A cluster of acute thebaine poisonings from non-food grade poppy seeds in the Australian food supply

Abstract

Introduction

Poppy seed tea is used for its opioid effects and contains multiple opium alkaloids, including morphine, codeine, papaverine, and thebaine. Animal studies indicate thebaine has strychnine-like properties, but there is limited literature describing human thebaine poisoning. We describe a cluster of acute thebaine poisoning in people ingesting tea made using poppy seeds with high thebaine content that entered the Australian food supply chain.

Methods

This is an observational study of patients poisoned after drinking poppy seed tea. Cases were identified by three prospective toxicovigilance systems: the Emerging Drug Network of Australia collaboration, the New South Wales Prescription, Recreational and Illicit Substance Evaluation program, and the Emerging Drugs Network of Australia Victoria study. We report characteristics of clinical toxicity in cases with reported ingestion of poppy seed tea and analytical confirmation of thebaine exposure.

Results

Forty cases presenting with multi-system toxicity following poppy seed tea ingestion were identified across seven Australian states/territories from November 2022 to January 2023. Blood testing in 23 cases confirmed high thebaine concentrations. All 23 were male (median age 35, range 16–71 years). All patients 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. The thebaine median admission blood concentration was 1.6 mg/L, with a range of 0.1–5.6 mg/L, and was the dominant opium alkaloid in all samples. Convulsions, acute kidney injury, metabolic acidosis, and cardiac arrest were associated with increasing median thebaine concentrations. Four patients were managed in the Intensive Care Unit, with two receiving continuous kidney replacement therapy (one also received intermittent haemodialysis) for kidney injury. There was one death.

Conclusions

Thebaine toxicity, like strychnine poisoning, resulted in neuromuscular excitation characterized by muscle spasm, rigidity, and convulsions. Severe toxicity, including acute kidney injury, metabolic acidosis, and cardiac arrest, appears dose-dependent.

Keywords:

• Poisoning
• thebaine
• poppy seed
• opioid
• toxicity

Introduction

Poppy seed tea is consumed for its opioid effects and involves soaking large amounts of dried Papaver somniferum seeds in water to remove opium alkaloids, in particular morphine, from the seed coating [1]. One case report estimates a regular user consumed the equivalent of 280 mg of oral morphine daily through drinking poppy seed tea [2]. The incidence of poppy seed tea consumption is uncertain. A New Zealand survey of 24 opioid-dependent patients attending an alcohol and drug service found that ten had used poppy seed tea before, with five using it as their main source of opioids [1].

Poppy seeds do not contain opium alkaloids, but their surface can become contaminated with alkaloids from the poppy latex being damaged by pests or during harvesting [3]. Many important opioid pharmaceuticals are produced from the opium poppy (Papaver somniferum). Some poppy variants like top1 (thebaine oripavine poppy 1) are cultivated exclusively by the pharmaceutical industry. Top1 accumulates thebaine due to its decreased bioconversion to morphine and codeine, resulting in a morphine-free but thebaine-rich latex [4]. The top1 is produced in Australia, France, and Spain [5] and is used in the manufacture of oxycodone, buprenorphine, naloxone and naltrexone [4]. Due to their rich thebaine content, poppy variants, including the top1 mutant, are not food-grade, but they may be used for other industries.

There is limited literature describing thebaine toxicity. Unlike morphine and codeine, the main mechanism of action of thebaine may be glycine inhibition, making it similar to strychnine in overdose [6]. We describe a cluster of thebaine poisonings occurring when top1 poppy seeds entered the Australian food supply chain.

Methods

This is an observational study of patients with analytically confirmed thebaine poisoning identified by three prospective toxicovigilance systems: the Emerging Drug Network of Australia (EDNA) collaboration, the Prescription, Recreational and Illicit Substance Evaluation (PRISE) program, and the Emerging Drugs Network of Australia Victoria (EDNAV) program. The Emerging Drug Network of Australia collaboration is a national multi-centre prospective toxicosurveillance system of illicit drug-related emergency department presentations in Australia; its methods of sample acquisition, analytical testing, and data collection are well described elsewhere [7]. Emerging Drugs Network of Australia Victoria is a state-based prospective toxicosurveillance system collecting clinical and analytical data from illicit drug presentations in the state of Victoria [8]. The Emerging Drugs Network of Australia Victoria program conducts comprehensive toxicological analysis on 22 cases collected weekly from a network of 16 metropolitan and regional Victorian emergency departments.

The Prescription, Recreational and Illicit Substance Evaluation program operates as a public health program providing access to extensive toxicology testing for cases of severe and unusual substance-related toxicity or clusters of overdoses in New South Wales. It is part of the collaborative state-wide rapid surveillance and public health response program to improve the health and well-being of people at risk or experiencing harm from alcohol and other drug use.

On 7 November 2022, the Queensland arm of the Emerging Drug Network of Australia first detected three similar cases of neuromuscular excitation following consuming poppy seed tea. This prompted a coordinated national investigation, which eventually identified 40 people with potential thebaine poisoning. Thebaine toxicity was first suspected after rapid toxicological testing of the admission blood specimens from the original patients showed elevated concentrations of the alkaloid. Analytical testing on an implicated poppy seed batch later revealed concentrations of thebaine, morphine and codeine of 5,110 mg/kg, 40 mg/kg, and 90 mg/kg, respectively. Further investigation revealed a large quantity of top1 poppy seeds had entered the food supply chain approximately two months earlier. Alerts to affected populations, healthcare workers, and ultimately the general public were published between 9–12 November 2022. The affected batches of poppy seeds were subject to a nationwide food recall on 15 November 2022. All patients clinically diagnosed with thebaine poisoning during the cluster, with samples available for analytical testing, are included in this series.

We obtained clinical data from the Emerging Drug Network of Australia, the Prescription, Recreational and Illicit Substance Evaluation and Emerging Drugs Network of Australia Victoria databases, as well as from the medical records of patients. We recorded baseline demographics, exposure details, symptoms (muscle spasm, rigidity, convulsions, cardiac arrest), treatments, laboratory investigations (blood lactate concentration, serum creatine kinase activity, serum creatinine concentration), locations of care, and length of stay. We defined rhabdomyolysis as creatine kinase activity >1,000 IU/L, acute kidney injury by Kidney Disease: Improving Global Outcomes (KDIGO) criteria [9], and metabolic acidosis as serum bicarbonate concentration <20 mmol/L. Treatments of interest included benzodiazepines, endotracheal intubation, inotropes, continuous kidney replacement therapy and intermittent dialysis. We recorded medians and ranges for continuous variables and performed all statistical analysis using Graphpad Prism 9 for MacOS (Graphpad Software La Jolla CA; www.graphpad.com).

Four regional laboratories performed testing for opium alkaloids (morphine, codeine, thebaine and laudanosine). All laboratories employed similar instrumental techniques, with Liquid Chromatography/Time of Flight Mass Spectrometry (LC/TOFMS) and/or Liquid Chromatography/Triple Quadrupole Mass Spectrometry (LC/MS/MS) for the identification and quantitation of drugs.

Ethics statement

The Sydney Children’s Hospitals Network Human Research Ethics Committee approved the inclusion of patients identified by the New South Wales Poisons Information Centre (2021/ETH00165). Sydney Local Health District Human Research Ethics Committee approved the inclusion of patients admitted to Royal Prince Alfred Hospital (LNR/18/RPAH/651). The Emerging Drugs Network of Australia Victoria study and the Emerging Drug Network of Australia study have received ethics approval from the Austin Hospital Human Research Ethics Committee (HREC/66506/Austin-2020) and South Metropolitan Health Service Human Research Ethics Committee (RGS0000003673), respectively. Emerging Drug Network of Australia is registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12621001234808).

Results

There were 23 cases of analytically confirmed thebaine poisoning between 1 November 2022 and 8 January 2023 across four Australian states – Queensland, New South Wales, Victoria, and Western Australia. All 23 were male with a median age of 35 years (range 16 to 71 years). Poppy seed tea was used regularly in 18/20 patients where this information was provided. The median amount of poppy seeds used to make the tea was 340 g (range 120 to 960 g), with the volume of ingested tea being unreliably reported. The opioid extraction technique, when described, was heterogenous and involved adding acid (usually lemon juice) in seven, using cold water in eight and warm or hot water in six.

Clinical features of toxicity

Clinical features described in Table 1 occurred within 4 h of the last ingestion. All patients had muscular spasms. Rigidity and convulsions were common, occurring in 9/23 and 6/23 cases, respectively. One patient sustained a fracture dislocation of their shoulder during a convulsion requiring reduction under anaesthetic. Management was largely supportive (Table 2), with most receiving benzodiazepines for treatment of myoclonus, muscle rigidity or convulsions. Five patients developed metabolic acidosis with hyperlactataemia. The median peak blood lactate concentration was 14.8 mmol/L (range 5.8 to 24.6 mmol/L). In two cases, metabolic acidosis with hyperlactataemia occurred in patients who had experienced myoclonus but not convulsions. Five patients developed rhabdomyolysis with a median peak creatine kinase activity of 2,510 IU/L (range 1,349 to 26,500 U/L). Five patients developed acute kidney injury with a median peak serum creatinine concentration of 309 μmol/L (4.49 mg/dL; range 123 to 703 μmol/L [1.39 − 7.95 mg/dL]). Two patients received continuous kidney replacement therapy for acute kidney injury; this continued for 10 days in one patient who has persistent chronic kidney disease (eGFR 60 ml/min/1.73 m²). There were two cases of cardiac arrest.

Table 1. Clinical features of 23 patients presenting with thebaine toxicity following drinking poppy seed tea in poisoning cluster.

Clinical features	Number
Muscle spasm or myoclonus	23
Rigidity	9
Convulsion	6
Metabolic acidosis	5
Rhabdomyolysis	5
Acute kidney injury	5
Cardiac arrest	2

Table 2. Treatment of 23 patients presenting with thebaine toxicity following drinking poppy seed tea in poisoning cluster.

Treatment	Number
Observation alone	4
Benzodiazepines	19
Oral route	14
Parenteral route	7
Unknown route	2
Endotracheal intubation	3
Inotrope therapy	3
Continuous kidney replacement therapy	2

The first, a 46-year-old man, called the ambulance for severe leg spasms an hour after drinking poppy seed tea brewed from 480 g of poppy seeds mixed with cold water and half a cup of lemon juice. On arrival of the ambulance, he was having a generalised tonic-clonic convulsion, during which he suffered a cardiac arrest with pulseless electrical activity. He had a return of circulation following endotracheal intubation and epinephrine 1 mg via intraosseous access. On arrival at the hospital, he had a profound metabolic acidosis (pH 6.5, PCO₂ 49 mmHg [6.53 kPa], bicarbonate concentration of 4 mmol/L, lactate concentration of 24.6 mmHg) and received epinephrine (peak dose 40 µg/min) and norepinephrine (peak dose 10 µg/min) infusions to maintain his blood pressure. He developed an acute kidney injury (baseline creatinine concentration of 67 μmol/L [0.76 mg/dL]; peak creatinine concentration of 309 μmol/L [3.49 mg/dL]) and rhabdomyolysis (peak creatine kinase activity of 26,500 IU/L). He gradually improved with supportive care. He was discharged home well on day 19. Presentation concentrations of opium alkaloids thebaine, codeine, morphine and laudanosine were 2.4 mg/L, 0.04 mg/L, 0.04 mg/L and <0.01 mg/L, respectively.

The second, a 60-year-old man, had a convulsion after drinking tea made from 950 g of poppy seeds, prompting an ambulance referral. On arrival of an ambulance, he was agitated and looked unwell with a mottled appearance. He had a further tonic-clonic convulsion during which he developed asystole. He had a return of spontaneous circulation after 13 min of resuscitation, endotracheal intubation and epinephrine 1 mg intravenously. On arrival at the hospital, he had circulatory shock with a profound metabolic acidosis (pH 6.8, PCO2 54 mmHg [7.2 kPa], bicarbonate concentration of 8 mmol/L, lactate concentration of 27 mmol/L). He developed rhabdomyolysis (peak creatine kinase activity of 2,510 IU/L) and an acute kidney injury (peak creatinine concentration of 472 μmol/L [5.34 mg/dL]) for which he underwent continuous kidney replacement therapy. He had ongoing convulsion activity over the next week and did not improve neurologically. Magnetic resonance imaging of the brain on day 11 confirmed a severe hypoxic brain injury. He died on day 14. Presentation concentrations of opium alkaloids thebaine, codeine, morphine, and laudanosine were 5.6 mg/L, 0.3 mg/L, 0.06 mg/L, and 0.06 mg/L, respectively.

Most patients (15/23) were managed within the Emergency Department, including the Short Stay Unit. Four patients were admitted to a medical ward, and a further four patients were admitted to the Intensive Care Unit. The median length of stay was 17.3 h (IQR 4.1 to 30.8 h). There was one death, as described above.

Analytical testing

Thebaine was the dominant opium alkaloid detected in all samples, though other poppy-derived alkaloids, including morphine, codeine and laudanosine, were also detected. The median thebaine concentration at presentation was 1.6 mg/L (range 0.1 to 5.6 mg/L). Convulsions, acute kidney injury, metabolic acidosis and cardiac arrest were associated with an increasing median thebaine concentration, although there was marked inter-individual variability [Figure 1]. Codeine was detected in 21 presentations with a median concentration of 0.04 mg/L (range <0.02 − 0.36 mg/L), while morphine was detected in 15 presentations with a median concentration of 0.04 mg/L (range <0.01 − 0.09 mg/L). Laudanosine was detected in 22 presentations with a median concentration of 0.02 mg/L (range <0.01 − 0.06 mg/L).

Figure 1. Median (black circle) and range (whiskers) of presentation thebaine concentrations for clinical features of thebaine toxicity in a series of 23 poisoned patients drinking poppy seed tea.

Discussion

Patients in this series had progressive neuromuscular excitation following the consumption of poppy seed tea made with thebaine-rich poppy seeds. All patients experienced muscle spasm. Rhabdomyolysis, rigidity, convulsions, acute kidney injury, metabolic acidosis and cardiac arrest occurred with increasing frequency in association with rising thebaine concentrations. This constellation of clinical features is very similar to strychnine poisoning. Rat models demonstrate that thebaine has a high affinity for glycine receptors, albeit with 100-fold less potency than strychnine itself [6], which supports the main mechanism of toxicity being glycine antagonism. Cases in this series were managed supportively with benzodiazepines to treat muscle spasm, and organ support in severe cases.

There are few reports of blood concentrations of Papaver alkaloids following poppy seed ingestion. In a fatal co-ingestion of poppy seed tea and phenazepam, postmortem alkaloid concentrations included a morphine concentration of 0.116 mg/L, codeine concentration of 0.085 mg/L, and thebaine concentration of 0.072 mg/L [10]. This concentration profile contrasted with results in this cluster. Our patients had thebaine concentrations that were much greater than the concentrations of morphine and codeine. Variable amounts of opium alkaloids have been detected in poppy seeds, but the quantities are generally low compared to those found in the sap or poppy latex [11]. In one American study of 22 different commercially available poppy seeds brewed into tea, the median concentrations of morphine, codeine, and thebaine were 75 mg/kg (range <1 to 2,089 mg/kg), 13.2 mg/kg (range <1 to 237 mg/kg) and 20.7 mg/kg (range <1 to 60 mg/kg) respectively[12]. The thebaine concentration in an implicated batch of poppy seeds in this cluster was approximately 40 times the highest concentration detected in this study [12].

The method of brewing poppy seed tea was heterogenous across the series, with patients using both hot and cold water and adding acidic compounds like lemon juice. Neither temperature nor lowering of the pH appeared to affect the extraction of morphine or codeine in a study that simulated poppy seed tea brewed from 22 different commercial poppy sources [12]. However, the same study did demonstrate that thebaine concentrations increased when acid was added, with almost twice the amount of thebaine extracted when 5% lemon juice was added to the solution [12].

One issue raised in this poisoning cluster following the release of public health alerts was the safety of using thebaine-rich poppy seeds in baking for the wider community. There is some evidence that suggests extended thermal treatment (40 min at 200 °C) or washing poppy seeds with water can reduce concentrations of morphine by approximately 50%. However, this was not noted when the poppy seeds were baked in a muffin (16 min at 200 °C) [11]. There were no cases of poisoning identified in this cluster following the ingestion of poppy seeds in food and the affected batches were recalled rapidly after the issue was identified. Interestingly, there is no current regulatory limit on opium alkaloids in food-grade poppy seeds in Australia.

This study has some limitations. It only included patients with laboratory confirmation of thebaine poisoning. Other thebaine poisonings likely occurred with a total number of patients possibly as high as 40 persons. Tea preparations likely varied. However, descriptions of tea preparations were missing in some cases and depended on patient recall in other cases. Given the variability in tea preparation, the association of dose and clinical effects was unable to be explored. We were unable to estimate the pharmacokinetics of thebaine because most patients had only one measurement and because intervals between exposure and analysis varied.

Conclusions

Thebaine toxicity appears similar to strychnine poisoning and resulted in neuromuscular excitation characterised by muscle spasm, rigidity, and convulsions. Features of severe toxicity included acute kidney injury, metabolic acidosis, and cardiac arrest. Thebaine toxicity should be considered in patients presenting with neuromuscular excitation following consumption of poppy seed tea.

Author contributions

KI, DR, JB, JS, and SG conceived the project. All authors contributed to data collection. KI analysed data and drafted the manuscript. All authors contributed substantially to its revision, approved the final version of the manuscript, and agreed to be accountable for all aspects of the work.

Acknowledgements

The study group would like to acknowledge the following people:

• NSW Health clinical and analytical collaborators through PRISE: Ingrid Berling, Sean Kelly, David Yoo, Rowena Penafiel, Andrew Dawson, Nick Buckley, Kirsty Hope, Una Nic Ionmhain, Betty Chan, Lucy Kuehn, Amy Thomson, Dushan Jayaweera, Jason Tran, Vanessa Shaw and Keira Glasgow and Health Protection NSW

• WA Public health (Communicable Disease Control Directorate): Jelena Maticevic and Rebecca Hogan

• SEATs Clinicians: Ben Weber and Andrew Kozman

• Queensland Health (Metro South and Sunshine Coast Public Health Units) and the Forensic and Scientific Services Organic Chemistry team

• Health.Vic clinical, analytical, and public health collaborators: Danny Csutoros, Aoife Hurley, Rebekka Syrjanen, Jennifer Schumann, Sarah Hodgson, Rachelle Abouchedid and Jared Castle.

Disclosure statement

No potential conflict of interest was reported by the authors.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The EDNA collaboration is supported by an NHMRC Ideas Grant (GNT2001107).