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EMplify # 19 – Cannabinoids: Emerging Topics in Use and Abuse

 

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EMplify # 19 –Cannabinoids: Emerging Topics in Use and Abuse

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Disclaimer: This is the unedited transcript of the podcast. Please excuse any typos.

Jeff: Welcome back to Emplify, the podcast corollary to EB Medicine’s Emergency Medicine Practice. I’m Jeff Nusbaum, and I’m back with my co-host, Nachi Gupta and we’ll be taking you through the August 2018 issue of Emergency Medicine Practice.

Nachi: This month’s topic is one that Jeff has significant personal experience with from his college days. We’re reviewing Cannabinoids -- and emerging evidence in their use and abuse.

Jeff: Um… that is definitely not true. I was actually a varsity rower in college... Are we still reviewing talking points together before we start recording these episodes?

Nachi: Sometimes…

Jeff: This month’s issue was authored by Mollie Williams, who is the EM residency program director at the Brooklyn Hospital Center. It was peer reviewed by Joseph Habboushe, assistant professor at NYU and Nadia Maria Shaukat, director of emergency and critical care ultrasound at Coney Island Hospital in Brooklyn, New York.

Nachi: We’re going to be talking about the pathophysiology of cannabinoids, clinical findings in abuse, best practice management, differences between natural and synthetic cannabinoids, and treatment for cannabinoid hyperemesis syndrome. So buckle up and get ready.

Jeff: As you’re listening through this episode, remember that the means that we are about to answer one of the CME questions from the end of the print issue. If you’re not driving while listening, be sure to jot down these answers and get your CME credit when we’re going through this issue..

Nachi: As of June 2018, there are 31 states, the District of Columbia, and 2 US territories that possess state and local-level laws allowing the use of cannabis medicinally or in recreational formulations. Marijuana actually maintains the highest lifetime use of an illicit drug used within the US.

Jeff: There are a shocking 22 million past-month users of marijuana in the US, followed by pain relievers at 3.8 million, and cocaine at 1.9 million. Clearly an important topic worth discussion, especially as synthetic products have become more widely available.

Nachi: And worth noting -- Colorado, where medicinal and recreational marijuana use has been decriminalized and later legalized, has shown a nearly 2-fold increase in prevalence of ED visits, which may be related to marijuana exposure.

Jeff: Medicinally, cannabinoids are currently used in treatment of chronic pain syndromes, complications of multiple sclerosis and paraplegia, weight loss due to appetite suppression in hiv/aids, chemotherapy induced nausea and vomiting, seizures, and many other neuropsychiatric disorders. In fact, cannabis use has been documented for medical use dating as far back as 600 BC in West and Central Asia.

Nachi: All of that being said though, there is an absence of high quality reviews and evidence to support the use of cannabinoids for any of the indications you just mentioned. And the US DEA maintains cannabis as a Schedule I substance.

Jeff: This DEA designation limits the ability to do research and obtain federal funding for such research. General lack of federal regulations on chemical content also lead to product variation, which may be a cause of an increased incidences of accidental overdoses.

Nachi: To attain the most up to date information for this article, Dr. Williams searched the PubMed and Cochrane Databases from 1950 to 2018. This produced predominantly case reports and retrospective studies. There were just a few randomized prospective studies – not surprising.

Jeff: Let’s get started with the pathophysiology. There are 3 cannabis species to be aware of: Cannabis sativa, cannabis indica, and cannabis ruderalis. Within these species, over 545 active cannabis-derived components have been described.

Nachi: There are ten main constituents of cannabis sativa. Of these, 9-tetrahydrocannabinol (delta-9-THC) and cannabidiol (CBD) are found in the greatest quantities. The neuropsychiatric and addictive properties of cannabis are due primarily to the delta-9-THC.

Jeff: THC and other cannabis derivatives work through the endocannabinoid system and other neuroregulators. The endogenous cannabinoid system has 4 components: (1) endogenous endocannabinoids, (2) receptors, (3) degradation enzymes, and (4) transport mechanisms.

Nachi: There are two endogenous endocannabinoids to know about: anandamide (AEA) and 2-arachidonoyl-glycerol.

Jeff: Cannabinoid receptors are broadly dispersed through the central nervous system, and to a lesser degree, also to other organ systems.

Nachi: Because CB receptors are concentrated within the central nervous system, they exert the majority of their effects on the neuropsychiatric systems. And -- yes that’s a double ding -- the cannabinoid 1 (or CB1) receptor is most responsible for cannabis-induced neuropsychiatric effects.

Jeff: Interestingly, the anti-emetic effects and possible palliative properties of cannabis derivatives are thought to be secondary to the inhibitory effects on serotonin receptors and the excitatory effects on the transient receptor potential vanilloid 1 (or TRPV1). More on TRPV1 later...

Nachi: So far we have been talking about cannabinoids from the cannabis plant, but with cannabis being illegal in many states, there has been a growing emergence of synthetic cannabinoids. Synthetics were initially developed in the 1980s largely for research purposes.

Jeff: Because the current DEA controlled substances schedule designations are based on original chemical names, synthetics have gained popularity as manufacturers are able to produce newer compounds and circumvent DEA designation as well as routine urine drug screening tests.

Nachi: You may be familiar with some of the street names for synthetics -- like spice, K2, scooby snacks, black mamba, kush, and kronic. These can often be purchased over the internet or through specialty smoke shops.

Jeff: Scooby Snacks, what a fantastic name, mooovingggg on… Synthetic cannabinoids often have greater affinity for the CB1 receptor than naturally occurring cannabinoids -- and synthetics can produce 100 times the effect. As a result, the presenting symptoms with synthetic intoxication can be difficult to differentiate from crystal meth or bath salt abuse.

Nachi: Manufacturers sometimes use solvents and other contaminants. Clusters of toxic ingestions and deaths have occurred. Emergency clinicians need to be aware of this and should report suspicious events immediately.

Jeff: For more on synthetic intoxications in the ED, be sure to take a look at the recent May 2018 issue of Pediatric Emergency Medicine Practice on Synthetic Drug Intoxication in Children if you haven’t already read it. Also, just a quick FYI - If you’re not a current subscriber to Pediatric Emergency Medicine Practice, we’re giving away a free copy of the issue specifically for our listeners. Just head over to ebmedicine.net/drugs for the PDF of issue.

Nachi: Free issue for our listeners, that’s nice! Let’s move on to a discussion about current indications for cannabinoids. So, there is no clear consensus on these indications, but there is some research of varying quality that supports the treatment of some chronically debilitating diseases with cannabinoids.

Jeff: A systematic review and meta analysis from 2015 found low quality evidence to support cannabis therapy for appetite suppression in hiv and aids patients; moderate quality evidence for treatment of chronic pain and spasticity; and also moderate quality evidence for some chronic debilitating diseases.

Nachi: While talking about evidence based medicine here, another review by the National Academies of Science, Engineering, and Medicine on possible associations between cannabis and cancers arising in the lungs, head and neck, or testicles -- showed no statistically significant associations exist.

Jeff: So in case that wasn’t clear - the overall evidence to support cannabis therapy in general is weak. Also, be aware that there are various formulations of cannabis that allow for different routes of administration. We’re talking oils, tinctures, teas, extracts, edibles like candies and baked goods, parenteral formulations, eye solutions, intranasal, sublingual, transmucosal, tablets, sprays, skin patches, topical creams, rectal suppositories, and capsules -- just to name, a few.

Nachi: A few! That seems pretty complete to me. Basically any way you can imagine, it seems like a route of administration has been explored. But of importance, these formulations have different absorption times -- as you might expect. The shortest duration to peak plasma levels of delta-9-THC is through the inhalation route, which can produce effects within 3 minutes. On the longer end, rectal cannabis administration can take up to 8 hours to reach peak plasma concentrations.

Jeff: Let’s talk about some of the clinical findings and systemic effects associated with cannabis use. First up is the link between cannabis use and stroke or TIA. Cannabis users who smoked at least once weekly had a 3.3 times higher risk of stroke or TIA.

Nachi: And there is moderate quality evidence that this link may be dose dependent. Larger amounts of cannabis use lead to cerebral vasospasm and a reduction in cerebral blood flow.

Jeff: In terms of psychiatric effects, several low-to-moderate quality studies have shown statistically significant associations between psychosis and self-reported cannabis use. Some association between high potency cannabis or synthetic cannabinoid use with new-onset psychosis or relapse in previous psychiatric disorders has also been found. Lastly, there is weak data supporting a correlation between cannabis use and depression.

Nachi: From a cardiovascular standpoint, cannabis use is associated with increased resting heart rate, hypertension, and decreases in the anginal threshold for patients with chronic stable angina. A 2001 study described an augmented risk of myocardial infarction within the first hour of cannabis use and found an almost 5-fold increase in those who reported smoking cannabis at least weekly when compared to those who smoked monthly or less.

Jeff: Dysrhythmias, qt prolongation, av blocks, myocarditis, and sudden death have all been reported with cannabinoids.

Nachi: In terms of pulmonary effects, these are not really related to cannabis use directly, but rather the smoke inhalation and combustion materials of synthetic cannabinoids. Effects from chronic use can be seen.

Jeff: Renally speaking, acute kidney injury and rhabdomyolysis are associated with synthetic cannabinoids and have been observed in several case reports. The rhabdo is believed to be due, in part, to associated seizures, muscle tremors, and agitation.

Nachi: Among metabolic abnormalities, patients can present with hyperthermia, hypoglycemia, hypokalemia, hyponatremia, and metabolic acidosis.

Jeff: Orally and dentally, dry mouth is the most common finding in acute cannabis toxicity. Chronic use has also been linked severe periodontitis.

Nachi: And ophthalmologically, there is of course the commonly seen conjunctival injection. Cannabis has also been found to decrease intraocular pressure when used topically -- and of note, there have also been rare reports of acute angle closure glaucoma and central retinal vein occlusion.

Jeff: While talking about clinical findings and systemic effects of cannabis use, we certainly need to go over cannabinoid hyperemesis syndrome (or CHS), which is -- quite simply put -- associated with frequent visits to the ED in chronic users. It presents with nausea, vomiting, and abdominal pain.

Nachi: CHS is commonly misdiagnosed as cyclical vomiting syndrome. After the legalization of marijuana in Colorado, it was reported that nearly twice as many patients had presented for what was thought to be cyclical vomiting syndrome. And ironically, though cannabis has been used as an anti-emetic, chronic use can cause the opposite reaction, leading to CHS, which is typically refractory to traditional anti-emetics.

Jeff: And the etiology of CHS is not well understood. Similarly the exact criteria for CHS is poorly defined. It presents as a recurrent and relapsing disorder that can be divided into 3 phases: prodromal, hyperemetic, and recovery.

Nachi: In the prodromal phase, patients complain of early morning nausea without vomiting, and they can have mild abdominal discomfort. This can last from months to years. In the hyperemetic phase, patients complain of severe, unremitting abdominal pain with repeated episodes of vomiting and retching. This is often associated with an inability to tolerate po.

Jeff: The hyperemetic phase lasts 24-48 hours and can lead to dehydration, electrolyte abnormalities, and weight loss. Patients may learn to relieve symptoms by compulsively bathing in hot water.

Nachi: Resolution of symptoms is seen when the patient stops using cannabis. This is during the recovery phase, which can last from days to months. But this can be short-lived if the patients begins using cannabis again.

Jeff: On that note, we should also touch on cannabis withdrawal. Termination of heavy and habitual use can lead to withdrawal syndromes within 48 hours. Symptoms here include irritability, anxiety, restlessness, sleep difficulty, seizures, and aggression. Medications that can be helpful include benzodiazepines, neuroleptic agents, and quetiapine in refractory cases.

Nachi: Moving on to the next sections in the article, let’s talk about differential diagnosis and prehospital care. The differential for acute cannabinoid intoxication, as you might suspect, is broad, and it includes some life threatening processes. We won’t list them here, but be sure to think broadly before deciding on cannabis as the cause of your patient’s symptoms.

Jeff: For the prehospital providers -- care here is mainly supportive. Provide airway protection as needed - gather information from the patient’s environment, looking for empty pill bottles or other empty packaging.

Nachi: Let’s move on to care once in the ED. All patients who are in distress and suspected of drug ingestion should be disrobed completely and placed on a cardiac monitor. Fully assess for trauma and place an IV in the patient. Search the patient’s clothing for drugs and paraphernalia, which may help in making the diagnosis.

Jeff: When getting a complete history from the patient, it may also be worthwhile to talk with any persons accompanying the patient to the ER for more information. In your history, be sure to ask about pattern of use and possible co-ingestions.

Nachi: When considering cannabis hyperemesis syndrome, a detailed history and physical exam is crucial for making the diagnosis. To differentiate between other etiologies of abdominal pain and vomiting, be sure to ask about the use of hot baths for relief, resolution of symptoms after stopping cannabis use, and predominance of symptoms in the morning hours.

Jeff: On physical exam, for cannabis intoxication, there isn’t a particular toxidrome to look for. Monitor vital signs closely, looking out for alterations in blood pressure and heart rate. A complete neurologic and mental status examination will be the key here.

Nachi: Decisions for lab testing should be dependent on the patient’s presentation. Possible tests include CBC, BMP, LFT’s, lipase, cpk, ckmb, troponin, urinalysis, urine drug screening, serum tox screens (for alcohol, aspirin, and acetaminophen), and any other drug levels for medications that the patient is taking for medicinal purposes, like phenytoin or lithium levels.

Jeff: One study supported point of care urine drug testing in the ED. However, know that acute cannabis intoxication can be difficult in the chronic user, as delta-9-thc will be present in urine for up to 24 days. Testing for synthetically derived cannabinoids is difficult due to changes in synthetic compounds.

Nachi: Interestingly, there are a number of medications that are associated with false positive cannabinoid screenings. These include ibuprofen, pantoprazole, efavirenz, and lamotrigine.

Jeff: For any patient arriving with suspected cannabis or synthetic abuse, consider checking an EKG. You’re looking for signs of ischemia, arrhythmia, and interval abnormalities. Serum and urine tox tests are not particularly helpful in the acute chest pain patient who is using synthetic marijuana.

Nachi: Not surprisingly, there are no specific diagnostic imaging modalities to help diagnose cannabis or synthetic cannabinoid intoxication. But imaging may help with assessing other disease states on a patient’s differential, so stay mindful of that.

Jeff: Now that we’ve talked about history, physical exam, and useful testing modalities, let’s talk about treatment for cannabis and synthetic cannabinoid toxicity… therapy is primarily focused on supportive care. Most ED visits only require a short stay.

Nachi: That’s right, there are no antidotes to give for treatment here. Be sure to look for and treat dehydration, acute renal failure, and rhabdo though. In severe cases of neuropsychotropic effect, give benzodiazepines, like lorazepam, to help with control.

Jeff: For GI effects, first-line treatment is traditional anti-emetics like ondansetron or metoclopramide. Recent literature and case reports have shown significant improvement with butyrophenones like haloperidol as a second-line treatment.

Nachi: While talking about treating the gastrointestinal effects of cannabis toxicity, let’s also discuss methods to control cannabinoid hyperemesis syndrome. The mainstays for treatment here are actually supportive therapy and cessation of cannabis use.

Jeff: And can you tell us more about why these patients crave hot showers and improve after? Is there a pathophysiology or mechanism to know about there?

Nachi: There is a well-studied theory here and it relates to the TRPV1 receptor that we talked about earlier. Temperatures in excess of 109 degrees Fahrenheit, acidic conditions, and compounds found in certain foods and plants (like cannabis) activate this receptor. It’s believed that intermittent and repetitive exposure to agonists of the TRPV1 receptor lead to a persistent state of nausea and vomiting. Desensitization of the receptor happens after repeated stimulation, and repetitive topical capsaicin or hot water is believed to function as an exogenous agonist.

Jeff: In any case of repetitive emesis, be sure to consider electrolyte replacement if needed. In many cases, hydration or repletion will need to happen through an IV. Proton pump inhibitors can also help in some cases where GI symptoms are a dominating complaint of the patient.

Nachi: Recent literature supporting the use of haloperidol for nausea and vomiting has found that symptoms improve approx 1hr after administration. This can decrease the need for observation or admission.

Jeff: Haloperidol works via dopamine 2 receptor antagonism. D2 receptors are found in high concentrations throughout the nervous system and bind with high affinity to haloperidol. The suggested starting dose is 2.5mg IV with a repeat dose of 5mg IV if needed. An RCT is underway in Canada on the use of ondansetron versus haloperidol with an estimated completion of July 2019.

Nachi: Capsaicin has similarly shown promise in cannabis hyperemesis syndrome through the TRPV1 receptor as we discussed already. Currently, there are no dosing recommendations or application instructions for capsaicin. There is some evidence supporting relief within 30 to 45 minutes, and capsaicin can be applied topically to any nonmucosal surface like the abdomen, chest, or back.

Jeff: So to recap -for cannabis hyperemesis syndrome, treat with anti-emetics, PPI’s, electrolyte repletion, and IV hydration as needed. As a second line treatment, consider haloperidol and topical capsaicin applied to the chest, abdomen, or back.

Nachi: Let’s talk about some special populations next -- starting with Pediatrics. According to data from 2012, of the 130 million people reporting illicit drug use within their lifetime, 25% were children between 12 and 17 years of age.

Jeff: And according to the national poison data system, states with marijuana use laws have seen a 30% increase in calls related to marijuana use by children. From 2010 to 2011, the number of ED visits by children aged 12 to 17 years old due to synthetic cannabinoid use also has doubled.

Nachi: Many children and adults believe that synthetic cannabinoids don’t pose serious health risks, as these are not illegal to purchase. And this class of drugs is particularly attractive to adolescents since it will not readily test positive on urine drug tests. All of this is very concerning for emergency clinicians.

Jeff: There have been several recent reports of myocarditis in association with marijuana use. One case resulted in death due to myocyte necrosis after an unknown amount of edible marijuana was consumed by a toddler.

Nachi: Horrific!

Jeff: And the exact mechanism through which the myocardial necrosis happens isn’t known.

Nachi: For all children and adolescents who present to the ED with alteration in mental status, psychosis, or chest pain -- be sure to screen for cannabis or synthetic cannabinoid use. There are case reports in the pediatric literature of STEMIs seen in patients without pre-existing cardiac disease or risk factors.

Jeff: Keep in mind that urine drug screens can be falsely positive from certain proton pump inhibitors, so if possible, assess a urine drug screen prior to starting a PPI in these patients.

Nachi: Moving on to our next special population… pregnant women. Know that it can be difficult to differential between hyperemesis gravidarum and cannabis hyperemesis syndrome in pregnant patients. Ask specific questions regarding marijuana use before and during the pregnancy.

Jeff: It’s also worth noting that cannabis is known to cause adverse outcomes on babies such as low birth weight and more frequent perinatal icu placement.

Nachi: Let’s move on to the final major section of the article, which is on the legal status of cannabis and cannabinoids. Much of the controversy surrounding cannabis for medicinal use relates to absence of quality evidence. More research is needed to evaluate potential public health risks posed by variations in quality and potency, potential impact to our healthcare system, and ability to legislate for synthetic cannabinoids.

Jeff: Though marijuana and all whole-plant derivatives are schedule I controlled substances, there are a few cannabinoid based drugs approved by the FDA for medicinal purposes -- with lower schedule designations. Dronabinol is a schedule III drug derived synthetically from delta-9-thc. It’s used in chemotherapy induced nausea/vomiting, as well as anorexia and weight loss from AIDS/cancer.

Nachi: Nabilone, a schedule II synthetic variant of THC, has been approved in treatment of aids-related anorexia and chemotherapy induced nausea also.

Jeff: Nabiximols, a plant derived cannabinoid, has been approved in europe and canada for multiple sclerosis induced spasticity and cancer-related pain. Nabiximols are not yet approved in the US.

Nachi: And lastly, we should mention cannabidiol, which is a schedule I controlled substance approved for treatment of seizures with 2 rare diseases -- lennox-gastaut syndrome and dravet syndrome. Compared with placebo alone cannabidiol and other medications have shown efficacy in lowering rate of seizures for these diseases.

Jeff: Lots of interesting stuff to look out for there in cannabinoid related medications. Alright, on to disposition -

Nachi: Most patients who present with uncomplicated acute cannabis or synthetic cannabinoid intoxication can be observed until clinically sober. Discharge home should be in the care of a sober family member or friend. Make sure that the patient knows not to operate vehicles or heavy machinery under the influence of drugs. Counsel them on drug abuse also.

Jeff: In more rare situations, patients will require admission. Consider this particularly for patients who have end-organ damage, rhabdomyolysis, acute renal failure -- evidence of cardiovascular, cerebrovascular, or ophthalmologic insults -- intractable vomiting, or acute psychosis.

Nachi: And for cannabinoid hyperemesis syndrome, patients may require admission for IV hydration and electrolyte correction. Once the patient is tolerating po and lab derangements have been corrected, they can be discharged.

Jeff: Let’s wrap up the episode with key points and clinical pearls…

Nachi: Marijuana is the most commonly used illicit substance in the US. States that have legalized marijuana for medical and recreational purposes are showing increased rates of marijuana abuse and dependence.

Jeff: When concerned for drug intoxication, search your patient’s clothing for drugs and paraphernalia on arrival.

Nachi: The neuropsychiatric and addictive properties of cannabis are due primarily to delta-9-THC.

Jeff: Synthetic cannabinoids have gained popularity as manufacturers are able to produce newer compounds and circumvent DEA designations as well as routine urine drug screening tests.

Nachi: Manufacturers of synthetic cannabinoids sometimes use solvents and other contaminants, which have caused clusters of toxic ingestions and death.

Jeff: The shortest duration to peak plasma levels of delta-9-THC is through the inhalational route. Effects can be seen within 3 minutes.

Nachi: Cannabis users who smoke at least once weekly can have a 3.3 times higher risk of stroke or TIA.

Jeff: The risk of myocardial infarction is increased within the first hour of use, and there is an almost 5-fold increase for individuals who smoke at least once per week.

Nachi: Acute kidney injury and rhabdomyolysis have been noted with synthetic cannabinoid use in several case reports.

Jeff: Cannabis intoxication is associated with many metabolic abnormalities like hyperthermia, hypoglycemia, hypokalemia, hyponatremia, and metabolic acidosis.

Nachi: Cannabis hyperemesis syndrome, which presents with abdominal pain and vomiting, is associated with frequent visits to the ED in chronic users.

Jeff: The mainstay for treatment of cannabis hyperemesis syndrome is supportive therapies and cessation of cannabis use.

Nachi: Patients with cannabis hyperemesis syndrome crave hot showers because of activation of the TRPV1 receptor.

Jeff: Topical capsaicin may also help in the treatment of cannabis hyperemesis syndrome through activation of the TRPV1 receptors.

Nachi: Haloperidol at 2.5mg IV may help in refractory vomiting associated with cannabis hyperemesis syndrome.

Jeff: Many children and adults do not believe synthetic cannabinoids pose serious health issues as the they are not illegal to purchase. This is incorrect.

Nachi: Most patients with acute uncomplicated cannabis intoxication can be observed and discharged. Admit if there are any signs of end organ damage, intractable vomiting, or acute psychosis.

Jeff: So that wraps up the August 2018 episode of Emplify.

Nachi: For those of you looking for CME - the address for this months credit is ebmedicine.net/E0818, so head over there right away to get the credit you deserve. Remember that the you heard throughout the episode corresponds to the answers to the CME questions.

Jeff: And don’t forget to grab your free issue of Synthetic Drug Intoxication in Children at ebmedicine.net/drugs specifically for emplify listeners. Feel free to share the link with your colleagues or through social media too. See you next time!


Meet the Hosts

Drs. Gupta and Nusbaum are practicing emergency physicians. Join Jeff, a former firefighter, and Nachi, a former mathematician, as they take you through the August 2018 issue of Emergency Medicine Practice: Cannabinoids: Emerging Topics in Use and Abuse.

Nachi Gupta, MD, PhD

Jeff Nusbaum, MD

Most Important References
 
  • 5. * Kim HS, Monte AA. Colorado cannabis legalization and its effect on emergency care. Ann Emerg Med. 2016;68(1):71-75. (Literature review; 21 studies)
  • 7. * Baron EP. Comprehensive review of medicinal marijuana, cannabinoids, and therapeutic implications in medicine and headache: What a long strange trip it’s been …. Headache. 2015;55(6):885-916. (Review)
  • 9. * Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015;313(24):2456-2473. (Retrospective chart review; 4 cases)
  • 64. * Tournebize J, Gibaja V, Kahn JP. Acute effects of synthetic cannabinoids: update 2015. Subst Abus. 2016:1-23. (Systematic review; 46 articles, 114 patients)
  • 83. * Wallace EA, Andrews SE, Garmany CL, et al. Cannabinoid hyperemesis syndrome: literature review and proposed diagnosis and treatment algorithm. South Med J. 2011;104(9):659-664. (Review)
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Last Modified: 12/12/2018
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