which may include hemodynamic pressure monitoring, to evaluate and guide fluid therapy in severe overdose.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (i.e., agitation, delirium, seizures, coma, hyperthermia, hypotension).
    b) Central venous or pulmonary artery pressure monitoring may be required to guide fluid resuscitation in patients with severe toxicity.

Methods

    A) POSITIVE IMMUNOASSAY
    1) Dimethylamylamine has a structural similarity to amphetamines and can cross-react with any immunoassay targeting amphetamine type compounds (Vorce et al, 2011).
    a) In one study, the Department of Defense typically uses a 3-tiered system to test for amphetamines. It was noted that initial screening using qualitative immunoassays were positive in the presence of DMAA. Confirmatory testing using liquid chromatography-tandem mass spectrometry was positive for DMAA in 92.3% of the false-positive samples (n=134) at a concentration of 6.0 mg/L (Vorce et al, 2011).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with significant persistent central nervous system toxicity (i.e., somnolence, coma, dysrhythmias) or persistent tachycardia should be admitted. Patients with coma, seizures, dysrhythmias, or cerebral hemorrhage should be admitted to an intensive care setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic or minimally symptomatic (nausea, self limited vomiting, mild tachycardia or headache) adults may be monitored at home following a minor exposure that was not a self-harm attempt . Asymptomatic children can be monitored at home following a minor (1 tablet of a dietary supplement containing DMAA) exposure, if a responsible adult is present.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (i.e., seizures, dysrhythmias, coma), or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate self-harm ingestions or symptomatic patients should be sent to a healthcare facility for observation for 6 to 8 hours.

Monitoring

    A) Monitor vital signs and mental status.
    B) Plasma levels are not clinically useful or readily available.
    C) Monitor serum electrolytes and renal function. Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (agitation, delirium, seizures, coma, hypotension, hyperthermia).
    D) Monitor liver enzymes and coagulation studies in patients who develop severe toxicity.
    E) Monitor creatinine phosphokinase in patients with prolonged agitation, seizures, hyperthermia or coma; monitor renal function and urine output in patients with rhabdomyolysis.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is not recommended because so little is known about the toxicity of dimethylamylamine. Agitation and seizures have occurred in a limited number of cases.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Gastrointestinal decontamination is unlikely to be necessary following a mild exposure. Consider activated charcoal if the ingestion was large and occurred recently, and the patient is cooperative and able to protect the airway.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MILD TO MODERATE TOXICITY: Limited data. Treatment is symptomatic and supportive. Monitor vital signs and mental status. Hypertension and tachycardia have been reported with exposure and were well tolerated; treat with benzodiazepines as necessary.
    2) SEVERE TOXICITY: Treatment is symptomatic and supportive. The goal of treatment is to manage agitation and prevent end-organ damage. Consider activated charcoal in recent, large overdoses (GI decontamination should be performed only in patients who are cooperative and can protect their airway or who are intubated). Treat agitation with benzodiazepines. Seizures may require aggressive use of benzodiazepines, propofol and/or barbiturates. Monitor and treat for dysrhythmias. Monitor core temperature and treat hyperthermia with aggressive benzodiazepine sedation to control agitation, external cooling. Neuromuscular paralysis and endotracheal intubation may be necessary in patients with severe hyperthermia. Monitor patient closely until symptoms resolve; the half-life of dimethylamylamine is unknown.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status. Plasma levels are not clinically useful or readily available. Monitor serum electrolytes and renal function.
    2) Obtain ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (i.e., agitation, delirium, seizures, coma, hypotension).
    3) Monitor creatinine phosphokinase in patients with prolonged agitation, seizures, hyperthermia or coma; monitor renal function and urine output in patients with evidence of rhabdomyolysis.
    4) Monitor liver enzymes and coagulation studies in patients with hyperthermia.
    5) Dimethylamylamine has a structural similarity to amphetamines and can cross-react with any immunoassay targeting amphetamine type compounds.
    6) Monitor patient closely until symptoms resolve; the half-life of dimethylamylamine is unknown.
    C) PSYCHOMOTOR AGITATION
    1) INDICATION
    a) If patient is severely agitated, sedate with IV benzodiazepines.
    2) DIAZEPAM DOSE
    a) ADULT: 5 to 10 mg IV initially, repeat every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    3) LORAZEPAM DOSE
    a) ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed (Manno, 2003).
    b) CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    4) Extremely large doses of benzodiazepines may be required in patients with severe intoxication in order to obtain adequate sedation. Titrate dose to clinical response and monitor for hypotension, CNS and respiratory depression, and the need for endotracheal intubation.
    5) Phenothiazines are not routinely recommended due to undesirable side effects (orthostatic hypotension and mental status changes).
    D) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Monitor fluids and electrolytes, if significant vomiting occurs. Replace with IV fluids and electrolytes as indicated.
    E) BODY TEMPERATURE ABOVE REFERENCE RANGE
    1) Hyperthermia was associated with death 2 patients that ingested dietary supplements containing 1,3-dimethylamylamine (Eliason et al, 2012). Symptoms should be treated aggressively.
    2) Place patient in a cool room.
    3) Minimize physical activity. Aggressively control agitation with IV benzodiazepines. Remove the patient's clothes, keep skin damp with tepid to cool water, and use fans to maximize evaporative heat loss.
    4) Place patient on a hypothermia blanket.
    5) Large doses of benzodiazepines may be needed to control neuromuscular hyperactivity. In severe cases sedation, neuromuscular paralysis and orotracheal intubation may be necessary.
    6) Immersion in ice water makes monitoring and resuscitation more difficult. It should be reserved for severe hyperthermia not responding to the above therapies.
    F) TACHYARRHYTHMIA
    1) Sedation with benzodiazepines to control agitation is sufficient in the vast majority of cases. Administer oxygen and IV fluids and correct hyperthermia as clinically indicated. If severe tachycardia persists and is associated with hemodynamic compromise or myocardial ischemia, additional therapy may be required.
    G) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    H) RHABDOMYOLYSIS
    1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
    2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
    3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
    4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
    5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).

Enhanced Elimination

    A) LACK OF EFFECT
    1) Hemodialysis and hemoperfusion are not of known value.

Range Of Toxicity

Summary

    A) TOXIC DOSE: Limited data. Two fatalities from a heat stroke like syndrome have been associated with the use of dietary supplements containing dimethylamylamine; the first case died within hours of exposure and the second case died several weeks later from complications due to sepsis. Cerebral hemorrhage was reported in a young adult after ingesting 2 dimethylamylamine (278 mg/capsule) capsules at a party; severe impairment of memory and abstract reasoning and mild impairment of speech and right hand coordination occurred.
    B) DIETARY SUPPLEMENTS: Dimethylamylamine can be found in some dietary and body-building supplements.

Minimum Lethal Exposure

    A) SUMMARY
    1) The toxic dose of dimethylamylamine is unknown (Eliason et al, 2012).
    2) Limited data. There have been 2 reports of military soldiers dying of a heat stroke like syndrome following the use of dietary supplements containing dimethylamylamine despite relatively mild ambient temperatures and physical exertion (Eliason et al, 2012).
    B) CASE REPORTS
    1) CASE REPORT: A 22-year-old infantry solider was running in place for approximately 10 minutes and collapsed and found to be pulseless; CPR was initiated. Upon admission, the patient was hyperthermic (40.8 degrees C) with dry hot skin. Ambient temperature was 23.9 degrees C and less than 40% humidity. Laboratory studies were significant for renal insufficiency (ie, potassium 7.4 mEq/L, creatinine 2.3 mg/dL), metabolic acidosis and elevated cardiac and muscle enzymes (creatine kinase MB 7.3 U/L, myoglobin 6227.2 mcg/L and troponin 1 cardiac 0.069 ng/mL). Aggressive care included cooling measures, endotracheal intubation and fluid resuscitation. The patient developed refractory asystole after 4 hours of resuscitation. Postmortem toxicology analysis was positive for DMAA (0.22 mg/L) and caffeine (2.9 mg/L) only. According to his friends he was taking a dietary supplement once daily for the past 4 weeks (Eliason et al, 2012).
    2) CASE REPORT: A 32-year-old female soldier with mild obesity and sickle cell trait collapsed after almost completing a 2-mile physical fitness test. She was found asystolic and CPR was initiated. Upon admission, the patient was unresponsive with severe hypotension (77/36 mmHg), tachycardia (109 beats/min) and hyperthermia (105 degrees F). Ambient temperature was 23 degrees C. She developed anion gap metabolic acidosis, renal and liver insufficiency and evidence of disseminated intravascular coagulation (prolonged PT, PTT and INR). The patient remained comatose and developed multiple organ failure (rhabdomyolysis, renal and liver failure, pancreatitis, DIC and pulmonary edema). A toxicology analysis performed 4 days after admission was positive for DMAA (0.04 mg/L) and caffeine (1.9 mg/L) only. Two supplements containing DMAA were found in her car; it was uncertain how long she had been taking the supplements or the amount. The patient improved briefly, but ultimately developed sepsis and died 5 weeks after admission (Eliason et al, 2012).

Maximum Tolerated Exposure

    A) CASE REPORT: A 21-year-old man experienced a cerebral hemorrhage after ingesting 2 dimethylamylamine (278 mg/capsule) capsules at a party. Thirty minutes after exposure he complained of a severe global headache followed by confusion, urinary incontinence and vomiting for several hours. He awoke with slurred speech and was admitted with confusion, right facial droop and right-sided weakness. A head CT showed a large hemorrhage in the left basal ganglia region causing a 5 mm midline shift. Following acute care he was transferred to a brain injury rehabilitation center. A multidisciplinary assessment indicated that the patient had severe impairment of memory and abstract reasoning, along with mild impairment of speech and right hand coordination. Laboratory analysis confirmed the presence of dimethylamylamine only (Gee et al, 2010).
    B) CASE REPORT: A 26-year-old male solider stationed in Afghanistan developed a severe headache after taking a weight lifting supplement called "Jack3d" (3 scoops/day; maximum recommended amount, for approximately 3 weeks) which was found to contain geranamine, caffeine, creatine monohydrate and amino acids. He continued to have severe pain behind the right eye and awoke later with left hemidysesthesia, weakness and lack of coordination. A CT scan confirmed a right midbrain-thalamic hemorrhage; repeat images showed that lesion was medically stable. The patient was returned to the US and diagnosed with Dejerine-Roussy syndrome (a thalamic hemorrhagic stroke). Other screening tests were negative and a small patent foramen ovale was considered noncontributory. He had a slight improvement of his left hemidysesthesia and was transferred for further rehabilitation (Young et al, 2012).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Dimethylamylamine (1,3-dimethylamylamine or DMAA) is a stimulant (Fleming et al, 2012). It is a straight chain aliphatic amine found naturally (low concentrations) in geranium flowers. Dimethylamylamine is an indirect sympathomimetic amine and has sympathomimetic physiological effects (both vasoconstrictive and cardiovascular effects), that acts as a norepinephrine reuptake inhibitor and/or a norepinephrine releasing agent (Cohen, 2013; Forrester, 2013).
    B) Historically, based on its vasoconstrictive action on nasal mucosa, dimethylamylamine had been used as a nasal decongestant (Forrester, 2013).

Toxicologic Mechanism

    A) Based on an animal study with methylhexanamine, the systemic toxicity of dimethylamylamine was greater than ephedrine, but less than that of amphetamines. In addition, its vasopressor effects were found to be more prolonged than epinephrine (approximately 3.5 times that of epinephrine) (Eliason et al, 2012).
    B) Since most dietary and/or supplements that contain DMAA also contain caffeine, the presence of both products may produce systemic toxicity at lower doses (such as caffeine and ephedra). In addition, many of these supplements also contain creatine. One study suggested that creatine along with an amphetamine derivative can result in dehydration and heat stroke by shifting water out of the extracellular space into the muscle cells. Two soldiers died of a heat stroke like syndrome (despite relatively low ambient temperatures and mild physical exertion) following DMAA supplement use (Eliason et al, 2012).

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