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Cathine (ATC A08AA07): Toxicological and Lactation Monograph

ATC class and general pharmacology

ATC code A08AA07 corresponds to cathine, also known as D-norpseudoephedrine. It is classified within ATC group A08, anti-obesity preparations, excluding diet products, and subgroup A08AA, centrally acting anti-obesity products. Cathine has historically been used as a short-term anorectic medicine, but it is also a naturally occurring psychoactive alkaloid in Catha edulis (khat).atcddd.fhi+2

Cathine is closely related pharmacologically and structurally to phenylpropanolamine, ephedrine, cathinone, and amphetamine-type stimulants. It is less potent than amphetamine and cathinone, but it remains a clinically relevant central nervous system and sympathomimetic stimulant. Both cathinone and cathine contribute to the stimulant properties of khat; cathinone is generally the more potent compound, whereas cathine is more stable and can persist longer after consumption.euda.europa+2

The anorectic action of cathine is mediated mainly through indirect sympathomimetic and monoaminergic effects. It acts as a norepinephrine- and dopamine-releasing agent and has alpha-1 adrenergic activity. Increased noradrenergic and dopaminergic signalling in hypothalamic and reward-related neural circuits contributes to reduced food intake, appetite suppression, increased wakefulness, locomotor stimulation, and weight loss. Experimental work has also implicated dopamine D1 and D2 receptor pathways in cathine-induced suppression of food intake and body weight.pmc.ncbi.nlm.nih+1

Cathine is absorbed after khat consumption, including through oral mucosa, and undergoes systemic distribution. In a pharmacokinetic study involving khat chewing, cathine had a mean elimination half-life of approximately 5.2 ± 3.4 hours, longer than the reported 1.5 ± 0.8-hour half-life of cathinone. This persistence is relevant when considering repeated maternal use and repeated infant exposure through breast milk.euda.europa+1

Toxicological profile

Cathine has a toxicological profile consistent with an amphetamine-like sympathomimetic stimulant. Its potential adverse effects include central nervous system stimulation, autonomic activation, cardiovascular stress, appetite suppression, sleep disruption, psychiatric symptoms, and potential misuse. Toxicity is particularly concerning with high doses, repeated use, combination with other stimulants or serotonergic medicines, and use by individuals with cardiovascular, psychiatric, or seizure disorders.drugs.ncats+1

Expected dose-related effects include increased alertness, restlessness, insomnia, anxiety, nervousness, irritability, tremor, headache, dry mouth, reduced appetite, nausea, constipation, urinary retention, and increased body temperature. Peripheral sympathomimetic actions may cause tachycardia, palpitations, elevation of blood pressure, vasoconstriction, and increased respiratory rate.drugs.ncats+2

Potential serious toxicity includes:

• Marked hypertension, tachyarrhythmia, chest pain, and myocardial ischaemia.
• Hyperthermia, dehydration, rhabdomyolysis, and metabolic complications in severe stimulant toxicity.
• Agitation, confusion, delirium, hallucinations, paranoia, or psychosis.
• Seizures, stroke, myocardial infarction, malignant arrhythmias, and cardiovascular collapse.
• Potential exacerbation of anxiety disorders, bipolar disorder, psychotic illness, and sleep disorders.
• Tolerance, compulsive repeated use, and dependence-related behaviours.

Much of the severe published cardiovascular literature concerns cathinone or synthetic cathinones rather than cathine alone. These substances should not be treated as toxicologically interchangeable: their potency, pharmacodynamics, dose, and exposure pattern differ. Nevertheless, cathine is a sympathomimetic stimulant, and khat use—which can expose a person to both cathinone and cathine—has been associated with increased heart rate, elevated blood pressure, acute coronary syndromes, myocardial infarction, arrhythmias, stroke, and cardiomyopathy in susceptible users.pmc.ncbi.nlm.nih+3

Cathine should be avoided in people with coronary artery disease, uncontrolled hypertension, tachyarrhythmia, structural heart disease, cerebrovascular disease, hyperthyroidism, glaucoma, severe anxiety, psychosis, a history of stimulant misuse, or clinically important eating disorders. Concomitant use with monoamine oxidase inhibitors, other anorectics, prescription stimulants, decongestants, cocaine, amphetamine-type drugs, or medicines that increase serotonin or catecholamine activity can increase the risk of hypertensive, cardiac, neurological, or psychiatric toxicity.

Lactation pharmacology and infant exposure

Unlike many older anorectic stimulants, there is direct—although limited—evidence that cathine enters human breast milk. In a pilot study of lactating women chewing khat leaves, norpseudoephedrine, identified as cathine, was detected in breast milk in several mothers. Cathine was also detected in the urine of one breastfed infant, demonstrating that transfer from maternal khat use to milk and infant systemic exposure can occur. The investigators concluded that khat use during lactation should be discouraged until the potential health risks are better defined.pubmed.ncbi.nlm.nih+2

This small study does not provide sufficiently robust data to calculate a reliable milk-to-plasma ratio, absolute infant dose, relative infant dose, dose–exposure relationship, or threshold below which exposure could be regarded as safe. It also cannot determine the frequency of adverse effects or establish long-term neurodevelopmental outcomes. However, it provides direct evidence that cathine-related exposure through breast milk is biologically real rather than purely theoretical.pubmed.ncbi.nlm.nih+1

Repeated maternal use is concerning because cathine has a mean half-life of approximately 5.2 hours, while khat contains multiple psychoactive constituents, including cathinone, cathine, and norephedrine. Thus, breastfed infants of mothers chewing khat may be exposed to a variable and poorly standardised mixture of sympathomimetic alkaloids rather than to cathine alone. The concentration of these compounds can vary according to plant material, freshness, amount chewed, duration of chewing, route of consumption, individual metabolism, and timing of feeds.euda.europa+2

Potential infant effects are inferred from cathine’s stimulant pharmacology, the documented transfer into milk, and the vulnerability of young infants. Possible manifestations include:

• Irritability, excessive crying, restlessness, tremor, or disturbed sleep.
• Poor latch, reduced suck, feeding difficulty, vomiting, diarrhoea, or reduced weight gain.
• Tachycardia, pallor, sweating, hypertension, or temperature instability.
• Increased wakefulness or, paradoxically, unusual lethargy following exhaustion or co-exposure to other khat constituents.
• Agitation, hyperexcitability, abnormal movements, or seizure-like activity in substantial exposure.
• Potential impairment of maternal milk production through appetite suppression, dehydration, sleep deprivation, or sustained sympathetic stimulation.

Newborns, preterm infants, infants with low birth weight, and infants with hepatic, renal, cardiac, or neurological disease are likely to be at increased risk because they have reduced metabolic and renal elimination capacity and lower physiological reserve.

Lactological safety assessment and clinical recommendations

Lactological safety assessment: Avoid during breastfeeding. Cathine should not be used as an appetite suppressant during lactation, and maternal khat use should be actively discouraged during breastfeeding. This assessment is supported by direct detection of cathine in breast milk and in the urine of a breastfed infant, inadequate infant safety data, the variable and uncontrolled composition of khat preparations, amphetamine-like neurocardiovascular toxicity, and the non-essential nature of stimulant-assisted weight reduction during lactation.drugs.ncats+2

Breastfeeding women should not start cathine for postpartum weight loss. The safer approach to postpartum weight management is gradual, adequately nourished weight reduction with dietary counselling, physical activity appropriate to recovery, management of sleep and mental-health factors, and assessment for medical contributors such as thyroid disease, diabetes, or medicines associated with weight change.

When cathine exposure results from khat use, clinicians should specifically ask about the plant product rather than asking only about “prescription medicines.” Khat chewing may not be recognised by the mother as drug use, and exposure cannot be inferred reliably from the apparent amount of leaves used. Clinicians should identify the amount and frequency of khat use, the timing of the last use, the possibility of concurrent tobacco, alcohol, caffeine, stimulants, prescribed medicines, or illicit drug exposure, and whether other household members may have access to the substance.

There is no evidence-based universal interval for temporary interruption of breastfeeding after cathine or khat exposure. A simple “pump-and-dump” time cannot be recommended with confidence because milk-concentration data are sparse, product composition is variable, cathine has a multi-hour elimination half-life, and co-exposure to cathinone and other alkaloids is possible. Decisions after one-time or repeated exposure should therefore be individualised with advice from a poison centre, clinical toxicologist, paediatrician, or lactation-medicine specialist.pmc.ncbi.nlm.nih+2

If exposure has occurred, the infant should be assessed for feeding, hydration, urine output, sleep and behaviour, weight gain, heart rate, respiratory status, and signs of autonomic stimulation. Urgent paediatric evaluation is indicated for poor feeding, repeated vomiting, dehydration, persistent irritability, tremor, rapid heartbeat, sweating, fever, breathing difficulty, abnormal movements, seizure-like activity, reduced responsiveness, or inadequate weight gain.

Maternal medical assessment is appropriate if there are palpitations, chest pain, severe headache, markedly elevated blood pressure, fainting, dyspnoea, agitation, confusion, or psychotic symptoms. Management should include supportive non-judgemental counselling, assessment for stimulant-use disorder where relevant, and linkage to culturally appropriate substance-use or mental-health services.

Clinical conclusion: cathine is not compatible with routine breastfeeding. The available human evidence confirms excretion into milk and infant absorption after maternal khat chewing, while the absence of reliable dose–response and infant-outcome data prevents a safe exposure threshold from being defined. Avoidance of cathine and khat is therefore the prudent lactological recommendation.pmc.ncbi.nlm.nih+2