Dr. Gustin's Blog

MDMA Microdosing for Depression and Anxiety

Usually when we think of MDMA, Molly's, Ecstasy, or Methamphetamine in the context of toxicology, we think of poisoning and overdose.  This blog is about the opposite, the treatment of depression and anxiety with very low doses of these methamphetamine-derived substances.  And the results have been surprising good.

Here's an article that describes the process and the science behind it.
 

MDMA-Assisted Psychotherapy Provides Lasting Benefit for PTSD

Adding 3,4-methylenedioxymethamphetamine (MDMA), also known as ecstasy, to intensive psychotherapy can significantly mitigate symptoms of posttraumatic stress disorder (PTSD), new research confirms.

 

One month after MDMA-assisted psychotherapy, 43% of patients no longer met criteria for PTSD, and 12 months after MDMA-assisted psychotherapy, 76% of participants no longer had PTSD, according to results of the US Food and Drug Administration (FDA)—regulated phase 2 clinical trial.

 

"The long-term results are the most significant finding from this latest trial, the largest ever completed of MDMA-assisted psychotherapy for PTSD," Brad Burge, director of strategic communications for the nonprofit Multidisciplinary Association for Psychedelic Studies (MAPS), which funded the study, told Medscape Medical News.

"The finding that about three quarters of participants no longer had PTSD a full year after receiving their last treatment with MDMA-assisted psychotherapy suggests that the treatment is not just ameliorating symptoms and is instead addressing the root cause of PTSD — specifically, a person's inner relationship with their past traumatic experiences," said Burge.

This treatment has the potential to "greatly improve the lives of people suffering from PTSD, regardless of the source of their trauma," lead investigator Marcela Ot'alora, of Aguazul-Bluewater, Inc, Boulder, Colorado, added in a news release.

 
 

"After treatment, a great majority of our participants have reported feeling more connected to themselves and to others, more joy, more compassion, and with new skills for facing life's challenges," Ot'alora noted.

The study was published online October 29 in the Journal of Psychopharmacology.

Durable Effect 

The double-blind, placebo-controlled, phase 2 pilot study included 28 patients (nine men, 19 women) with chronic PTSD resulting from military service, sexual assault, and other causes. The study compared two active doses of MDMA (100 and 125 mg) with a low dose of MDMA (40-mg active placebo; control group) as an adjunct to psychotherapy.

 

The course of double-blind treatment included 13.5 hours of nondrug psychotherapy and 16 hours (two day-long sessions) of either full-dose or low-dose MDMA-assisted psychotherapy.

 

After completing the initial double-blind portion of the study, patients who initially received active-dose MDMA received a third day-long session with active-dose MDMA and 4.5 additional hours of nondrug psychotherapy. Patients initially assigned to the low-dose control group then received three day-long active-dose MDMA sessions and 18 additional hours of nondrug psychotherapy.

 

The primary outcome was change in total scores on the the Clinician-Administered PTSD Scale–IV (CAPS-IV) 1 month after the second session of MDMA-assisted psychotherapy.

 

In the intent-to-treat (ITT) set, the active-dose groups demonstrated the largest reduction in PTSD symptoms at the primary endpoint. The mean changes in CAPS-IV total scores were −26.3 with the 125-mg dose and −24.4 with the 100-mg dose, compared with −11.5 with the 40-mg dose. However, the results did not reach statistical significance.

 

In the per protocol (PP) set, there was a significant main effect in change of CAPS-IV total scores at the 125-mg dose (−37.0; P = .01) and a trend toward significance with the 100-mg dose (−24.4; P = .10), compared to 40-mg dose (mean change, −4.0).

 

"Although significant group differences were detected only in the PP set for the primary outcome, over half of participants in the ITT set who received active MDMA doses reached a 30% or greater drop in CAPS-IV total scores compared to 16.7% in the 40 mg group," the investigators note in their report.

 

After the third MDMA session, both the 100-mg and the 125-mg dose groups showed further reductions in CAPS-IV scores, "providing evidence that an additional session significantly improved PTSD outcomes," they note.

 

"Importantly," they write, the gains were maintained over 12 months after all groups had received active doses of MDMA, with 76% of patients no longer meeting the criteria for a diagnosis of PTSD.

 

"I would not say that our treatment is a 'cure.' Not meeting criteria for PTSD means that the symptoms are not severe enough to warrant a diagnosis of PTSD," Ot'alora cautioned in email to Medscape Medical New.

 

The fact that CAPS-IV scores continued to improve between the 2-month and 12-month follow-up assessments supports the theory that MDMA helps to "catalyze a therapeutic process that continues long after the last drug administration," the investigators write.

 

The secondary outcome measures of depression, sleep problems, and dissociation all showed significant reduction of symptoms at 12 months compared to baseline.

 

"These findings are noteworthy," the researchers say, "given that participants had moderate to extreme PTSD and had previously failed to benefit from psychotherapy, including approaches thought to be relatively effective (cognitive behavioral therapy [CBT] and eye movement desensitization reprocessing [EMDR]), and pharmacological treatment, including medications for depression and anxiety."

 

Safety Confirmed

The study replicated previous studies that showed an acceptable risk profile for MDMA, with no MDMA-related serious adverse events, the researchers say. The most frequent adverse reactions (reported by at least 40%) during treatment sessions were anxiety and jaw clenching/tight jaw, followed by headache, muscle tension, dizziness, fatigue, and low mood.

 

The most common adverse reactions reported 1 week following treatment included insomnia, low mood, irritability, and ruminations. Most were mild to moderate and decreased in frequency dduring the week following treatment. Temporary elevations in heart rate, systolic blood pressure, and temperature were recorded during MDMA sessions and did not require medical intervention.

 

This is the first MDMA trial to use multiple therapy teams with newly trained therapists implementing the manualized approach.

 

"Our study demonstrated that different therapy teams were able to get similarly robust results, further strengthening the case for MDMA-assisted psychotherapy as a promising option for the treatment of PTSD," Ot'alora said in the release.

 

If approved, "the only people with permission to do this treatment will be clinicians who have gone through MAPS training," Ot'alora told Medscape Medical News.

 

As reported by Medscape Medical News, the FDA granted breakthrough therapy designation to MDMA-assisted psychotherapy for PTSD in August 2017. The FDA stated that the approach "may demonstrate substantial improvement over existing therapies" and agreed to expedite its development and review.

 

Pivotal phase 3 clinical trials of MDMA-assisted psychotherapy for PTSD began in September 2018. They will enroll up to 300 patients across 16 sites in the United States, Canada, and Israel. If the phase 3 trials demonstrate significant efficacy and an acceptable safety profile, FDA approval is expected by 2021.

 

Potential for "Dramatic Improvement"

Reached for comment, Matthew Johnson, PhD, of the Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, said the results are "very promising" and clearly warrant further, larger-scale research into MDMA in the treatment of PTSD.

 

"The best treatments we have for PTSD are trauma-based psychotherapies, with the strongest evidence for prolonged exposure therapy and cognitive processing therapy. However, the rates at which patients are able to adhere to these long-term therapies is very low," noted Johnson, who was not involved in the study.

 

"Some medications have been shown to work better than placebo, but the magnitude of improvement is very small, much smaller than for those who are able to complete trauma-based psychotherapies. The present study results are consistent with previous research on MDMA treatment for PTSD, with long-term results showing that a substantial portion of participants no longer met criteria for having PTSD," Johnson told Medscape Medical News.

 

As for limitations, he noted that the study was relatively small for a group-comparison study.

 

"The low-dose group, which served as a comparison group, actually showed substantial improvements of a similar magnitude as the higher-dose groups after blinded MDMA sessions," said Johnson.

 

"This was stated to be driven by a single participant. It is unknown whether this was a result of placebo (expectation) effect, a result of the interactions during preparation, or a result of even the low dose of 40 mg having efficacy.

 

"A larger trial would help to address this ambiguity. However, these are understandable limitations of a smaller trial, and the results are consistent with the potential for dramatic improvement of PTSD," he added.

 

Mayer Bellehsen, PhD, director, Mildred and Frank Feinberg Division of the

 

Unified Behavioral Health Center for Military Veterans and their Families in Bay Shore, New York, said new treatments for PTSD are needed.

 

"PTSD can be a disabling condition that affects people from all backgrounds. While first-line treatments such as cognitive-behavior therapies can be effective, a good number of individuals are unable to complete these treatments. It is therefore necessary to develop novel treatments for individuals suffering from PTSD," Bellehsen told Medscape Medical News.

 

He agreed that further research on a larger scale is needed, but added, "the positive results in this study and from prior studies suggest that MDMA-assisted psychotherapy is gaining attention as a promising new treatment approach."

 

The Multidisciplinary Association for Psychedelic Studies funded the study. Several authors have financial relationships or are employee of MAPS Public Benefit Corporation. Dr Johnson and Dr Bellehsen have disclosed no relevant financial relationships.

 

J Psychopharmacol. Published online October 29, 2018. Full text

 

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Brain Damage From Alcohol Continues After Abstinence

Some recent research has elegantly established that when an alcoholic stops drinking brain damage persists and actually progresses.  

Damage to the brain caused by alcohol continues during the first few weeks of abstinence, a finding that refutes the notion that the brain begins to normalize immediately after individuals stop drinking.

"Until now, nobody could believe that in the absence of alcohol the damage in the brain would progress," study investigator Santiago Canals, PhD, of the Institute of Neuroscience of Alicante, Consejo Superior de Investigaciones Científicas–Universidad Miguel Hernández, Spain, said in a news release.

The study was published online April 3 in JAMA Psychiatry.

The researchers assessed microstructural alterations in white matter after long-term alcohol exposure and during early abstinence in 91 men (mean age, 46) who had alcohol use disorder (AUD).

The men were hospitalized and were undergoing detoxification treatment, which guaranteed that they did not drink alcohol. Thirty-six healthy men of similar age who did not have AUD served as control persons.

The researchers found diffuse microstructural changes in white matter in the men with AUD compared with the control persons. These changes primarily affected the right hemisphere and the frontal region of the brain. These changes progressed during 2 to 6 weeks of abstinence.

"The study was not designed to look further in time, also due to the fact that our results were unexpected," study coinvestigator Wolfgang Sommer, MD, PhD, of the University of Heidelberg, Germany, told Medscape Medical News.

"Other studies looked at a longer time horizon and typically found signs of recovery, both of the brain structure and its function. Nevertheless, we need more research to understand what is going on here and what are the temporal aspects of the underlying phenomena," said Sommer.

The researchers replicated their observations in an established rat model of excessive alcohol consumption.

"The fact that the findings in humans mirror those in rats may establish a relationship between the observed changes and alcohol consumption, which is difficult to verify based on human results only, given the large heterogeneity of the abuse patterns, medication for relief of withdrawal symptoms, and comorbidities among patients with AUD," the researchers write.

"This result establishes the utility of diffusion imaging for monitoring the brain status as a possible noninvasive biomarker of AUD progression and, potentially, of treatment response," they add.

"These types of translational studies are crucial to help fill in gaps in addiction research," Marisa Silveri, PhD, director of the Neurodevelopmental Laboratory on Addictions and Mental Health, McLean Hospital, Belmont, Massachusetts, and associate professor of psychiatry at Harvard Medical School, Boston, told Medscape Medical News.

"The findings do fly a little in the face of what we know, because when people become abstinent, it usually doesn't take them long for things like brain chemistry and cognition to improve, somewhat after abstinence. But it's studies like these that uncover some more micro level cellular indicators that tell us that just because you can recover some function, it doesn't necessarily mean the brain is returned to a healthy state," said Silveri.

"That's an important message because people often think that when they no longer feel the acute intoxicating effects of alcohol, that it's not still having an effect, and we do know from many studies that there are residual effects of alcohol intoxication on neurobiology.

"The brain is a fantastic orchestra of networks, and understanding some of the subtler changes and what they mean is work that is most needed," she added.

The study appeared in the following journal: 

JAMA Psychiatry. Published online April 3, 2019. Abstract

 

Kraton Products Cause Illness-Heavy Metal Poisoning

Final results of tests performed by the US Food and Drug Administration (FDA) on 30 kratom products confirm the presence of heavy metals, including lead and nickel, at concentrations not considered safe for human consumption, the FDA said Wednesday. 

The FDA first warned of "disturbingly" high levels of heavy metals, including lead and nickel, last November, as reported by Medscape Medical News.  The FDA has posted a list of the kratom products and concentrations of heavy metals found in them on its website. Based on reported patterns of kratom use, heavy kratom users may be exposed to levels of lead and nickel many times greater than the safe daily exposure, the FDA warns in a statement. 

Based on these test results, the typical long-term kratom user could potentially develop heavy metal poisoning, which could include nervous system or kidney damage, anemia, high blood pressure, and increased risk of certain cancers, the agency adds.

"Over the last year, the FDA has issued numerous warnings about the serious risks associated with the use of kratom, including novel risks due to the variability in how kratom products are formulated, sold and used both recreationally and by those who are seeking to self-medicate for pain or to treat opioid withdrawal symptoms," FDA Commissioner Scott Gottlieb, MD, said in the statement. 

Gottlieb said the FDA has been "attempting to work" with the companies whose kratom products contain high levels of heavy metals.  The agency has released the final laboratory results to the public to "help make sure consumers are fully informed of these risks." "The data from these results support our public warning about the risk of heavy metals in kratom products. The findings of identifying heavy metals in kratom only strengthen our public health warnings around this substance and concern for the health and safety of Americans using it," he added. 

No Approved Use Kratom is derived from the leaves of the kratom tree (Mitragyna speciosa), which is native to Thailand, Indonesia, and Papua New Guinea. The botanical's popularity has been increasing in the United States, with manufacturers — and those who take it — claiming it can help treat pain, anxiety, depression, and more recently, opioid withdrawal. Last year, an analysis of kratom by FDA scientists found that its compounds act like prescription-strength opioids. In addition to heavy metal contamination, kratom products have also been found to be contaminated with Salmonella, resulting in numerous illnesses and product recalls. Kratom has been linked to numerous deaths in the United States. There are currently no FDA-approved uses for kratom, and the agency has advised against using kratom or its psychoactive compounds mitragynine and 7-hydroxymitragynine in any form and from any manufacturer. 

Health providers are encouraged to report any adverse reactions related to kratom products to MedWatch, the FDA's safety information and adverse event reporting program.

Updates on Illicit Drug Overdose

Drug overdose remains a significant concern worldwide, with nearly half a million deaths annually. In the United States, drug overdoses are the leading cause of death for adults younger than 55 years. Drug-related deaths now outnumber those attributed to motor vehicle accidents and homicides. According to information from the Centers for Disease Control and Prevention (CDC), the drugs most commonly involved in overdose deaths include opioids (eg, fentanyl, heroin, oxycodone), cocaine, methamphetamines, and benzodiazepines.

 

Naloxone has been lifesaving in many scenarios, so the CDC recently issued recommendations regarding its use in patients taking opioids. The CDC recommends that clinicians strongly consider prescribing or coprescribing naloxone and providing education about its use in these types of patients taking opioids:

  • Those who are receiving opioids at a dosage of 50 morphine milligram equivalents per day or greater
  • Those who have respiratory conditions such as chronic obstructive pulmonary disease or obstructive sleep apnea (regardless of opioid dose)
  • Those who have been prescribed benzodiazepines (regardless of opioid dose)
  • Those who have a nonopioid substance use disorder, report excessive alcohol use, or have a mental health disorder (regardless of opioid dose)

The CDC also recommends naloxone in patients who are at high risk for experiencing or responding to an opioid overdose, including the following:

  • Those known to use heroin or illicit synthetic opioids or misuse prescription opioids
  • Those using other illicit drugs such as stimulants, including methamphetamine and cocaine
  • Those receiving treatment for opioid use disorder, including medication-assisted treatment with methadone, buprenorphine, or naltrexone
  • Those with a history of opioid misuse who were recently released from incarceration or other controlled settings where tolerance to opioids has been lost

Most of the deaths from synthetic opioids are from fentanyl. Most of the increases in fentanyl deaths in recent years do not involve prescription fentanyl but are related to illicitly made fentanyl mixed with or sold as heroin—with or without the users' knowledge—and increasingly sold as counterfeit pills.

In the event of an overdose, pertinent history may be obtained from bystanders, family, friends, or emergency medical services (EMS) providers. Pill bottles, drug paraphernalia, or eyewitness accounts may assist in the diagnosis of opioid toxicity. Occasionally, a trial of naloxone administered by an EMS provider is helpful to establish the diagnosis in the prehospital setting.

Patients with opioid toxicity characteristically have a depressed level of consciousness. Opioid toxicity should be suspected when the clinical triad of central nervous system (CNS) depression, respiratory depression, and pupillary miosis are present. Clinicians must be aware that opioid exposure does not always result in miosis (pupillary constriction), and that respiratory depression is the most specific sign. Drowsiness, conjunctival injection, and euphoria are frequently seen.

Drug screens are widely available but rarely alter clinical management in patients with uncomplicated overdoses. Drug screens are most sensitive when performed on urine. Positive results are observed up to 36-48 hours postexposure, but wide variations are possible depending on test sensitivity, dose, route of opioid administration, and the patient's metabolism. In patients with moderate to severe toxicity, performing these baseline studies is appropriate:

  • Complete blood cell (CBC) count
  • Comprehensive metabolic panel
  • Creatine kinase (CK) level
  • Arterial blood gas (ABG) determinations

According to American Heart Association guidelines, clear evidence suggests that cocaine can precipitate acute coronary syndrome, and that trying agents that show efficacy in the management of acute coronary syndrome may be reasonable in patients with severe cardiovascular toxicity. Agents that may be used as needed to control hypertension, tachycardia, and agitation include:

  • Alpha-blockers (eg, phentolamine)
  • Benzodiazepines (eg, lorazepam, diazepam)
  • Calcium channel blockers (verapamil)
  • Morphine
  • Sublingual nitroglycerin

The American Heart Association does not recommend any one of these agents over another in the treatment of cardiovascular toxicity due to cocaine; however, benzodiazepines are often used as first-line treatment.

Cardiopulmonary complaints are the most common presenting manifestations of cocaine abuse and include chest pain (frequently observed in long-term use or overdose), MI, arrhythmia, and cardiomyopathy. In individuals with cocaine-associated MI, median times to the onset of chest pain vary with the route or form of cocaine use: 30 minutes for intravenous use, 90 minutes for crack, and 135 minutes for intranasal use.

Temperature dysregulation is also a problem with cocaine intoxication. Hyperthermia is a marker for severe toxicity, and it is associated with numerous complications, including renal failure, disseminated intravascular coagulation, acidosis, hepatic injury, and rhabdomyolysis. Dopamine plays a role in the regulation of core body temperature, so increased dopaminergic neurotransmission may contribute to psychostimulant-induced hyperthermia in cocaine users, including those with excited delirium.

No laboratory studies are indicated if the patient has a clear history of cocaine use and mild symptoms.

If a history of cocaine use is absent or if the patient has moderate to severe toxicity, appropriate laboratory tests may include:

  • CBC count
  • Electrolytes, blood urea nitrogen, creatinine, and glucose levels (basic metabolic panel)
  • Glucose level
  • Pregnancy test
  • Calcium level
  • ABG analysis
  • CK level
  • Troponin level (cocaine use does not affect the specificity of troponin assays)
  • Urinalysis
  • Toxicology screens

Acute and long-term methamphetamine use may lead to abnormal findings on examination of the following organ systems:

  • Cardiovascular
  • CNS
  • Gastrointestinal
  • Renal
  • Skin
  • Dental

There are specific cardiovascular findings associated with acute and long-term methamphetamine use:

  • Tachycardia and hypertension is frequently observed
  • Atrial and ventricular arrhythmias may occur
  • Chest pain from cardiac ischemia and infarction following methamphetamine use has been reported, and patients are at risk because of accelerated atherosclerosis from chronic use; acute aortic dissection or aneurysm has been associated with methamphetamine abuse
  • Hypotension may be observed with methamphetamine overdose with profound depletion of catecholamines
  • Acute and chronic cardiomyopathy results directly from methamphetamine cardiac toxicity and indirectly from chronic hypertension and ischemia; intravenous use may result in endocarditis; patients may have dyspnea, edema, and other signs of acute congestive heart failure exacerbation

The euphoric effects produced by methamphetamine, cocaine, and various designer amphetamines are similar and may be difficult to clinically differentiate. A distinguishing clinical feature is the longer pharmacokinetic and pharmacodynamic half-life of methamphetamine, which may be as much as 10 times longer than that of cocaine.

Methamphetamine can cause significant CNS and psychiatric activation, so patients who present to emergency departments for acute intoxication often require physical restraint and pharmacologic intervention. Hyperactive or agitated patients can be treated with droperidol or haloperidol, which are butyrophenones that antagonize CNS dopamine receptors and mitigate the excess dopamine produced from methamphetamine toxicity. These medications should be administered intravenously, with doses adjusted based on the symptoms. Droperidol has been subject to a black box warning by the US Food and Drug Administration based on concerns of QT prolongation and the potential for torsades de pointes. As a result, some institutions restrict its use. However, it is important to note that the black box warning specifies dementia-related psychosis and is not supported by the literature for doses below 2.5 mg.

If sedation fails to reduce blood pressure, antihypertensive agents such as beta-blockers and vasodilators are effective in reversing methamphetamine-induced hypertension and tachycardia. With regard to choice of beta-blockers, labetalol is preferred because of its combined anti–alpha-adrenergic and anti–beta-adrenergic effects. Labetalol has been shown to safely lower mean arterial pressure in patients with positive cocaine test results. Carvedilol, like labetalol, is a nonselective beta-blocker with alpha-blocking activity and may also be effective for this indication. Esmolol is advantageous because of its short half-life but must be administered via intravenous drip. Metoprolol has excellent CNS penetration characteristics and may also ameliorate agitation.

Oral benzodiazepine overdoses, without co-ingestion of another drug, rarely result in significant morbidity (eg, aspiration pneumonia, rhabdomyolysis) or mortality; however, in mixed-drug overdoses, they can potentiate the effect of alcohol or other sedative-hypnotic agents. Overdose of ultrashort-acting benzodiazepines (eg, triazolam) is also more likely to result in apnea and death than overdose with longer-acting benzodiazepines. Of the individual benzodiazepines, alprazolam is relatively more toxic than others in overdose.

Immunoassay screening techniques are most commonly performed when benzodiazepine overdose is suspected. These tests typically detect benzodiazepines that are metabolized to desmethyldiazepam or oxazepam; thus, a negative screening result does not rule out the presence of a benzodiazepine.

As with any overdose, the first step is an assessment of the patient's airway, breathing, and circulation, and any issues should be addressed rapidly. In any patient with an altered mental status, blood glucose level should be checked immediately. The cornerstone of treatment in benzodiazepine overdoses is good supportive care and monitoring. Single-dose activated charcoal is not routinely recommended because the risks far outweigh the benefit. Altered mental status greatly increases the risk of aspiration following an oral activated charcoal dose.

Flumazenil is a competitive benzodiazepine receptor antagonist and the only available specific antidote for benzodiazepines. Its use in acute benzodiazepine overdose is controversial, however, and its risks usually outweigh any benefit. In long-term benzodiazepine users, flumazenil may precipitate withdrawal and seizures; in patients taking benzodiazepines for a medical condition, flumenazil may result in exacerbation of the condition. Flumazenil should not be used in patients with long-term benzodiazepine use or in any patient at an increased risk of having a seizure, including those with a seizure history, head injury, co-ingestion of a benzodiazepine and tricyclic antidepressant or other proconvulsant, or even a possible ingestion of a proconvulsant.

In general, when it is the sole agent used, the clinical presentation of heroin poisoning and its diagnosis hold little challenge for experienced healthcare practitioners. The diagnosis of heroin poisoning should be suspected in all comatose patients, especially in the presence of respiratory depression and miosis.

Respiratory depression, due to heroin's effect on the brain's respiratory centers, is a hallmark sign of overdose. However, the presence of tachypnea should prompt the search for complications of heroin use, such as pneumonia, acute lung injury, and pneumothorax, or an alternative diagnosis, such as shock, acidosis, or CNS injury. Tachypnea may also be seen in overdoses of pentazocine or meperidine.

Symptoms generally develop within 10 minutes of intravenous heroin injection. Patients who survive heroin poisoning commonly admit to using more than their usual dose, using heroin again after a prolonged period of abstinence, or using a more concentrated street sample. Coma, respiratory depression, and miosis are the hallmarks of opioid overdose.

Mild hypotension and mild bradycardia are commonly observed with heroin use. These are attributable to peripheral vasodilation, reduced peripheral resistance and histamine release, and inhibition of baroreceptor reflexes. In the setting of heroin overdose, hypotension remains mild. The presence of severe hypotension should prompt a search for other causes of hypotension, such as hemorrhage, hypovolemia, sepsis, pulmonary emboli, and other causes of shock.

Gastric lavage in the setting of oral heroin overdose is generally not recommended because it has no documented value. Furthermore, gastric lavage is contraindicated in "body packers" and "body stuffers," who have ingested packages of drugs, because the procedure may rupture a package. Activated charcoal is becoming increasingly controversial because of the risk of aspiration and charcoal pneumonitis. It may be indicated for orally ingested narcotics with large enterohepatic circulation (eg, propoxyphene, diphenoxylate) but is of no value in pure heroin overdose.

Psychelic Drugs Used to Treat Depression and Anxiety-Toxicology

A very interesting study has recently been done on the effects of a psychedelic substance in a small mitigated-psychedelic dose in the treatment of resistant depression and anxiety. The following is a synopsis of the key points from a recent Medscape article.  The relevance of this study to toxicology is that psychelics can have severe side-effects, some even long-lasting or permanent, even in customary doses, as noted below. Practitioners who treat their patients with these substances should be aware of the medicolegal liability and health risks.

Read more: Psychelic Drugs Used to Treat Depression and Anxiety-Toxicology

Fluorquinolones can kill

New warning from the FDA-- a warning about Aortic Aneurysm Risk With Fluoroquinolones in patients being treated for common infections

The agency is urging healthcare providers to avoid prescribing the powerful antibiotics to patients with or at risk for an aortic aneurysm, such as those with peripheral atherosclerotic vascular disease, hypertension, certain genetic conditions such as Marfan syndrome and Ehlers-Danlos syndrome, and the elderly. This antibiotic is one of the most commonly prescribed antibiotics for braonchitis, sinusitis, bladder infections, and pneumonia.

"Although the risk of aortic aneurysm or dissection is low, we've observed that patients are twice as likely to experience an aortic aneurysm or dissection when prescribed a fluoroquinolone drug," FDA commissioner Scott Gottlieb, MD, said in the Drug Safety Communication.

"For patients who have an aortic aneurysm or are known to be at risk of an aortic aneurysm, we do not believe the benefits outweigh this risk, and alternative treatment should be considered."

The FDA reviewed adverse event reports and four recently published observational studies showing an increased risk of aortic aneurysm or dissection associated with fluoroquinolone use, which can lead to dangerous bleeding or even death.

The underlying reason for this increased risk cannot be determined, the statement notes. The background risk of aortic aneurysm also can vary depending on the population — from nine events/100,000 people/year in the general population to 300 events/100,000 people/year in the highest-risk individuals.

"For some patients, the benefits of fluoroquinolones may continue to outweigh the risks for treatment of serious bacterial infections, such as pneumonia or intra-abdominal infections, but there are other serious, known risks associated with these strong antibiotics that must be carefully weighed when considering their use," Gottlieb said. 

The FDA has issued several prior safety communications about fluoroquinolone use, including in  July 2018 (significant decreases in blood sugar and certain mental health side effects),  July 2016  (disabling side effects of the tendons, muscles, joints, nerves, and central nervous system),  May 2016 (restrict use for certain uncomplicated infections),  August 2013  (peripheral neuropathy), and  July 2008  (tendinitis and tendon rupture). 

 

Edible Marijuana is Potentially Dangerous

The number of cannabis-associated emergency department (ED) visits has risen sharply since marijuana was legalized in Colorado. New data show that although inhalable cannabis use accounts for most of these visits, edible cannabis is tied to a disproportionate number of visits, and patients present with different symptoms.

Although less frequent overall, edible cannabis products lead to more acute psychiatric events and cardiovascular symptoms than inhaled exposure. Researchers at the University of Colorado report their findings in an article published online recently in the Annals of Internal Medicine.

Edible cannabis has been considered to be more toxic than inhalable cannabis, particularly in light of accumulating poison center data on its associated adverse events (AEs) and anecdotal reports from adult users. In addition, the only deaths in Colorado that have been conclusively linked to cannabis use have involved edible products.

Nevertheless, the relative potential harms of inhalable and edible cannabis products have been poorly characterized.

With this in mind, Monte and colleagues conducted a study to compare adult ED visits related to edible and inhalable cannabis use. Using chart review, the researchers tracked 9973 ED visits to the University of Colorado Health emergency department from 2012 through 2016 that included an ICD-9 or -10 code for cannabis use. Of those, they found that 2567 (25.7%) of the visits were related to cannabis, with 238 of these (9.3%) linked to edible products.

The most common causes of cannabis-linked ED visits were gastrointestinal symptoms (30.7%), intoxication (29.7%), and psychiatric symptoms (24.7%).

Visits as a result of inhalable cannabis were more likely than those because of edibles to involve gastrointestinal symptoms, the most common of which was cannabinoid hyperemesis syndrome (18% vs 8.4%; mean difference, 9.6 percentage points; 95% confidence interval [CI], 5.7 - 13.5).

In contrast, visits due to edible cannabis more commonly involved acute psychiatric symptoms (18% vs 10.9%; mean difference, 7.1 percentage points; 95% CI, 2.1 - 12.1), intoxication (48.3% vs. 27.8%; mean difference, 20.5 percentage points; 95% CI, 13.9 - 27.1), and cardiovascular symptoms (8% vs 3.1%; mean difference, 4.9 percentage points; 95% CI, 1.4 - 8.4).

For patients using edible cannabis, the ED visits were also more likely to be shorter (2 hours vs 3 hours) and less likely to lead to hospitalization (18.9% vs 32.9%; P < .001) than they were for patients using inhalable cannabis.

The researchers also determined that, although edible cannabis accounted for just 0.32% of the states total cannabis sales (in kilograms of tetrahydrocannabinol [THC]) between 2014 and 2016, it was responsible for 10.7% of cannabis-related ED visits in Colorado during that period.

If inhalable and edible cannabis were equally toxic and resulted in the same number of ED visits, based on the study, 0.3% of cannabis-attributable visits would be due to use of edible products. The observed proportion of cannabis-attributable visits with edible exposure was about 33 times higher than expected (10.7% vs 0.32%) if both routes of exposure were equally toxic.

This data establishes that states considering cannabis legalization should take into account the relative toxicity of edible products. It may be best to limit edible products to medical indications in order to minimize pediatric exposures and mitigate the excessive rate of adult ED visits associated with these products. At the very least, users must be educated about the delayed kinetic profile and the increased risk for acute psychiatric and adverse cardiovascular events associated with edible ingestion.

Nora D. Volkow, MD, and Ruben Baler, PhD, from the National Institutes of Health, Bethesda, Maryland, highlight the important clinical and public health implications of these findings. There are several reasons why edible cannabis often leads to worse outcomes than inhalable cannabis. Because orally-ingested THC is absorbed more slowly than inhaled THC, people using the edible products find it harder to titrate the doses required to produce the desired effects. This is compounded by the slower clearance of orally-ingested THC from the body, which can result in accumulation in people who take extra doses in an attempt to achieve the desired drug effect more quickly.

In addition, the relatively harmless appearance of edibles and the variability in their labeling accuracy further contribute to overconsumption of these products.

Acknowledging that the complete range of potential adverse health consequences from cannabis consumption remain incompletely understood, the editorialists suggest that future research into the adverse effects of cannabis should focus on THC and content, route of administration, doses consumed, sex, age, body mass index, and the medical conditions for which it might be used.

The results of this recent study also underscore the urgent need for greater oversight of manufacturing practices, labeling standards, and quality control of cannabis products marketed to the public.

Ann Intern Med. Published online March 25, 2019.

 

EPA Alert: Methylene Chloride Banned

The Environmental Protection Agency (EPA) says it will issue a rule that bans the sale of methylene chloride to consumers but allows for its continued use in commercial products.

The deadly chemical is found in paint and furniture strippers. Many stores, including Lowe’s and Walmart, had already stopped selling products with methylene chloride. The ban includes the manufacturing, processing, and distribution of the chemical for consumers. Alexandra Dunn, the EPA’s assistant administrator for chemical safety, says in a press release: "This rule answers calls from many affected families to effectively remove these products from retail shelves and retail distribution channels, providing protection for the American public."

Environmental advocates say the rule doesn’t go far enough.  "They’ve excluded workers who are the most vulnerable population," says Lindsay McCormick, project manager, chemicals and health, for the Environmental Defense Fund in Washington, DC. "It’s a day late and a dollar short here."

The nonprofit group Safer Chemicals, Healthy Families says at least 64 people have died from exposure to methylene chloride since 1980. Many of those deaths were among workers who were refinishing bathtubs. Bathtub refinishers often work in poorly ventilated spaces. Methylene chloride is heavier than air, so it sinks and collects in low places like bathtubs, right where refinishers hold their heads as they work.

Methylene chloride is metabolized to carbon monoxide and replaces and blocks oxygen in the blood. When inhaled, it can cause headaches, nausea, dizziness, seizures, coma, and death. Over the long term, it increases the risk of cancer, and may alter cognitive function permanently. 

The EPA has estimated that as many as 32,000 workers use methylene chloride on the job. Yet the EPA will continue to allow the use of the compound for workers even though they are at risk for adverse health events.

The EPA says it will take public comments for the next 90 days. Those comments will inform a future rule that could establish a training, certification, or limited-access program for methylene chloride for commercial uses.

FENTANYL OVERDOSES AND DEMOGRAPHIC DISPARITIES

Fentanyl overdoses are increasing at a dramatic rate in the United States.  Visits to Emergency Rooms are far more frequent now than they were just a few years ago.  Fentanyl is a synthetic opiate that when blending with heroin becomes a life-threatening toxic cocktail as it is 50-100 times more potent than morphine.  Physician in the ER when treating cardiorespiratory complications from an assumed heroin overdose must be mindful of the possibility that Fentanyl may have contaminated the ingested drug.  The Narcan reversal agent requirements may be higher for Fentanyl.  Here are three recent newspaper articles describing the scourge.

The Washington Post (3/20, Achenbach) reports that “the synthetic opioid fentanyl has been driving up the rate of fatal drug overdoses across racial and social lines in the United States, with the sharpest increase among African Americans, according to a new analysis by the Centers for Disease Control and Prevention.” Data show the African American death rate “from fentanyl-involved drug overdoses rose 141 percent each year, on average, from 2011 to 2016, the study showed.” Meanwhile, the overdose death rate “for Hispanics rose 118 percent in that period every year on average, and 61 percent for non-Hispanic whites.”

The Washington Time  (3/20, Healy) reports that during the study period, 2011 to 2016, “more than 36,000 Americans died with fentanyl in their systems” and the “majority of those deaths – 18,335 – occurred in 2016 alone.” The Times adds that “fentanyl was first approved by the Food and Drug Administration back in 1968.”

NPR (3/21, Bebinger) reports that the study also indicates “men are dying after opioid overdoses at nearly three times the rate of women,” and there is “an especially steep rise in the number of young adults ages 25 to 34 whose death certificates include some version of the drug fentanyl.”

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