Gas Station Herbals
Want to know what leaf can cause symptoms of an opioid overdose? Use of what herbal has resulted in liver transplants and also causes a rash called crocodile skin? Listen to find out!
This is the Pick Your Poison podcast. I’m your host Dr. JP and I’m here to share my passion for poisons in this interactive show. Will our patients survive this podcast? It’s up to you and the choices you make. Our episode today is called Gas Station Herbals. Want to know what leaf can cause symptoms of an opioid overdose? Use of what herbal has resulted in liver transplants and also causes a rash called crocodile skin? Then stay tuned!
Today’s format is a little different, we’re going to do two cases and two substances instead of one. Both topics have been in the news recently and both cases are relatively short, so I thought we could do them together.
Case 1
A 39-year-old woman presents to the emergency department, unresponsive. She’s cyanotic meaning blue colored lips and fingers. She's not breathing and her oxygen saturation is 50% on room air, half of the normal 100%.
What do you do first? As always, the ABCs. Clearly, this is an airway and breathing problem, requiring attention before anything else. The intern puts a bag valve mask over her face, holding it tightly to create a seal. He squeezes the bag to fill her lungs with breaths of 100% oxygen.
You have two options here. The first is to intubate her and put her on the ventilator. Option number two is also question number one. You could try an antidote first. If you choose the antidote, what should you give?
Intralipid or 20% soybean oil
naloxone or Narcan
Physostigmine
Methylene blue
Answer: B. naloxone.
This appears to be an opioid overdose. She has an altered mental status and a depressed respiratory status. You could make a good argument for either option, intubate or try naloxone, so both are acceptable. As long as her oxygen levels improved with bag mask ventilation, I’d try a dose of naloxone before putting her on a ventilator in the hopes of avoiding intubation altogether. You order half a milligram of naloxone, starting low to avoid precipitating withdrawal. The nurse pushes it. The patient’s eyes flutter open and she takes a few breaths. A good sign, so you give another dose. After the second dose, she's groggy but awake and breathing on her own. Her oxygen saturation rises to 100% on room air.
You ask her what happened prior to arrival. She says she has no idea. When you ask about illicit drugs, she adamantly denies them and she also denies use of prescription opioids. You maintain a healthy dose of skepticism, having heard this story before and later finding out that in fact the patient did take an opioid. You order some basic labs, a chest x-ray to check for pulmonary edema, fluid in the lungs, that can occur with opioid use and reversal. The nurse asks if you want a urine drug screen, the intern says yes.
An hour later, the intern calls you back into the room. The patient is unresponsive and barely breathing, again. You give her another dose of naloxone, this time the full 1 mg dose that previously worked. Again, the patient wakes up and, again, denies opioid use. The intern checks the chart, her results are all normal including her drug screen.
What's going on? Is the patient lying or telling the truth? Doesn't the drug screen prove she's not using drugs? If you've been listening to this podcast, you know the urine drug screen rarely proves anything, and, certainly, never rules out drugs of abuse or other toxins.
Let’s talk for a minute about the urine drug screen for opioids. The standard screen tests for morphine, meaning it identifies naturally occurring opioids like heroin and codeine because they’re metabolized to morphine. It doesn’t capture synthetic opioids like fentanyl and methadone because these are metabolized differently. The test is about 50% sensitive for semisynthetic opioids like oxycodone and hydrocodone i.e. Percocet and Vicodin. It’s a coin toss if the test will be negative or positive after use of these drugs. Some hospitals add tests specifically for methadone and fentanyl.
Even if we knew with 100% certainty our patient used an opioid, the test could still be negative. Why? It takes some time for the drug to be metabolized and get into the urine. For example, if she overdosed minutes before arrival and we collected her urine immediately, the test might be negative.
The urine drug screen, as usual, doesn’t give us the answer, but our patient denies opioid use, so something else is going on here. She reports a history of anxiety and takes sertraline, an SSRI, as prescribed by her primary care doctor. As you're discussing this, her husband arrives. He says she took something this morning to help her anxiety.
Question 2. What “over-the-counter” drug could the patient have taken giving symptoms of an opioid overdose?
Kava
K2 (spice)
Khat
Kratom
Answer: D. Kratom. Kratom is a substance you may have heard of as it’s become
increasingly popular. Kratom comes from a tree found in Southeast Asia, called Mitragyna speciosa. The leaves from this tree have been used for a thousand years by indigenous people for many purposes. Traditionally the leaves were chewed or dried and brewed into tea or poultices for wounds. Labors took, and still take, kratom to increase productivity and reduce fatigue. It’s used to treat ailments from diabetes, to fever, diarrhea and pain. Also, it’s used to treat opioid use disorders and withdrawal.
The leaves contain a number of alkaloids, the main active ingredients are mitragynine and 7-hydroxymitragynine. Mitragynine and the other compounds in kratom, have many effects on receptors in the brain and body, the full spectrum of effects of the kratom plant are still being researched. We do know mitragynine binds to opioid receptors, thus the reason our patient’s presentation had the classic symptoms of an opioid overdose. And the reason the overdose responded to naloxone, reversing the binding of mitragynine to opioid receptors.
The patient says she got in trouble with her boss at work. Afraid of losing her job, she bought three bottles of kratom from a gas station to treat her anxiety. The label said high potency kratom and promised to balance the mood after drinking. She drank them all about an hour prior to arrival. She doesn’t remember anything else, until she woke up in the ER.
In the US and other countries, kratom has become popular as a supplement. Instead of leaves, it’s found as a powder, as extracts and in liquid formulations. It’s advertised to treat many issues but commonly anxiety, depression and opioid withdrawal. As a supplement, it’s unregulated by the FDA in the US. Strangely, it’s illegal to import kratom into the US, but not illegal to have it or sell it. It’s usually imported from Asia, seizures occur at ports of entry. Apparently, this is relatively easy to circumvent without putting kratom on the bill of lading. Despite its legality, US manufacturers operate under a cloak of secrecy. Employees of some companies report they weren’t told what the green powder they worked with was and what to expect from exposure.
With this secrecy in particular and with all supplements in general, lack of regulation leads to problems. First, unregulated dosing. You have no idea how much kratom is really in a bottle from a gas station. Second, contamination. In the US, a large number of Kratom products were recalled after bacterial contamination with Salmonella. In Sweden, nine deaths occurred after use of a kratom preparation that contained O-desmethyltramadol. This is a metabolite of a pharmaceutical drug, the opioid pain reliever, tramadol.
A Tampa Bay Times investigation in 2023 found 580 people in Florida over a 10-year period died with deaths related to kratom. In most cases multiple substances, including fentanyl were present. This brings up an additional concern, drug interactions. Kratom is metabolized in the liver by enzymes called the P450 system. Specifically, kratom inhibits subtypes CYP2D6 and CYP3A which are responsible for metabolizing many, many pharmaceuticals including opioids, benzodiazepines and antidepressant SSRIs, like Prozac and sertraline.
Forty-six of the deaths were found to be associated with kratom alone. In contrast, few complications are reported from kratom use in Southeast Asia, though these numbers are rising. The discrepancy? Probably two reasons. The first is underreporting, the second is dose related. The amount of mitragynine naturally in the leaves of the tree is relatively low. Similar to cocaine in cocoa leaves and THC in marijuana from the 1960s. It’s not to say taking coco leaves or kratom leaves is without risk, however it is a lower risk than taking the drugs in concentrated doses, like snorting cocaine or taking kratom preparations touting high concentrations. For reference, 20 leaves contain approximately 17 mg of mitragynine. Users in might chew 1-3 leaves at a time, with heavy users chewing 10 leaves per day. So that’s 9 mg of mitragynine in leaves of heavy users. You can buy kratom shots with 150 mg in one bottle.
Kratom causes respiratory failure as with our patient. It can cause kidney and liver failure, seizures. It also causes withdrawal symptoms in habitual users and neonatal abstinence syndrome, or withdrawal in babies whose mothers used regularly during pregnancy. Withdrawal is similar to opioid withdrawal including diffuse body pain, watery eyes, a runny nose, vomiting and diarrhea. Many users feel the withdrawal is easier to tolerate than opioid withdrawal, though this may be dose related.
With chronic use, kratom causes skin hyperpigmentation in sun exposed areas, like the face and arms. Mitragynine causes increased melanocyte stimulation and high levels of melanin.
The legal status of Kratom is mixed both in the US and around the world. It is legal in some countries like the Netherlands, regulated in others, and illegal in Singapore and Malaysia. In the US in 2016, the FDA attempted to make it a schedule 1 drug, given safety concerns. However, this led to objections from Congress. The outcry was ostensibly from those with chronic pain and substance use disorders, saying kratom was safer than alternatives. More likely the real reason is the 1.5-billion-dollar kratom industry in the US and the $4 million dollars spent on lobbying. Instead, the FDA listed it as a drug of concern. Since then, several states and counties have banned it on their own.
Kratom has been banned in Thailand since 1943. Apparently, not out of concern for users, but rather out of concern for revenue. The Thai government controlled the opium industry along with taxes from sales. Thanks to the taxes, opium was expensive and users shifted to kratom as a cheaper alternative. The government made Kratom illegal to protect its revenue. In 2019, the regulations loosened, allowing limited medical use and research.
As I mentioned, kratom is addictive. Treatment hasn’t really been studied, but success with approaches to treat opioid disorders is reported, including buprenorphine, methadone and counseling.
I ventured online to see how easy it was to buy. Exceedingly easy. It’s found at gas station, convenience stores, kratom bars, kava bars and online shops. I was astonished by the variety of ways to buy it. You can by powder by the kilo, kratom gels, gummies, honey sticks, and chocolate. You can vape it, more on the serious problems related to vaping anything in another episode.
You find the effects of some of these products associated with the vein color of the leaves. The white vein variety is reported to have more mild stimulant effects, the green vein variety for pain and the red variety for stronger pain relieving and sedating effects. This is definitely not scientifically validated.
After the second dose of naloxone, you observe the patient for six hours. She remains awake and alert. You discharge her home uneventfully with her husband and a plan to follow up with psychiatry for help with her anxiety.
Certainly, it would’ve been better if she’d only drank one bottle of kratom, but the unregulated nature of these supplements was also part of the problem. Bottom line gas stations aren’t the best place for healthcare, same for aphrodisiacs, see episode 1. Stick to ice cream and soda at the convenience store.
Case 2
A 34-year-old man presents to the emergency department complaining of weakness and fatigue. The vital signs recorded in his chart are normal. Walking into the room, the first thing you notice is his skin. It’s bright yellow and he has a rash.
He says he's been feeling generally weak and tired for the past week. He initially thought it was the flu, until his skin and eyes started turning yellow. He denies medical problems, says he's not taking any medicines and has no allergies. He denies alcohol, tobacco and drug use. On exam, he has scaly skin his face and trunk. The whites of his eyes are yellow, scleral icterus in medical terms. The rest of his exam is unremarkable.
His lab results come back normal except for his liver function tests. Unlike our last episode, this patient with yellow skin is in fact jaundiced. His bilirubin is very high at 20 mg/deciliter. For reference, normal is 1 mg/deciliter or less. The other liver function tests, the ALT and AST are mildly elevated.
You return to the room to get some more history. He hasn’t had any abdominal pain to suggest gallstones, or any reason to have been exposed to infectious hepatitis. Certainly, we would start a workup for causes of liver disease including an ultrasound to check his pancreas and gallbladder, as well as hepatitis A, B and C serologies. Steroids can also cause this pattern of liver failure. He denies exposure to these drugs for any reason, prescribed or otherwise. Your last question, finally, yields some useful information.
You ask about supplements. He reports he has been taking something to help with stress. He says he has family and work-related problems and a friend recommended it to help him relax. He didn't mention it earlier, assuming because it’s all natural it’s safe. You bite back your usual response about cocaine and heroin. Both all natural and neither are safe.
Question 3. What supplement did the patient use?
Kratom
Kava kava
Salvia divinorum
Belladonna
Answer: The truth: this was a bit of a trick question. The answer is both A. kratom and B. kava. Kratom can cause liver toxicity and causes a similar pattern with the liver function tests, though only a few cases have been reported. The patient denies kratom use but admits to kava kava which causes liver toxicity much more commonly.
The pattern of the lft abnormalities, with a high bilirubin and mildly elevated AST and ALT is a classic presentation of kava toxicity. Patients complain of flu-like symptoms, generalized malaise and fatigue, then become jaundiced.
Kava is a plant from the South pacific, the Latin name is Piper methysticum, meaning intoxicating pepper.
Question 4. What dose kava mean in Tongan?
Bitter
Sweet
Sour
Salty
Answer: A. Kava means bitter, describing its taste. Historically, it was made into a drink used for ceremonial purposes. The leaves were chewed or crushed and mixed with water or coconut milk. It’s still used ceremonially in Tonga and Fiji. In modern times, it's now used as a social beverage, sometimes in place of alcohol. Participants gather around a large bowl, the leaves are mixed, usually with water, resulting in a brown liquid which is then shared. Kavalactones, the active ingredients, cause users to feel calm and relaxed. It's become popular as a supplement around the world, being touted for anxiety and stress relief.
The specific route via which kava causes hepatotoxicity is unclear and several different mechanisms have been proposed. There few reports of hepatotoxicity or other side effects from Pacific islanders. Like kratom, it’s unclear if this is due to underreporting, or if its dose related. Also, like kratom, kava affects the p450 enzymes in the liver, meaning that it may cause significant drug interactions. Something I came across is a difference in metabolism between Pacific Islanders and Caucasians. Kava may be metabolized via the CYP2D6 enzyme, 10% of Caucasians are slow metabolizers, meaning low enzyme activity. Only 1% of Asians are slow metabolizers. Slow metabolism might predispose to hepatotoxicity. This is an unproven, but interesting hypothesis.
Kava hepatotoxicity is supposedly an uncommon side effect. However, as a toxicologist I've seen quite a bit of it. Strangely, I've seen a number of kava users who know that it causes hepatotoxicity and when they get jaundiced, they come to the emergency department. They’re of course advised to stop kava use, but return again a few months later with a similar presentation. Most cases of hepatotoxicity resolve with cessation of exposure. However, serious complications do occur. Deaths from fulminant hepatic failure occur and a number of patients have required liver transplants, including a 14-year-old girl who took kava for 3 months. The risk of liver toxicity occurs with subacute or chronic exposure. One dose won’t cause liver disease. It’s unproven if the liver problems are a dose response relationship, though it’s likely the case. Alcohol coingestion increases the risk of hepatotoxicity.
The drug does have psychoactive effects, it produces mild euphoria, sedation and relaxation. Studies regarding its utility in reducing anxiety are mixed with some showing a benefit and others showing no effect compared to placebo.
Remember our patient was jaundiced – due to hepatotoxicity- and had a rash. Is the rash also from kava? Yes. The rash starts on the head and spreads down the body, resolving when kava exposure stops. It causes, I hope you’re ready for this, a reversible ichthyosiform pellagroid dermopathy, sometimes called crocodile skin.
Outside of its traditional use in the Pacific islands, kava can be found in many forms including the whole root, powdered roots, paste formulations. Liquid formulations include flavored beverages, shots, and teas.
Kava was used in Europe in the 1900s as a diuretic and to treat gonorrhea. I'm beginning to wonder if there's any compound that wasn't tried for treatment of gonorrhea and syphilis. In the 2000s, a number of countries banned kava after reports of its hepatic toxicity. Surprisingly most of these bands were later lifted. Germany for example banned it in 2002, then reversed it due to the rarity of complications. For example, the risk of hepatoxicity while real, is less than the risk of liver failure from alcohol and acetaminophen (Tylenol or paracetamol). There are regulations and restrictions in some countries, but generally speaking, it’s found in most places. In the US it is legal, though the FDA issued a warning in 2002 about liver toxicity.
Back to our patient, his workup for liver disease is negative. You discharge him home, recommend he stop kava use and follow up for repeat LFTs with his primary care doctor. When you check up on his chart a week later, you see his liver function is back to normal.
These are fictional cases, as are all our cases, to protect the innocent. But they are based on real poisonings. I wanted to share these stories with you and the facts about kratom and kava, as they are associated with a lot misinformation and false claims. Are they as dangerous as fentanyl? Do I expect to see an epidemic of deaths related to these two drugs? No, but that doesn’t mean they are safe, and certainly unregulated use is dangerous and unpredictable.
Question #5, the last in today’s podcast. Which famous explorer’s crew members described the rash caused by kava?
Christopher Columbus
Ferdinand Magellan
Francis Drake
James Cook
Post your answers on our Twitter and Instagram feeds both @pickpoison1. Follow and you’ll see the answer when I post it. Remember, never try anything on this podcast at home or anywhere else.
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