Poisoning from non-food grade poppy seeds

This Issue of the Journal contains two clinical research papers that describe a cluster of acute thebaine poisonings in those ingesting tea made using poppy seeds with high thebaine content that entered the Australian food supply chain in 2022 [1,2].

Poppy seed tea

Mature poppy seeds do not contain opium alkaloids, but their surface can become contaminated with alkaloids as a result of pest damage and during harvest [3]. Opium alkaloids detected in samples of poppy seeds and poppy seed-containing foods include phenanthrenes, principally morphine, codeine, thebaine, and oripavine, and benzylisoquinolines, principally papaverine, noscapine, and laudanosine [3]. As opioids come primarily from the alkaloid residue retained on the seeds, “unwashed seeds” are an important marketing claim for purveyors of poppy seeds sold for substance misuse purposes.

Poppy seed tea is made by washing or soaking large quantities of commercially available Papaver somniferum seeds (0.2–2.0 kg of seeds are often used [4]) in hot or cold water, usually in the presence of lemon juice or citric acid. Some individuals prefer to reduce the volume by boiling and adding fruit-flavoured powder. The process can take up to 12 h, but usually lasts 1–2 h. In one study, the highest transfer rates (71% for morphine, 96% for thebaine, and 100% for codeine, noscapine and papaverine) were achieved at 90 °C for 5 min [5].

As poppy seeds harvested in different years or from different regions of the world contain a wide range of alkaloid concentrations, the tea prepared from differing varieties of seeds will also exhibit wide variations in the identity and concentrations of these alkaloids.

Croitoru et al. [4] determined the amount of morphine and codeine in poppy seed tea made from different types of poppy seeds available on the Romanian market using four different infusion methods. Concentrations of morphine ranged between 0.1 mg/kg and 243.26 mg/kg, depending on the source and preparation. In the case of codeine, the concentrations ranged from below the level of toxicological concern to 88.58 mg/kg, again dependent on the source and preparation.

Pelders and Ros [6] analyzed the concentrations of opiates present in poppy seeds from seven different origins (Dutch, Australian, Hungarian, Spanish, Czech, and two Turkish) and found the morphine concentration varied from 2 mg/kg to 251 mg/kg and codeine from 0.4 mg/kg to 57.1 mg/kg; no other opiate was detected.

In four samples of poppy seed tea prepared by investigators in New Zealand, the concentration of morphine ranged from 10 mg/kg to 105 mg/kg and the concentration of codeine from 3.1 mg/kg to 11.2 mg/kg of poppy seeds [7]. Cassella et al. [8] assayed Australian poppy seeds and reported a morphine concentration of 107 mg/kg, a codeine concentration of 31.8 mg/kg and a thebaine concentration of 20.7 mg/kg.

In another study reported from the United States, various poppy seed products were purchased from online sources and extracted with four home-brewing methods representative of recipes found on drug user forums [9]. Morphine, codeine, and thebaine concentrations quantified in the tea extracts by liquid chromatography-tandem mass spectrometry ranged from <1 mg/kg to 2,788 mg/kg, from <1 mg/kg to 247.6 mg/kg, and from <1 mg/kg to 124 mg/kg, respectively, dependent on source and preparation [9].

The concentrations of codeine, morphine, thebaine, papaverine, and noscapine in Indian poppy seeds were 44 mg/kg, 167 mg/kg, 41 mg/kg, 67 mg/kg, and 230 mg/kg, respectively [10]. In poppy seeds from the Netherlands, the concentrations of codeine, morphine, thebaine, papaverine, and noscapine were 1.8 mg/kg, 39 mg/kg, 1.0 mg/kg, 0.17 mg/kg, 0.84 mg/kg, respectively [10].

A Papaver somniferum mutant known as top1 accumulates the morphine and codeine precursors, thebaine and oripavine, as it does not complete their biotransformation into morphine and codeine [11]. In 2022, top1 non-food grade poppy seeds entered the Australian food supply chain, and some 40 people drank tea made from these seeds [1,2]. Analytical testing on an implicated poppy seed batch found in Queensland later revealed median concentrations of thebaine, morphine, and codeine of 5,110 mg/kg, 40 mg/kg, and 90 mg/kg, respectively [1]. In batches of implicated poppy seeds in New South Wales, median concentrations of thebaine, morphine, and codeine were 6,200 mg/kg, 15 mg/kg, and 120 mg/kg, respectively [2]. Analysis of a sample of poppy seed tea used by one patient showed a thebaine concentration of 830 mg/L, a codeine concentration of 17 mg/L, and a morphine concentration of 2 mg/L [2].

As these studies confirm, a variable but clinically significant amount of morphine, codeine, thebaine, and other alkaloids can be extracted and then consumed by drinkers of poppy seed tea. Drinking poppy seed tea may be more common than is generally appreciated. In a survey completed by 24 patients at an opioid rehabilitation center in New Zealand, 46% reported that they had tried poppy seed tea [7]. Five of the 24 patients reported poppy seed tea as their main source of opioids. Two of the 24 patients had opioid use disorder from other opioids and used poppy seed tea to manage withdrawal symptoms. Dependence has been described [12].

Poisoning from poppy seed tea

Prior to these Australian reports [1,2], only a small number of cases of intoxication from the ingestion of poppy seed tea had been reported worldwide [1–17]; several ingestions resulted in death [9,18–21]. In a study published in this Journal [22], a further four deaths and 14 non-fatal overdoses involving poppy seed tea ingestions were reported to America’s Poison Centers and the United States Food and Drug Administration. At least 17 other deaths have been described online (http://www.poppyseedtea.com/Other%20Deaths%20Page.html). Poppy seed tea has also been injected intravenously [23].

One of the first reported ingestions of poppy seed tea involved a 26-year-old baker who was witnessed to have a tonic-clonic seizure [16]. He was delirious afterward, struggling against hallucinatory figures. He was taken by ambulance to hospital, but when he arrived, his delirium had resolved. His post-ictal state suggested a toxic encephalopathy, but the patient initially denied taking drugs. Blood taken on the day of the seizure was found to contain a high concentration of morphine (approximately 2.92 mg/L). High concentrations of morphine were also found in his blood and urine over a 3-week period. When informed of these results, he admitted to drinking poppy tea at night in the bakery. A sample of the tea he prepared had a morphine concentration of 140 mg/L. At the time of the seizure, he was drinking up to 2 L of tea each day made from 4 kg of seed. His daily intake of morphine was as much as 280 mg.

Thebaine

The clinical reports [1,2] published in this Issue are unusual in that the cohort of Australian patients who ingested poppy seed tea was poisoned predominantly not by morphine but by thebaine. As thebaine poisoning is rare, experimental studies will first be described before clinical data are reviewed.

Thebaine toxicity: experimental studies

In vitro studies undertaken by Goldinger et al. [24] showed that of several opiate agonists and antagonists, thebaine had the highest affinity for the specific [³H]strychnine-binding subunit of the glycine receptor. However, with a half maximal inhibitory concentration (IC₅₀) of about 1 µM, it was more than 100 times less potent than strychnine (IC₅₀ = 0.006 µM). The affinity of thebaine for the gamma-aminobutyric acid (GABA) receptor was considerably less, with an IC₅₀ of 300 µM.

Limited data indicate that thebaine exhibits a higher acute toxicity than morphine. Following administration of thebaine by gavage, the mean lethal dose (LD₅₀) was 54 mg/kg body weight in mice and 114 mg/kg in rats [3], values which are much lower than the LD₅₀ for morphine (LD₅₀ 524 mg/kg in mice; 335 mg/kg in rats).

Administration of thebaine 2–3 mg/kg intravenously to cats or 2.5 mg/kg intravenously to rabbits, respectively, rapidly induced convulsive activity in both species [25]. Furthermore, clonic-tonic convulsions induced by thebaine in rabbits led to the death of these animals within 1 min. In the case of morphine, much higher doses (40–55 mg/kg intravenously) were required to induce severe respiratory depression and the death of the rabbits [25]. Administration of higher doses of thebaine (12.5 mg/kg administered in five consecutive doses of 2.5 mg/kg every 10 min) intraperitoneally to cats produced hyperreflexia, increased urination and defecation as well as salivation of the animals [25]. Hyperreflexia was manifested by a generalized motor response to any auditory, tactile, or visual stimulus. Navarro and Elliott [25] demonstrated that injection of thebaine 2–2.5 mg/kg intraperitoneally in cats or thebaine 0.4-1.5 mg/kg intravenously in rabbits increased their respiratory rate. Additionally, low-dose thebaine produced sedative effects in cats.

In another study [26], rats were administered thebaine 20 mg/kg intraperitoneally. Fifteen of the 26 animals showed “convulsive behaviour”, seven rats suffered major convulsions, and four died. The rats appeared sedated during non-convulsive intervals; hyperthermia was not observed. The effects of thebaine were compared to those of morphine 15 mg/kg, 30 mg/kg, or 60 mg/kg intraperitoneally. Doses of morphine 15 mg/kg and 30 mg/kg resulted in an initial depression of activity followed by an increase in activity and body temperature; 60 mg/kg produced profound depression of both activity and body temperature, maximal at 2 h. Respiratory depression also occurred in these animals, and about one-half showed cyanosis. None of the rats that were administered morphine 15 mg/kg, and very few receiving 30 mg/kg, showed cyanosis.

Based on these studies, thebaine is more toxic than other opium alkaloids, including morphine, and has differing clinical effects.

Thebaine: pharmacokinetics

Following a subcutaneous dose of [³H]thebaine 5 mg/kg to rats, the maximum brain and plasma concentrations were 937 µg/kg and 1,076 µg/L at 0.5 h and 1 h, respectively; these declined to non-detectable concentrations at 24 h [27]. The corresponding half-lives of thebaine in rat plasma and brain were 1.1 h and 1.5 h, respectively. Thebaine is extensively metabolized; O-demethylation at position 3 or position 6 and the N-methyl group and, to a small extent, 14-hydroxylation and glucuronide conjugation are the main metabolic pathways [27]. Thebaine was eliminated in urine as free and glucuronide-conjugated metabolites. Free thebaine excretion over 96 h following a 5 mg/kg subcutaneous dose was 16.7% in urine and 4.3% in faeces [27].

In the Australian study [2], three patients with features of thebaine poisoning had thebaine blood concentrations of 2.1 mg/L, 2.2 mg/L, and 4.1 mg/L and apparent thebaine elimination half-lives of 14.8, 8.3, and 11.6 h, respectively.

Thebaine poisoning

The clinical reports [1,2] published in this Issue provide the most comprehensive data on thebaine poisoning reported to date. Some 40 patients presented with multi-system toxicity following poppy seed tea ingestion [1]. There was analytical confirmation of thebaine concentrations in 23 cases; the median blood thebaine admission concentration was 1.6 mg/L, with a range of 0.1–5.6 mg/L, and was the dominant alkaloid in all samples [1]. All 23 patients with analytical confirmation of the diagnosis experienced muscle spasms; rigidity was described in nine, convulsions in six, while rhabdomyolysis, acute kidney injury, and metabolic acidosis occurred in five patients. There were two cardiac arrests [1]. Convulsions, acute kidney injury, metabolic acidosis, and cardiac arrest were associated with increasing median thebaine concentrations [1].

Details on four other patients have been published in whom there was analytical confirmation that thebaine was involved, though the alkaloid was not always quantified, and in two cases, other non-opiate drugs were involved [18,20]. Thus, the contribution of thebaine to the patient’s presentation is difficult to ascertain.

A 33-year-old man prepared poppy seed tea by mixing 2 pounds of poppy seeds with approximately 2 L of water and shaking it vigorously for 10–15 min [13]. Soon after ingestion of half the tea, the patient reported feeling “intoxicated” and then fell asleep. His wife later found him unresponsive and called the emergency medical services. Paramedics administered naloxone with complete reversal of sedation. He underwent approximately 4 h of observation in the emergency department and was discharged home after being given alprazolam 1 mg orally for anxiety. One hour after arrival home, his wife found him unconscious and cyanotic. She again called the emergency medical services, and he received naloxone with complete reversal of symptoms. In the emergency department, a urine drug screen was positive for opiates and benzodiazepines only. The patient was admitted to the intensive care unit for observation. He did not require any further naloxone. Analysis of the tea using liquid chromatography with tandem mass spectrometry followed by quantitative opiate analysis confirmed the presence of morphine (1,090 mg/L), codeine (62.1 mg/L), and thebaine (quantitative testing not done) with no additional opioids. Although thebaine was detected, it is more likely that the poisoning was due to morphine.

A 32-year-old man who suffered from epilepsy was found unresponsive in a legal poppy field in the South of Spain [21]. The emergency medical services responded and pronounced the man dead. His friends explained that the deceased had presented with about 30 min of convulsions and was not breathing. The peripheral blood contained the following concentrations of opiates: thebaine 0.10 mg/L, free morphine 0.13 mg/L, and codeine 0.48 mg/L. The gastric contents contained thebaine 2.8 mg, free morphine 1.25 mg, and codeine 0.28 mg.

A 42-year-old man was found unresponsive in bed by his wife when she returned home from work [18]. He was pronounced dead at the scene. His wife was aware that he drank poppy seed tea, and a small glass vial labelled “phenazepam purity 99%” was found in the bedroom. Blood samples were taken from the subclavian vein at post-mortem, and free phenazepam was found at a concentration of 386 µg/L. Unconjugated morphine and codeine were quantified in the blood at concentrations of 116 µg/L and 85 µg/L, respectively, by liquid chromatography with tandem mass spectrometry. Thebaine was quantified in the blood by gas chromatography with mass spectrometry at a concentration of 72 µg/L, which is lower than the concentrations found in some survivors [1,2], suggesting that other drugs contributed substantially to a fatal outcome.

A 25-year-old male with a history of substance misuse, who was in the process of being discharged from military service, was found dead in bed [20]. His girlfriend stated that the deceased had recently purchased several pounds of poppy seeds to make into tea. Free morphine was found at a concentration of 0.94 mg/L and free codeine at a concentration of 0.11 mg/L (without 6-monoacetylmorphine) using liquid chromatography with tandem mass spectrometry. Thebaine and laudanosine were detected but not quantified. Also detected was a mitragynine concentration of 0.87 mg/L and a gabapentin concentration of 10 mg/L. Without quantification of thebaine, its contribution, if any, to a fatal outcome is uncertain.

Conclusions

Clinicians need to be aware that unwashed poppy seeds are widely available in many countries through private websites or via well-known sellers online, yet their sales and distribution are legal. Depending on the source, these seeds may contain sufficient alkaloid residue to produce tea with substantial morphine and thebaine content. Thus, the ingestion of poppy seed tea can cause not only psychoactive effects but, if a sufficient amount is ingested, severe poisoning and death. Regular poppy seed tea drinkers can develop dependence and opioid use disorder. From a public health perspective, the message is clear. Poppy seed tea is not a benign “natural” beverage; drinking such tea is not a harmless activity. Government and regulatory agencies need to accept the potential dangers of poppy seed tea and work to close the loophole that allows large quantities of unwashed poppy seeds to be sold online as a “legal high”.

Disclosure statement

No potential conflict of interest was reported by the author.

Additional information

Funding

The author reported there is no funding associated with the work featured in this article.