An Autopsy Case of Dextromethorphan Poisoning
2024 Volume 46 Issue 2 Pages 221-226
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2024 Volume 46 Issue 2 Pages 221-226
A woman in her 30s who was being treated for a mental illness with several psychotropic drugs was admitted to the hospital after being found in a state of unconsciousness and respiratory arrest at home. She was pronounced dead 12 hours after she was discovered. Her autopsy revealed symmetrical hemorrhagic necrosis in the putamen on both sides of her cerebrum. Although many drugs were detected in her blood, all of those other than dextromethorphan (DXM) were within or below the therapeutic range. Her blood DXM was 1.73 μg/ml at admission and 1.61 μg/ml at autopsy, which were within the toxic range or coma-to-death range. The cause of death was diagnosed as DXM poisoning. DXM can cause hallucinations and euphoria if taken in excess, but since it is available as an over-the-counter drug at general pharmacies, an increasing number of young people are overdosing on it, mistakenly believing it to be a safe drug with few side effects. We believe that further social measures against DXM are necessary in Japan, such as disseminating correct knowledge in society and regulating over-the-counter sales.
Dextromethorphan (DXM) is a powerful non-narcotic antitussive drug that has almost the same antitussive effect as the narcotic codeine phosphate. DXM is considered relatively safe and is not only prescribed as a medical drug but also included in many general cold medicines and sold as an over-the-counter (OTC) drug at pharmacies without a prescription. However, DXM can lead to abuse and dependence. It is reported to inhibit NMDA receptors at high doses, causing hallucinogenic and dissociative effects [1, 2]. Standard doses of DXM in Japan range from 5 mg to 30 mg, and up to 120 mg in 24 hours. Symptoms ranging from mild stimulation to euphoria and hallucinations can occur at doses of 100 mg to 300 mg [3]. Dissociation can occur at doses of 300 mg to 600 mg, and complete dissociation and coma can occur at doses of 600 mg or higher [3]. DXM abuse among young people has spread rapidly in various countries in recent years, and has become a social problem [4, 5]. Although the mechanism has not been elucidated, patients with DXM addiction have a high 1-year relapse rate of 89.29%, and baseline depression and anxiety are positive predictors of relapse [6]. Deaths related to DXM use have also been reported overseas [1, 7–9].
Dextromethorphan overdose has recently become a problem in Japan as well [10], but we can’t find any manuscripts that describe it in detail. We performed an autopsy on a case thought to have been caused by DXM poisoning and will report it along with our discussion.
A woman in her 30s had been receiving treatment for schizophrenia, depressive neurosis, insomnia, symptomatic epilepsy, and neuropsychiatric seizures for 13 years. About a year before her death, she had taken large amounts of medicines and was admitted to the hospital. The name and amount of the drug she took at the time, as well as the details of her treatment at the hospital, are unknown.
At 9:30 p.m. on the day before she died, a security camera recorded her jumping from the second-floor balcony of her home and falling face down after an argument with her family. The camera then recorded her getting up and going into her home by herself. At around 5:30 a.m. on the day of her death, she lost consciousness in the living room of her home. Her family found her collapsed due to respiratory failure. She was admitted to the hospital, where resuscitation efforts briefly restarted her heartbeat, but she was pronounced dead at 5 p.m. A whole-body CT scan and a clinical examination of blood revealed no specific findings that could be linked to the cause of death. An on-site screening kit of her urine was positive for benzodiazepines, and a serum Liquid chromatograph mass spectrometry (LC-MS/MS) drug screening test detected multiple drugs, such as nitrazepam, DXM, acetylpheneturide, mirtazapine, flunitrazepam, and alprazolam. None of the drugs were of abnormally high concentrations as estimated by a drug screening test. As a result, the cause of death was determined to be unknown at the hospital, and the body was sent to us for an autopsy the day after her death.
It was discovered after her death that she had sent messages to her family by her smartphone shortly after midnight on the day of her death, saying things like, “I can’t stand up,” “My eyes hurt from OD,” and “I’m dizzier than ever.” It seemed that OD here was used as an abbreviation for overdose.
Macroscopic findings
The woman was 145 cm tall and weighed 57.2 kg. In addition to injuries caused by medical procedures, she had subcutaneous lesions on the soles of both of her feet. There were intramuscular hemorrhage, calcaneal fracture, epidermal abrasion, and subcutaneous hemorrhage on the right side of the head, face, and extremities, which were assumed to have occurred by a fall from a high place with the left and right feet in a low position. The damages were not severe, and could not be considered the cause of death. The organs were congested, and there was symmetrical softening and mild hemorrhage in the left and right putamen of the cerebrum (Figure 1A). One hundred eighteen gram of black liquid, not containing tablets, was found in the stomach. There was no urine left. These injuries were not of fatal significance. No other abnormal findings were observed.
Histopathological findings
After fixing the primary organs in formalin, 4 μm formalin-fixed paraffin-embedded tissue sections were prepared and observed after HE staining. Histological findings also showed congestion in the primary organs and mild pulmonary hemorrhage. Although there was no evident stenosis of the basilar artery or vertebral artery, the bilateral putamen was edematous, and there were diffuse small hemorrhagic foci (Figure 1B). A diagnosis of hemorrhagic necrosis was made. There were no abnormalities in the other organs.
A: Frontal section of the cerebrum. Softening with mild bleeding was observed on the bilateral sides of the putamen. B: Histological finding of putamen (HE staining) Diffuse edema with small bleeding was observed, like hemorrhagic cerebral necrosis.
Drug Screening
Zero point five milliliter of femoral blood was pretreated, and the extract was screened for drug toxicity using gas chromatograph mass spectrometry (GC/MS) and LC-MS/MS [11, 12]. Table 1 shows the screening results, in which caffeine and nicotine and their metabolites are not listed. Table 1A shows the drugs prescribed to this case before her death, and Table 1B indicates the drugs whose prescription could not be confirmed. The acquisition route for B is unknown. Ethanol was not detected in the blood or gastric supernatant.
| A | Nitrazepam Valproic acid | Flunitrazepam Mirtazapine | Alprazolam |
| B | Ketoprofen Tranexamic Acid | Propranolol | Chlorphenesin |
| Dextromethorphan (DXM) | |||
Quantitative results
Table 2 shows the quantitative results. The six drugs in Table 2 were detected during screening, and brotizolam was added because it had been prescribed by her primary care doctor. Samples such as blood at admission, femoral blood, thigh muscle, and supernatant of stomach contents at autopsy were analyzed. According to the above screening method, sodium valproate was measured using the GC/MS instrument, and other drugs were measured using the LC-MS/MS instrument. For reference, the range of literature values for each symptom is shown on the right side of Table 2 [13]. There was little difference in drug concentrations in the blood at the time of admission and autopsy, except for valproate. The patient did not respond adequately to resuscitation until death at 12 hours after being transported to the hospital. Drug metabolism at the hospital had hardly progressed. The concentrations of drugs other than DXM in the blood at the time of transportation to the hospital and in the femoral blood at autopsy were in the therapeutic range or below the therapeutic range. The DXM concentration was 1.73 µg/m l at the time of admission and 1.61 µg/m l at autopsy, both of which were approximately seven times the upper limit of the therapeutic range and reaching the toxic to lethal range. The DXM of the gastric supernatant at autopsy was 26.8 μg/m l, more than 16 times that of femoral blood, and the difference was more than that of the other drugs.
| Time | Admission | Autopsy | Reference [13] | ||||
|---|---|---|---|---|---|---|---|
| blood | femoral blood | thigh muscle | stomach contents | therapeutic blood level | poisoning blood level | coma-death blood level | |
| Nitrazepam | 0.079 | 0.109 | 0.247 | nd | 0.03-0.1 | 0.2 | 5 |
| Flunitrazepam | 0.015 | 0.013 | 0.007 | nd | 0.005-0.015 | 0.05 | 0.11-0.74 |
| Alprazolam | 0.017 | 0.007 | 0.013 | 0.041 | 0.005-0.08 | 0.1-0.4 | 0.3 |
| Brotizolam | 0.001 | 0.001 | 0.001 | 0.002 | 0.001-0.02 | 0.02 | 0.01-0.03, 0.21 |
| Valproic acid | 14.15 | 6.25 | na | 5.32 | 40-150 | 120, 150-200 | 556, 720 |
| Mirtazapine | 0.118 | 0.117 | na | 0.73 | 0.03-0.3 | 0.16, 1-2 | 2-3 |
| DXM | 1.73 | 1.61 | 4.1 | 26.8 | 0.01-0.23 | 0.1-2.8 | 1.1-20 |
na: not analyzed, nd: not detected, DXM: Dextromethorphan
In this case, the injury from the jump the day before death could not have been the cause of death, and no other injuries or diseases were found that could have caused death. Although there were many drugs in the blood collected at admission to the hospital and at autopsy, only the blood concentration of DXM far exceeded the therapeutic range, reaching the toxic to the fatal level, and the content in the stomach was even higher, indicating that a large amount of DXM may have been ingested orally. There were no white DXM tablets or powder pieces in the stomach contents. It is unclear how she had obtained the DXM or how long she had been taking the drug. Some common cold medicines include antipyretic analgesics, ephedrine, codeines, and antihistamines, but these ingredients were not detected by drug screening in the samples of the deceased patient. It is therefore presumed that the deceased took a large amount of DXM drug, which is similar to a single drug, rather than general cold medicine.
Dextromethorphan undergoes o-demethylation to yield the main active metabolite dextrophan. There are four major physiological mechanisms of the action of dextrophan [14]. The first mechanism is that it binds to the sigma-1 receptor (σ 1 receptor) and produces an antitussive effect [15] for which it is used due to its physiological effects. DXM does not bind to μ-opioid receptors or δ-opioid receptors, so it is thought to have fewer side effects than morphine or codeine, making DXM more useful than other antitussive drugs such as the narcotic codeine phosphate.
The second through fourth mechanisms of dextrophan, discussed below, are unrelated to its antitussive effects but can cause adverse events and may be related to the overdose and cause of death in the present case. The second mechanism is the inhibition of NMDA (N-methyl-D-aspartate) receptors in the brain. Functions such as excitatory synaptic transmission, learning, and memory are suppressed, resulting in hallucinations, euphoria, dissociation, and coma [1, 2]. A third mechanism inhibits the reuptake of peripheral adrenergic neurotransmitters, leading to the accumulation of noradrenaline in the synaptic cleft, resulting in symptoms such as hypertension, tachycardia, mydriasis, and sweating [2, 16]. The fourth mechanism is binding to serotonin receptors and causing hyperactivity of serotonergic neurons, leading to symptoms of serotonin syndrome such as muscle rigidity, autonomic instability, and rhabdomyolysis [17–19]. Serotonin syndrome does not need to be an overdose, but can occur even at standard doses when DXM is combined with SSRIs (Selective Serotonin Reuptake Inhibitors), SNRIs (Serotonin and Noradrenaline Reuptake Inhibitors), MAOIs (Moroamine Oxidase Inhibitors), cocaine, TCAs (Tricyclic Antidepressants), or other serotonergic drugs [18, 19]. The Mirtazapine detected in this case is classified as a noradrenergic/specific serotonergic antidepressant (NaSSA), which blocks the 5-HT 2 and 5-HT 3 receptors among serotonin receptors and has antidepressant effects. It activates only the 5-HT 1A receptor [20]. Mirtazapine is one of the other serotonergic drugs mentioned in the previous paragraph. It may cause serotonin syndrome if used in combination with DXM. In this case, administration of mirtazapine may have enhanced the effects of DXM. The effects described above are consistent with the course of this case, and the concentration in the body suggests that the cause of death was DXM poisoning due to oral administration of a large amount of DXM.
In this case, softening foci with hemorrhage was observed symmetrically in the left and right putamen, which was considered to be a sign of hemorrhagic necrosis. It has been reported that c-fos increase predominantly in the left and right putamen after DXM administration [21]. Since c-fos is an indicator of neural activity, it was thought that excessive intake of DXM caused the putamen to become overactive. Bilateral simultaneous putaminal hemorrhage is a rare condition, but in addition to being caused by rupture of the nuclear striatal artery in hypertension, it may also appear due to methanol poisoning [22, 23]. In methanol poisoning, the blood flow from the Rosenthal vein at the basilar area, which returns from the putamen, becomes poor due to circulatory disorders, and formic acid, a methanol metabolite, accumulates in the putamen and inhibits cytochrome oxidase in the mitochondria, resulting in intracellular hypoxia. It is thought to cause bilateral symmetrical hemorrhagic necrosis in the putamen, which has a high oxygen demand and is vulnerable to oxygen deprivation [24, 25]. Such cases have been reported to exhibit extrapyramidal symptoms such as parkinsonism and cognitive impairment [22, 24]. In this case, as well, it may be possible that overactivity of the putamen due to DXM caused a hypoxic state and triggered hemorrhagic necrosis of the putamen.
As mentioned above, DXM is not a safe drug with few side effects. DXM is relatively easy to obtain in OTC drugs and is used to treat hallucinations, euphoria, etc. Information that DXM is a safe antitussive drug with few side effects is erroneous. Dextromethorphan abuse by young people has been rapidly spreading [4, 5]. Unless drastic preventive measures are taken, DXM overdoses and poisonings will continue to increase in Japan. Society needs to understand the circumstances of people who have overdosed on DXM and to provide medical treatment. Furthermore, it is necessary to regulate OTC sales of DXM in Japan, to promote appropriate reporting activities regarding DXM to society, and to protect against the easy spread of information on social media.
The authors declare that they have no known conflicting financial interests or personal relationships that could have appeared to influence the work reported in this paper.
The datasets generated during the current report are available from the corresponding author on reasonable request.
