04/25/17

Pesticides, Fungi and Pot

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In 2015, two Colorado marijuana users sued the state’s largest marijuana grower, claiming it used a dangerous agricultural fungicide on its pot plants. The fungicide, Eagle 20, contains the chemical myclobutanil, which becomes poisonous when ignited. The allegations were that while Eagle 20 is approved for certain edible products, it is not approved for smokable products like marijuana and tobacco. The lawsuit said: “Persons who smoke cannabis that has been sprayed with Eagle 20 inhale … poisonous hydrogen cyanide.” The company, LivWell, maintained its plants are safe.

The two individuals alleged they were not aware of LivWell’s use of Eagle 20 on their cannabis when they bought it. Had they known, they would not have smoked LivWell’s cannabis. They were asking for a monetary reimbursement for their unused product and were also demanding that LivWell stop using the Eagle 20 fungicide on its cannabis. The plaintiff’s lawyer said that to his knowledge, this was the first product liability action filed against the legal marijuana industry. LivWell’s owner said: “Testing of our finished product by an independent, state-licensed lab approved by the City of Denver showed that our products are safe – as we have always maintained.”

In the end, the lawsuit was dismissed. The Denver judge who heard the case said the plaintiffs couldn’t sue because they were not actually harmed. They bought and then consumed the pot without any repercussions. The written opinion noted there were no allegations that the cannabis did not perform as it was supposed to; and both consumers smoked it without harm. LivWell’s owner said this had been a ploy intended to smear the company’s name. “The people behind this case do not want the commercial cannabis industry to succeed and will try anything to bring down the industry.”

Setting aside the rhetoric from the lawyers on both sides of the dismissed lawsuit and LivWell’s owner, the use of pesticides on marijuana is a growing concern for the industry. The marijuana website The Cannabist has an archived page on marijuana pesticides with fourteen articles published between December 4, 2015 and July 29, 2016. Their titles range from: “Check Your Stash: Are you consuming pesticide-peppered pot? Full recall list” to “State releases hundreds of recalled pot batches after they tested pesticide-free.”

Ricardo Baca and others, writing for The Cannabist, said Denver’s Department of Environmental Health has issued 26 recalls of marijuana and pot products since September of 2015. The Colorado Marijuana Enforcement Division has issued 26 recalls in the form of administrative holds between February and July of 2016. The recalls originated from an executive order issued by the governor of Colorado in November of 2015. Within the order, the governor said: “Until scientific assessment establishes which additional pesticides can be safely applied to marijuana, marijuana contaminated by an Off-Label Pesticide shall constitute a threat to the public safety.”

At the core of legal cannabis’ pesticide problem in Colorado is the state’s lack of a pesticide certification for marijuana testing labs. So while cannabis testing facilities are certified by the state’s health department to test for potency and contaminants, the Colorado Department of Public Health and Environment is still working with other agencies, labs and industry to develop proficiency standards and testing certification requirements for pesticide tests.

Reporting originally for The Denver Post, David Migoya and Ricardo Baca, noted how The Post revealed in its own testing that a number of marijuana-infused products contained high levels of pesticides that shouldn’t be used on cannabis. The Catch-22 is that there is no pesticide specifically approved for use with marijuana, because pesticide chemicals are regulated by the EPA. And since cannabis is illegal under federal law, there are no federal standards. “As a result, there have been no tests to show how pesticides used on marijuana could affect consumers or whether their use is safe.” Colorado state agriculture officials have allowed certain pesticides to be used on marijuana as long as it does not violate the restrictions of the product’s label.

Ron Kammerzell, a senior director in the Colorado Department of Revenue, which oversees the state Marijuana Enforcement Division (MED), said the state’s responsibility was to make sure the marijuana is safe for the consumer and not contaminated by pesticides. The top priority is to keep pesticide-contaminated products from getting to consumers. He added that pesticides were a challenging area fro testing, so they wanted to be sure they did it right. “Once we have mandatory testing for pesticides, that will be a game-changer in terms of making sure that we’re minimizing these types of contaminations.” Kammerzell hopes to have the state’s pesticide testing certification program implemented sometime in 2017.

Writing for Slate, Rachel Gross noted how cannabis vendors are pitching healthier, organic marijuana to their customers. “Like wine aficionados, certain weed smokers have always had a reputation for being connoisseurs.” The U.S. legal cannabis industry was projected to bring in almost $7 billion in 2016. The founder of Clean Green, a marijuana-certifying program, said: “These are sophisticated buyers, the same people who are buying organic food and organic coffee.” The industry is becoming more industrialized and corporate and the fear is that industrial pot is laced with pesticides.

Consider the gram of weed you can buy, right now, in the four states (Washington, Oregon, Colorado, and Alaska) and Washington, D.C., where recreational marijuana is legal (or the 24 states where it’s available for medical purposes). Before it was sealed in that baggie, it was a plant. That plant likely got sprayed with fungus-, insect-, and disease-killing chemicals. Before it was a plant, it was a seedling. That seedling may have sat in soil that had been fumigated with even more pesticides. And before that seedling got planted, the grow room that would one day be its home was probably bug-bombed and lined with pest strips, which are laced with chemicals that linger in enclosed spaces.

Thanks to the series of recalls, like those noted above in Colorado, consumers are becoming more aware of the pesticide issues in the marijuana industry. The Oregonian found abnormally high levels of pesticides in nearly half the products sold in state dispensaries. “Those pesticides included a common roach killer, half a dozen human carcinogens, and a fungicide [myclobutanil] that allegedly turned into hydrogen cyanide when heated.” The dose is the issue. Even a toxic substance like hydrogen cyanide could be harmless in a small enough dose. Oregon is working closely with the state of Washington and Colorado to coordinate which pesticides should be tested for in cannabis.

Researchers at UC Davis recently announced a study that found medical marijuana contained “multiple bacterial and fungal pathogens that may cause serious and even fatal infections.” Smoking, vaping or inhaling aerosolized marijuana may pose a serious health risk to individuals, especially those with impaired immune systems. George Thompson, one of the study’s authors, noted where patients with impaired immune systems are routinely advised to avoid exposure to plants and certain raw foods because of the risk of infection. “But at the same time, they are increasingly turning to medical marijuana to help them with symptom control. Because microorganisms known to cause serious infections in immunocompromised patients were found to be common on marijuana, we strongly advise patients to avoid it.”

They publically voiced their concerns in a letter to the editor of the journal Clinical Microbiology and Infection. There is a copy of the letter here. The news media also picked up on the study. Claudia Black, writing for The Sacramento Bee, said the uneasy news comes as a majority of states have eased laws on medical and recreational marijuana, and a majority of U.S. doctors support the use of medical marijuana for symptoms such as pain, nausea and loss of appetite during chemotherapy and other treatments. George Thompson was quoted as saying it was a big oversight to not warn patients with compromised immune systems to avoid marijuana. “It’s basically dead vegetative material and always covered in fungi.”

The study gathered marijuana from 20 Northern California growers and dispensaries. The analysis of marijuana for the study was done by Steep Hill Labs, a cannabis testing company. “The analysis found numerous types of bacteria and fungi, including organic pathogens that can lead to a particularly deadly infection known as Mucor.” There is a misconception that if it is from a dispensary, the marijuana must be safe. But that’s not the case, according to Joseph Tuscano, another one of the researchers. “This is potentially a direct inoculation into the lungs of these contaminated organisms, especially if you use a bong or vaporization technique.” You can watch a CBS Sacramento news video on the study posted on YouTube here.

So it’s not just that the anti-pot people are out to sink the industry. Its customers are concerned about the presence of pesticides in their pot. Researchers are finding that some marijuana contains common bacteria and fungi that poses a danger to individuals with compromised immune systems. The marijuana industry is going through some serious growing pains. But the question begs to be asked, did the states that legalized recreational and medical marijuana run ahead of the regulatory and bureaucratic changes needed to support it?

04/14/17

An Opioid Shell Game

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Heroin sales and overdoses get a significant mount of attention, but we need to also remember that since 2002, the number of deaths related to controlled prescription drugs (CPD) have outpaced those for cocaine and heroin COMBINED. And the number of individuals who report current use of CPDs is more than those reporting use of cocaine, heroin, methamphetamine, MDMD and PCP (phencyclidine) combined. Each day, 129 individuals die from a drug overdose in the U.S. And yes, five of the seven most prescribed CPDs are opioids. The other two are amphetamine (i.e., Adderall) and methylphenidate (i.e., Ritalin and Concerta).

This information was taken from a yearly statistical summary published by the DEA called the National Drug Threat Assessment (NDTA). The 2016 NDTA Summary covers a wide range of data and classes of drugs. There’s even information on the various drug cartels operating in the U.S. This article will focus on CPDs.

The first figure (Figure 26) gives a comparison of the drug poisoning deaths for prescription drugs, cocaine and heroin from 2007 to 2014. Then Figure 29 shows the top five CPDs distributed nationwide in the BILLIONS of dosage units. Far and away from all the other CPDs, hydrocodone and oxycodone are the most prescribed drugs in the U.S. Both of these figures were taken from the 2016 NDTA Summary.

Not surprisingly, the number of admissions to publically funded treatment facilities for non-heroin opiate/synthetic abuse was 24% higher in 2013 than in 2008. The number of admissions has declined since 2011, but that has been offset by an increase in heroin use between 2011 and 2013.

Recently there has been an increase in the abuse of stimulant medications, specifically amphetamine. Between 2006 and 2011 the nonmedical use of Adderall increased by 67%.  Emergency department visits related to Adderall almost tripled between 2005 and 2010. Misuse of ADHD medications as a class resulted in a 76% increase in poison control interventions from 2005 to 2010.

Young adults 18-25 years old represent the majority of the increase in Emergency Department visits, despite children comprising the largest subset of ADHD diagnoses. Many high school and college age students display limited knowledge of either the side effects or the addictive nature of Adderall. This coincides with the popular reputation of the drug on college campuses as a study-aid to improve concentration, and not something harmful or addictive. This contributes to the increased rate of non-medical use among adults.

Looking at concerns with prescription drug use and misuse from another perspective, a report by Quest Diagnostics suggested many Americans are misusing their prescription drugs. In their 2016 Prescription Drug Monitoring Report, Quest Diagnostics found that 54% of patient specimens showed signs of prescription drug misuse. For the purposes of their analysis, a consistent result was when a patient was taking a prescribed drug appropriately. An inconsistent result meant the patient was either not taking their prescribed drug, was taking drugs in addition to those that were prescribed, or was taking drugs that hadn’t been prescribed to them. These three combined causes of “inconsistent test results” indicated potential drug misuse in the Quest report.

About 45% of the inconsistent specimens showed evidence of patients taking drugs in addition to what was prescribed to them, “suggesting the potential for dangerous drug combinations in a sizeable number of patients.” This 2015 finding was considerably higher than other years. STAT News quoted Quest’s medical affairs director as saying, ““The discovery that a growing percentage of people are combining drugs without their physician’s knowledge is deeply troubling, given the dangers.” Of particular concern is the combination of opioids and sedatives, which can lead to respiratory depression, coma and death. The following graphic was taken from the Quest Diagnostics report.

Quest also examined the drug groups associated with the highest number of inconsistencies, by age groups. Unfortunately, given their composite sense of “inconsistent test results,” it is not clear what caused the top inconsistent drug classes. For example, we can speculate that in the under age 10 category, the top two drug inconsistent classes (amphetamine and methylphenidate) were likely due to no drug found, meaning those children were prescribed, but not taking their ADHD medications. The same can be said for the various places that “marijuana metabolite” appeared. However, the inconsistent classes for benzodiazepines, opiates and oxycodone are not distinguished by cause. So while benzodiazepines are noted as the top inconsistent drug class for every age group over 25, it is not clear if that meant they were taken in addition to what was prescribed or not.

One exception to this was with heroin and benzodiazepines. Quest found 1.56% of their tests were positive for heroin. Among adults who tested positive for heroin, 28.6% were also positive for benzodiazepines. Among those who combined these two drugs, 92.3% of the benzodiazepines were not prescribed.

The Fix, an addiction and recovery website, enlisted Peter Grinspoon, the author of Free Refills: A Doctor Confronts His Addiction, to look at the study. Dr. Grinspoon observed that Quest Diagnostics is in the business of doing urine drug testing, so they are interested in promoting drug testing. He went on to say:

Drug tests simply aren’t that accurate. They’re subject to human and lab error, and are rife with both false positives and false negatives. Savvy drug users can outsmart these tests. Any drug testing needs to be interpreted in the context of who is using the drug and why they are using it.

It is true that Quest Diagnostics makes money by increasing the amount of urine testing it does; that it is interested in promoting and highlighting drug-testing. But this was the fifth Prescription Drug Monitoring Report done by Quest. Additionally, Quest provides testing services to about half of all physicians and hospitals in the U.S. So the claim in the report, that it is “well positioned to identify trends in prescription drug monitoring and misuse” is legitimate.

Further, Dr. Grinspoon’s comments on the inaccuracy of urine testing seem overstated. Yes, there are false positives and negatives; and labs can make mistakes. But he gave the impression these errors happen so often that drug testing was a questionable, unreliable procedure. The FDA, among other sources, considers laboratory testing of urine samples to be the most reliable way to confirm drugs of abuse.

He also seems to assume the testing in the Quest report included drug users given urines as part of their treatment within drug treatment programs, which is not the case. Quest specifically stated that drug rehabilitation clinics and addiction specialists were excluded from the analysis “given the higher rates of testing and potentially higher rates of inconsistency.” There is no reason for a drug user to want to outsmart a urine test done in conjunction with their ongoing medical treatment that I can imagine.

The bottom line is that I think the Quest Prescription Drug Monitoring Report still provides helpful and valuable information on the dangerous practice of combining prescription medications. But prescription drug misuse is just one third of a kind if opioid shell game. Along with heroin and fentanyl, it keeps us trying to guess where the next opioid crisis will be.

04/4/17

CBD and the DEA

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As 2016 drew to a close, the DEA announced its decision to classify cannabis extracts separately under the federal government’s Schedule I category. As Victoria Kim reported for The Fix, the ruling sent ripples of panic through the marijuana industry, playing on fears of what is ahead as our country grew closer to a Donald Trump presidency. While the DEA sees the change as marking a clear distinction between cannabis and it extracts, the marijuana industry sees it as saying that those who sell CBD oil are in violation of federal law. However, according to the DEA, the decision was made to more closely align U.S. policy with the United Nations, which already treats cannabis and its extracts separately.

Writing for Leafly, Bruce Barcott described the DEA announcement as an attempt “to criminalize the status of cannabidiol (CBD).” Hundreds of thousands of people around the country who rely on CBD products will be forced find CBD on the black market, according to the CEO of Women Grow. She said the rule “has the potential to inflict substantial harm to a legitimate industry that has been operating legally worldwide for over a decade.”  The executive director of the Cannabis Business Alliance said it creates “unfair barriers for companies with cannabidiol in their products.”

Cloaked in the guise of a bureaucratic technicality, DEA Administrator Chuck Rosenberg made an aggressive bid to wrap CBD into the Controlled Substances Act as a federally illegal Schedule I drug.

In an article he wrote for Leafly on the day of the DEA announcement, Barcott noted where the acting administrator for the DEA said the new code would allow the DEA to track quantities of marijuana extract separately from marijuana. The changes bring U.S. regulations into compliance with international drug-control treaties and present no major change in the law. “Rather it serves to clarify and reinforce the DEA’s position on all cannabis extracts, including CBD oil.” All marijuana extracts will continue to be treated as Schedule I controlled substances.

So what is the uproar if the DEA is merely bringing U.S. regulations in line with international regulations—if marijuana extracts were already Schedule I controlled substances? Barcott said the new rule clarifies the DEA’s position after the 2014 farm bill allowed certain states to grow hemp and blocked federal law enforcement from interfering with state agencies, hemp growers and agricultural research. Hemp-derived CBD oil is available nationwide on web sites and through mail order services. “Those operations survive on the assumption that cannabidiol products below the legal threshold for THC percentage in hemp (0.3 percent or less) are technically legal.” Barcott suggested the rule now says you can grow hemp, but if you try to extract CBD oil from it, the DEA considers that a federal crime.

First, hemp-based CBD products do not have the therapeutic benefits they claim to have. Writing for High Times, Mike Adams noted in his 2014 article, “The Difference Between Hemp Oil and High-CBD Strains,” that while CBD was still illegal in most of the U.S., its rise as “the rock star of the medical marijuana industry” provided the opportunity for some hemp businesses to “market a variation of knockoff CBD treatments that they claim have the same healing power as popular strains such as Charlotte’s Web.” These so-called “knockoff CBD treatments,” while technically similar to medical marijuana strains with CBD, “do not provide the same health benefits as high-CBD cannabis strains.”

However, after patients began submitting complaints about some of these products, including “Real Scientific Hemp Oil,” claiming they were making them sick, a research firm dedicated to cannabidiol education – called Project CBD – launched a full-blown investigation into the matter. After six months, the organization emerged with a 30-page report entitled “Hemp Oil Hustlers: A Project CBD Special Report on Medical Marijuana Inc., HempMeds and Kannaway,” which began as a curious look into an umbrella penny stock company, but transformed into a dissection of the hemp oil industry and its sometimes shady business practices.

Project CBD published a report in 2014 that investigated hemp oil products. The introduction of the report said that Project CBD did not believe that industrial hemp was an optimal source of CBD. On page 13 of the report is a quote from a press release of the Hemp Industries Association. The quote clearly indicates its position:

 It is important for America farmers and processors of hemp to understand that most CBD in products mislabeled as ‘hemp oil’ is a co-product of large-scale hemp stalk and fiber processing facilities in Europe where the fiber is the primary material produced at a large scale. CBD is not a product or component of hemp seeds, and labeling to that effect is misleading and motivated by the desire to take advantage of the legal grey area under federal law. Hemp seed oil does not contain any significant quantity of CBD.

So the hue-and-cry about the DEA’s clarification means that the loophole opened by the 2014 farm bill for hemp CBD products has been closed. Retailers selling “knockoff CBD treatments” of questionable medicinal value will now have to stop selling these products or face possible federal prosecution. This is a good thing. But what about the new 7350 drug code proposed by the DEA?

In the Federal Register, vol. 81, no. 240, under “Why a New Code Number is Needed,” it was noted that U.N. conventions on international drug control treated cannabis extracts differently from marijuana and THC. So creating a new drug code for marijuana extracts would allow for more appropriate accounting of these materials consistent with existing treaty provisions. The existing schedules contained in DEA regulations include marijuana as a Schedule I drug (drug code 7360). This listing includes “any material, compound, mixture, or preparation, which contains any quantity of the substance, or which contains any of its salts, isomers, and salts of isomers that are possible within the specific chemical designation.”

Until now, the DEA has used the 7360 drug code for all marijuana extracts. The proposed rule change recommends that a new drug code, 7350, should be used for marijuana extracts. Marijuana extracts “will continue to be treated as Schedule I controlled substances.” In other words, they were always Schedule I substances.

The Single Convention on Narcotic Drugs and 1971 Convention on Psychotropic Substances are international treaties that provide for the international control of marijuana. The schedules under the Single Convention prohibit the production and supply of specific drugs as well as drugs with similar effects—except for drugs under license for specific purposes, such as medical treatment and research. Many of the provisions of the Controlled Substances Act (CSA) under which the DEA operates were drafted to comply with these Conventions. Both the CSA and the Single Convention list drugs in four schedules, but their classification schemes mean different things. For one, drugs can be in more than one schedule under the Single Convention.

In the Single Convention, the most stringent controls are in Schedule IV; and all Schedule IV drugs are also listed in Schedule I. So placing a drug into both Schedule I and Schedule IV “imposes the most stringent controls under the Single Convention.” Cannabis or marijuana falls into three listings within the Single Convention. Cannabis is the flowering or fruiting tops of the cannabis plant (with the resin not extracted). Cannabis resin is the separated resin, crude or purified, obtained from the cannabis plant. Then there are the extracts and tinctures of cannabis.

The Single Convention placed “cannabis” and “cannabis resin” under both Schedule I and IV of the Convention, the most stringent level of control under the Convention. While “cannabis resin” is extracted from “cannabis,” the Single Convention specifically controls “extracts” separately. Extracts of cannabis are controlled only under Schedule I of the Convention, which is a lower level of control than “cannabis resin.”

Cannabis resin and cannabis (marijuana) will continue under the drug code for marijuana (drug code 7360). The DEA changes will distinguish cannabis extracts from cannabis resin, by defining “marijuana extract” to exclude material referenced as “cannabis resin” under the Single Convention. The new code number created by the DEA is as follows:

Marihuana Extract—7350 ‘‘Meaning an extract containing one or more cannabinoids that has been derived from any plant of the genus Cannabis, other than the separated resin (whether crude or purified) obtained from the plant.’’

Not only does this distinction bring U.S., CSA regulations in line with the Single Convention, it creates a category for medicinal cannabis extracts to be scheduled differently from the recreational cannabis products that fall within the “7360” drug code. Cannabis resin products such as shatter, wax, honey, budder and others will remain classified as 7360—along with the flowering or fruiting tops of the cannabis plant that are rolled into joints or smoked in pipes. But cannabis or marijuana extracts, coded with the 7350 drug code, could be reclassified into a lower CSA Schedule. As the science of CBD research demonstrates the medicinal efficacy of CBD more clearly and consistently, this could be done without rescheduling cannabis bud and flower or cannabis resin. No wonder companies selling marijuana and hemp-based CBD products don’t like the new DEA ruling.

03/24/17

Not Meant for Human Consumption

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In September of 2015 federal and city authorities raided around 80 locations throughout NYC in a crackdown on the importation, distribution and sale of synthetic cannabinoids. Ten people were indicted and a minimum of 100 kilograms of illegal synthetic compounds was confiscated. This was enough to produce 260,00 retail packets with a street value of near $30 million. The operation imported the compounds in powdered form from China through commercial delivery services (like UPS and Federal Express). Then in a Bronx processing facility, the compounds were mixed with solvents and sprayed onto tea leaves.

Most of the ten individuals indicted were of Yemeni descent; four were still at large at the time of the raid. One of the indicted, but at large, individuals seems to have tipped off his operation in July of 2014 when he was stopped for using a cell phone while driving. He consented to a search of his vehicle, where DEA agents found $644,338 IN CASH. When his Queens home was searched, they found an additional $150,935.

The agents say they then read Deiban his Miranda rights but that he nonetheless told them the greater sum came from the sale of synthetic narcotics and was bound for a store in the Bronx. They also say Deiban said the smaller sum came from Bronx and Queens stores that sell his synthetic pot.

He also boasted about selling his products over eBay. He was questioned about a number of keys he had on his person, some of which he said belonged to a warehouse where he stored his synthetic marijuana. But he was not willing to tell DEA agents the warehouse’s address unless the DEA agents guaranteed he would not go to jail. The case was settled in November of 2014. Under the terms, Deiban did not admit to any of the allegations and he was repaid $477,163.80 of the seized money.

Instead of counting his blessings, Deiban allegedly sought to make more dough. The September 2015 complaint says that in the past year, Deiban and his cronies imported at least 220 pounds of banned powdered substances used to make K2 or “spice”—enough to manufacture at least 260,000 packets.

The above incidents really happened, even though they seem to be suspiciously like an Onion satire of really dumb drug dealers. You can read the Department of Justice announcement of the September 2015 indictments here. Additional information noted above can be found in an article on The Daily Beast here and a New York Daily News article here.

This isn’t the first time there has been a Yemeni connection to the sale and distribution of synthetic cannabinoids in the U.S. In 2014, a raid on a Birmingham Alabama warehouse found hundreds of thousands of Spice (synthetic marijuana) packets. Sales of the product were linked to $40 million in wire transfers to Yemen. Read more about this in “Strange Bedfellows: Terrorists and Drugs.”

If you aren’t too familiar with Spice and other so-called new psychoactive substances (NPS), here are some key facts from a World Health Organization “fact file on new psychoactive substances.” There are more than 500 different types of NPS recorded as of March of 2016. The number of NPS as of October 2015 was 602, 55% higher than in 2014. By December 2015, that total would rise to over 644, according to the UNODC Global SMART Update. The most common NPS are synthetic cannabinoids, which mimic the effects of THC, the main psychoactive ingredient in marijuana. “Collecting information on new psychoactive substances is difficult due to the sheer number and speed with which they appear on the market.”

The UN Office on Drugs and Crime (UNODC), the lead agency in international drug control, has identified nine groups of new psychoactive substances. These include synthetic cannabinoids, which mimic the effects of the main psychoactive substance of cannabis, THC; synthetic cathinones, which have stimulant properties and induce feelings of empathy; and phenthylamines, which have stimulant and hallucinogenic properties. Of new psychoactive substances reported in 2014, 39 per cent were synthetic cannabinoids; 18 per cent were phenethylamines and 15 per cent were synthetic cathinones.

UNODOC publishes a Global SMART (Synthetics Monitoring:  Analyses, Reporting and Trends) Update twice a year. Volume 16, published in September of 2016, said that synthetic drugs were one of the most significant global drug problems. As noted above over 644 NPS were reported from 102 different countries. “New NPS continue to emerge every year at an average rate of about one substance per week, making research and monitoring activities critical in improving understanding of the dynamic nature of the problem.” You can download a copy here.

NPS are diverse in terms of their effects and chemistry. Those identified so far seem to mimic the effects of the six main groups of substances controlled under international drug conventions. The six groups are: opioids, synthetic cannabinoid receptor agonists, dissociatives, like PCP, classical hallucinogens like LSD, sedatives/hypnotics like diazepam, and stimulants like cocaine and amphetamine-type stimulants. The following pie chart from the Global SMART Update illustrates the proportion of NPS by their pharmacological effect. The chart indicates how the three NPS noted above, synthetic cannabinoids, synthetic cathinones, and phenthylamines account for 88% of the total proportion of NPS indentified by December of 2015.

A major area of concern is with the unknown adverse health risks associated with using NPS. Obtaining health-related and toxicological data is crucial for making scheduling decisions with NPS. Synthetic cannabinoids have been linked to both fatal and non-fatal intoxications, along with seizures, tachycardia and hypertension. Synthetic cathinones like MDPV have been associated with severe agitation, violent behavior, tachycardia, psychosis paranoia and fatal intoxications. Dangers are accentuated by intentional mislabeling of products, as was noted above, as well as their unknown purity and composition.

The internet is an important distribution channel. It provides easy, anonymous and low-risk supply of NPS. Not to mention the high rewards to suppliers and retailers. Websites may be in different countries from those where the NPS are manufactured and/or where they are supplied. “The disparity of laws in various regions poses a challenge in adopting a comprehensive approach for the prosecution of violations.” Then there is the sale of products on the darknet, which is only accessed by anonymizing software.

The number of NPS and the rapidity with which new ones emerge presents a challenge to drug control systems. Placing a potentially harmful substance under legal control can be a lengthy process of evidence-gathering and a scientific review of its harms. This means there is a time lag between emergence of an NPS and when legal control is implemented. “NPS manufacturers o en exploit this inevitable me lag by developing and marketing alternative substances to circumvent established controls. “

In the U.S., the 2016 National Drug Threat Assessment (NDTA) reported that NPS are available throughout the U.S. The two most common are synthetic cannabinoids and synthetic cathinones. Although synthetic cannabinoids are usually ingested by smoking, they are also available as a liquid or oil to use in e-cigarettes or vape pens. In 2015, synthetic cannabinnoids were found in counterfeit Xanax bars. Calls to the AAPCC, the American Association of Poison Control Centers, totaled 7,779. This was a 111% increase over 2014. This was the highest number of calls recoded since the drugs first appeared on the market. See the following figure taken from the 2016 NDTA.

Inmates in prisons and jails use synthetic cannabinoids because they aren’t typically tested for in mandatory drug screens. “The drugs are also difficult to detect during screenings by prison officials and narcotics dogs.” Liquid cannabiniods are sprayed onto paper products, like greeting cards or letters, and then dried. When successfully smuggled into a prison, the drug-saturated pages are torn into small squares, then chewed or smoked. In October of 2015, the FBI issued a warning that synthetic cannabioids in prisons may result in inmates becoming agitated and aggressive.

The foil packets used to package synthetic cannabinoids can be purchased in bulk. The empty packets are already branded with various cartoon logos and brand names. The contents of the packets can vary widely. A DEA forensic lab tested 28 identical packets from one seizure in 2015. “The packets contained a total of seven different synthetic cannabinoids.” Many contained more than one variety of synthetic cannabinoid.

Ironically, the synthetic cannabinoid problem seems to have originated by classifying marijuana as a Schedule I controlled substance. In 1970, marijuana and its cannabinoids were given a Schedule I designation. This meant that marijuana was difficult to obtain for research on its therapeutic effects. Then John W. Huffman and his team of researchers at Clemson began developing cannabinoid compounds to aide in the research of multiple sclerosis, HIV/AIDS, and chemotherapy. Their research was funded by: the National Institute on Drug Abuse (NIDA).

Over the next twenty years, they developed 450 synthetic cannabinoid compounds. Some of those, including: JWH-018, JWH-073, JWH-210, JWH-250, and JWH-081 are among the dozens of synthetic cannabinoids on the streets today. Notice the compound names begin with Huffman’s initials: “JWH.” Like any self-respecting scientist, he published his research, which included step-by-step instructions on how to recreate the substances. Then around 2008, JWH-018 appeared in Germany as a recreational alternative for marijuana known as “Spice” and “K2.” Huffman said: “I always had a hunch that someday somebody would say, ‘Hey, let’s try smoking them.’ … These things are dangerous—anybody who uses them is playing Russian Roulette. . . . We never intended them for human consumption.”

03/14/17

Fentanyl: Fraud and Fatality

© Alexi Novikov

In December of 2016, several former pharmaceutical executives and managers of Insys Therapeutics were arrested on charges they participated in a nationwide conspiracy to bribe medical practitioners to prescribe one of the company’s fentanyl products, Subsys. The medication is approved for treating cancer patients suffering intense episodes of breakthrough pain. “In exchange for bribes and kickbacks, the practitioners wrote large numbers of prescriptions for the patients, most of whom were not diagnosed with cancer.” The indictment also alleges that these same former Insys executives conspired to “mislead and defraud” health insurance companies who were reluctant to approve payment for Subsys when it was prescribed for non-cancer patients.

The Special Agent in Charge of the Boston Field Division of the FBI said top executive of Insys Therapeutics, Inc. allegedly paid kickbacks and committed fraud in selling the highly addictive opioid. “The indictment also alleges that the conspiracy to bribe practioners and to defraud insurers generated substantial profits for the defendants, their company, and for the co-conspirator practioners.” The investigative team included multiple federal agencies, including: FBI, FDA Office of Criminal Investigations; Health and Human Services (HHS), U.S. Postal Service, the Department of Labor, and the Department of Veterans Affairs.

Reporting for STAT News on the indictments, David Armstrong said a Florida doctor was invited to Insys headquarters near Phoenix, where sales officials took him out for a night on the town. In a text message to a sales rep, one of the company’s regional sales managers said: “He had to have had one of the best nights of his life.”  The next week the doctor wrote 17 prescriptions for Subsys, when he usually wrote three. “He also received $260,050 in payments over three years for participating in the Insys speaking program — something federal officials allege was nothing more than a mechanism for bribing doctors.”

Subsys was launched in March 2012 into a crowded field of competitors, which included other brand-name medications and several generics. The drug was approved only for cancer patients with intense flares of pain — a narrow market — and only about 2,000 doctors in the country prescribed fentanyl products. The drug is also expensive, costing thousands of dollars a month.

Prosecutors allege the company overcame these challenges with a speaker program, where “educating” doctors on the use of the drug was actually a way to bride them. A former chief executive of Insys wrote to sales managers that they needed to make it clear to sales reps how having one of their top targets as a speaker “can pay big dividends for them.” Doctors didn’t need to be good speakers; they just needed to “write a lot of” Subsys prescriptions. The indictment did not identify any of the parishioners by name who allegedly received and kickbacks.

To sweeten the pot, the Insys employees allegedly scheduled speaking events at establishments owned by doctors, or their families and friends. The events allegedly had little do with education: They were often held at high-priced restaurants and attendees were frequently just friends of the doctor hired as the speaker, the indictment alleges. Fake names were used on sign-in sheets, and some events had no attendees at all, according to prosecutors.

The cancer market for Subsys was considered to be “small potatoes” by one of the indicted former Insys executives. While the alleged bribes led doctors to prescribe more prescriptions for Subsys, insurance companies were reluctant to pay when the drug was prescribed for non-cancer patients. So a system was created to deceive insurers into paying for off-label uses of the drug, which is incidentally, quite expensive. A call center was created at Insys to handle insurance reimbursement approvals for doctors prescribing Subsys.

Employees in this unit are alleged to have contacted insurers, giving the appearance they were calling from the doctor’s office.  Along with the supposedly deceptive medical information given to the insurers, they reportedly said patients had difficulty swallowing, which meant Subsys, as a nasal spray, had a distinct advantage over similar products that were in pill form. “Employees of the unit were rewarded with lucrative financial bonuses if the entire unit met a weekly target of reimbursement approvals.”

The Subsys fiasco is not the only fentanyl-related contribution to the opioid problem in the U.S. Two years ago the DEA issued a nationwide alert on fentanyl as a threat to health and public safety. State and local labs reported 3,344 fentanyl submissions in 2014, an increase from 942 in 2013. “In addition, the DEA has identified 15 other fentanyl-related compounds.” Warnings were issued to law enforcement about guarding against fentanyl absorption through the skin or accidental inhalation of airborne powder, as it is 30 to 50 times more potent than heroin. Ingesting as small as .20 mg to 2mg of fentanyl can be lethal. The following image, taken from the 2016 National Drug Threat Assessment (NDTA), illustrates the size of 2mg of fentanyl compared to a penny.

 

Globally, fentanyl abuse has increased in Russia, Ukraine, Sweden and Denmark. Mexican authorities have seized fentanyl labs run by the drug cartels. Intelligence indicated the precursor chemicals for fentanyl have come from companies in Mexico, Germany, Japan and China.

According to the 2016 NDTA, licit fentanyl is only diverted on a small scale. Illicit fentanyl, typically manufactured in China or possibly Mexico, is smuggled into the U.S. across the border with Mexico. Traffickers usually obtain fentanyl and mix it with heroin on their own. This happens at a variety of locations, including homes and even hotel rooms.

In August 2015, the DEA Manchester, New Hampshire DO, along with the Salem, New Hampshire Police Department, conducted an enforcement operation at a fentanyl mill in a hotel in New Hampshire. The traffickers used a hotel room kitchenette for mixing heroin and fentanyl together. Upon entry by law enforcement officers, the traffickers attempted to dispose of the drugs down the sink, spilling the highly lethal drugs all over the room.

Traffickers in the U.S. are also using fentanyl powder and a pill press to create counterfeit pills of oxycodone and other drugs. Officials in New Jersey and Tennessee seized pills that appeared to be oxycodone. But laboratory analysis indicated they were fentanyl or acetyl fentanyl. In May of 2015, Orange County Police Officers in California seized what appeared to be black tar heroin. “Upon laboratory analysis, the substance was revealed to be fentanyl and showed no traces of heroin or any other drug.”

In another article for STAT News, David Armstrong described the China connection with fentanyl. Raw fentanyl and the machinery necessary for assembly-line production of the drug are coming from Chinese suppliers. “The fentanyl pills are often disguised as other painkillers because those drugs fetch a higher price on the street, even though they are less potent, according to police.” A Southern California fentanyl lab had a dozen different packages shipped to mail centers and residences. A box labeled as a “Hole Puncher” was in fact a quarter-ton pill press. “The Southern California lab was just one of four dismantled by law enforcement in the United States and Canada in March [of 2016].”

In British Columbia, police raided a lab at a custom car business that was allegedly shipping 100,000 fentanyl pills a month to Calgary, Alberta. Federal agents shut down a Seattle lab set up in the bedroom of a home in a residential neighborhood. Police near Syracuse New York raided a similar residential lab, where they were warned by the people there not to touch the fentanyl without gloves because of its potency. “The emergence of decentralized drug labs using materials obtained from China — and often ordered over the Internet — makes it more difficult to combat the illicit use of the drug.” See “Buyer Beware Drugs” for more on this topic.

In January of 2017 the acting administrator of the DEA met with Chinese officials to address the synthetic drug crisis in the U.S. He said: “These meetings underscore our improving relationship and cooperative efforts as we work to stem the flow of dangerous synthetic opioids and related chemicals.  I appreciate the good work they are doing in China to help us address our opioid epidemic.” The DEA maintains an office in Beijing and hopes to expand its presence in China. Hopefully, if the China connection with fentanyl is turned off, the future outlook from the 2016 NDTA will not be as bleak.

Fentanyl will remain an extremely dangerous public safety threat while the current production of non-pharmaceutical fentanyl continues. Fentanyl poses not only a threat to users, but also to law enforcement personnel and postal service employees as minute amounts of the drug are lethal and can be inadvertently inhaled or absorbed through the skin. Although many drug users avoid fentanyl, still others actively seek it out for its strong and intense high. In 2015 traffickers expanded the historical fentanyl markets as evidenced by a massive surge in the production of counterfeit tablets containing the drug, and manipulating it to appear as black tar heroin. The fentanyl market will continue to expand in the future as new fentanyl products attract additional users.

In February 2017, Time reported that China announced that carfentanyl (carfentanil)and three related synthetic opioids would be added to its list of controlled substances effective March 1, 2017. The DEA called China’s action a potential “game changer.” Russell Baer, a DEA special agent said: “It’s a substantial step in the fight against opioids here in the United States. . . We’re persuaded it will have a definite impact.” In October, the Associated Press identified 12 Chinese companies the offered carfentanyl for export. That same month China began evaluating whether to add it and three other fentanyls to its list of controlled substances. “Usually, the process can take nine months. This time, it took just four.”

03/3/17

Shatter and Psychosis

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Dr. Kiri Simms is an emergency psychiatrist in Victoria, British Columbia. Two years ago she saw her first patient with marijuana-induced psychosis. The person was very young and very disconnected from reality. “She was very, very ill.” Shatter, a butane hash oil product, was the only drug she used. In the past, most people did not become psychotic with marijuana use alone, Dr. Simms said. “That has changed with these butane hash oil products.”

Dr. Simms said she’s seeing an increased severity and intensity of symptoms with some people at her emergency department (ED). In the past year, she estimated she’s treated ten people who had used shatter and whose problems were severe enough to require a stay in psychiatric intensive care or on one of their inpatient wards. People are often surprised they experienced psychotic symptoms from using marijuana products, she said.

It used to be that people did not become psychotic from marijuana use alone. Infrequently, individuals with a family history of schizophrenia might have a psychotic experience after smoking marijuana, but not any more. It’s not like the old days, where symptoms would pass in a few hours or days. Now Dr. Simms said they are seeing people who sometimes take weeks and occasionally months for their psychotic symptoms to clear.

The above discussion was in an interview she did with Greg Craigie the host of the CBC radio program, On the Island. You can read excerpts or follow a link to hear the full interview here. Craigie followed the Simms interview with one he did with Rebecca Jessemen, the senior policy advisor for the Canadian Centre of Substance Abuse. She said they were really concerned with minimizing the risk of harm with youth, as marijuana legalization moves closer in Canada. “That includes key messages such as delaying initiation of use, reducing frequency of use, and reducing the quantity of use… Part of that is quantity in terms of concentration too.”

Not surprisingly, the interview and web story prompted several mostly negative Facebook comments rejecting a link between shatter and psychosis. Accusations were made of this being false news, that CBC was spreading anti-cannabis propaganda, etc. You can read an article about Craigie’s interview with Rebecca Jessemen here. But this is not fake news. There is a clear, known association of marijuana use and psychotic episodes. And with higher THC content in a marijuana product, the risk of a psychotic episode increases.

Do people react differently to the same dose of THC? Does cannabidiol (CBD) reduce the psychotic effects of THC? There was an experiment done at the Institute of Psychiatry at King College, London that looked at the relationship of the effects of the two main cannabinoids in cannabis, THC and CBD. You can watch a video of a reporter participating in the experiment here.

She was given pure THC and a mixture of THC and CBD. On the THC and CBD mixture, the reporter said she seemed flippant; on pure THC, she just didn’t care. The mixture of THC and CBD left her with the giggles: “No matter how hard I tried to take the experiment seriously, it all seems hilarious.”

With pure THC, she was suspicious, introverted; “weird.” Every question seemed to have a double meaning. She felt morbid. “It’s like a panic attack.” “It’s horrible. It’s like being at a funeral . . . Worse . . . It’s just so depressing. You want to top [kill] yourself.”

The researchers used the Positive and Negative Syndrome Scale (PNASS), a standard test to measure changes in psychotic symptoms. On the PNASS sub scale used, changes above four was clinically significant; changes that would be associated with schizophrenic psychosis. She scored fourteen. The effects on the reporter were temporary and would not be long lasting. But the video clearly shows how higher concentrations of THC can induce temporary psychotic symptoms in normal individuals.

In a NPR interview, Dr. Nora Volkow, the director of the National Institute for Drug Abuse (NIDA) said while no one would question that marijuana can trigger temporary symptoms of psychosis in some people, it is not clear whether cannabis alone can trigger schizophrenia. “You can have a psychotic episode from the use of marijuana without it turning into schizophrenia. . . . It’s very distressing, but you’ll get out of it.” While drugs like marijuana and methamphetamine can lead to experiencing symptoms like paranoia and disorganized thinking, that’s very different from schizophrenia.

Dr. Volkow suggested the studies show that people with schizophrenia tend to smoke pot. People with an emerging schizophrenic disorder maybe “trying to self-medicate because they just don’t feel right.” Volkow believes if someone has a vulnerability to schizophrenia smoking it could trigger a psychotic episode. Without the predisposition, “you can smoke all the marijuana you want and it will make no difference.” Volkow did acknowledge the dramatic increase in people showing up in the emergency department with a temporary psychotic episode could be related to “a much more potent marijuana.”

But not everyone has the same opinion; that there is a clear distinction between schizophrenia and marijuana-induced psychosis. Sir Robin Murray, a psychiatrist at King’s College in London said 20 years ago he would tell patients that cannabis was safe. “It’s only after you see all the patients that go psychotic that you realize—it’s not safe.”

Krista Lisdahl, a clinical neuropsychologist, said that if marijuana is causing schizophrenia, this happens during an individual’s early years of development. There hasn’t been an increase in the number of people with schizophrenia; the number still hovers around 1%. However, studies do show that the earlier someone starts using marijuana, the more likely they will develop a psychiatric disorder in general.

A report by DAWN (Drug Abuse Warning Network) found that ED visits due to marijuana increased by 52% between 2004 and 2011. This was lower than the increase in ED visits for anti-anxiety and insomnia medications (124%), narcotic pain relievers (153%), antipsychotics (71%), and stimulants like ADHD medications (292%).  Nevertheless, Sir Robin Murray said the data strengthens the case of an association between cannabis and the risk for schizophrenia. A study in The Lancet which he published suggested marijuana with around 15% THC could increase the risk of schizophrenia 5 times. “We think about 5 percent of people will go psychotic instead of 1 percent.”

Our findings show the importance of raising public awareness of the risk associated with use of high-potency cannabis, especially when such varieties of cannabis are becoming more available. The worldwide trend of liberalisation of the legal constraints on the use of cannabis further emphasises the urgent need to develop public education to inform young people about the risks of high-potency cannabis.

A 2014 article in Frontiers in Psychiatry, Gone to Pot,” reviewed the emerging evidence of a connection between cannabis and psychosis/psychotic disorders, including schizophrenia. The review was comprehensive and suggested cannabis may be a component in the emergence of psychosis. But the precise nature of these associations remains unclear. However, the relationship has been evident since the mid 1800s. One of the earliest studies of marijuana and psychosis was done by the French psychiatrist Jacques-Joseph Moreau, and reported in his 1845 book, Hashish and Mental Illness. Moreau said hashish (cannabis resin) could precipitate:

 … acute psychotic reactions, generally lasting but a few hours, but occasionally as long as a week; the reaction seemed dose-related and its main features included paranoid ideation, illusions, hallucinations, delusions, depersonalization, confusion, restlessness, and excitement. There can be delirium, disorientation, and marked clouding of consciousness.

Consistent with the YouTube video of the Kings College experiment linked above, cannabis extract and THC alone have been shown to produce a range of transient symptoms similar to the positive symptoms of schizophrenia: “suspiciousness, paranoid and grandiose delusions, conceptual disorganization, fragmented thinking, and perceptual alterations. Additionally, cannabis and THC also result in depersonalization, derealization, alterations in sensory perception, and feelings of unreality.” A double-blind, randomized, placebo-controlled study by D’Souza et al. found that THC produced transient positive psychotic symptoms. A similar study replicated these findings in healthy individuals with a lower THC dose than D’Souza et al.

Several studies suggest a “window of opportunity” hypothesis, meaning there is a critical period during early adolescence “where the brain is particularly susceptible to the psychosis-inducing effects of cannabis.” The premise suggests cannabis may affect the brain during a critical period of development and maturation. Cannabis could disrupt one or more of these maturation processes.

By disrupting the endocannabinoid system and interfering with neurodevelopmental processes, exogenous [from outside of an organism] cannabinoids may provide a biologically plausible mechanism by which exposure to cannabinoids during adolescence may increase the risk for the development of schizophrenia.

While there has been a notable increase in the rates of cannabis use over the past four decades, there has not been an increase in the prevalence of schizophrenia. The authors admit these results are difficult to explain in the context of their review showing how “the relationship between cannabinoids and psychosis fulfills many but not all of the traditional criteria for causality.” One possible explanation is that schizophrenia rates are lagging behind increased rates of cannabis consumption. In other words, we need to look for a future increase of schizophrenia rates with a cannabis connection.

Given the evidence presented above, it is likely that cannabis is an important component cause in the development of psychotic disorders. This causal role is apparantly magnified when cannabis exposure occurs at an earlier age, in greater quantities, and over a longer time-course. Further, as was discussed in this review, specific populations (i.e., those with a genetic vulnerability or a history of childhood abuse) may be particularly susceptible to the causal effects of cannabis. In conclusion the authors said:

Acute exposure to both natural and synthetic cannabinoids can produce a full range of transient symptoms, cognitive deficits, and psychophysiological abnormalities that bear a striking resemblance to some of the features of schizophrenia. Also clear is that, in individuals with an established psychotic disorder, cannabinoids can exacerbate symptoms, trigger relapse, and have negative consequences on the course of the illness. Finally, exposure to cannabinoids in adolescence confers a higher risk for psychosis outcomes in later life and the risk is dose-related. However, it should be remembered that the majority of individuals who consume cannabis do not experience any kind of psychosis.

So the On the Island interview with Dr. Simms was not an example of fake news or anti-marijuana fear mongering. While the dangers of cannabis use don’t approach those portrayed in the classic cult film Reefer Madness, there is growing evidence of a risk of psychotic symptoms with higher levels of THC in marijuana products like shatter. And there is an increased risk of psychosis later in life for a subgroup of adolescents who use marijuana. The evidence is not conclusive at this time, but can we afford to just wait-and-see if wide spread recreational marijuana use conclusively causes the adverse effects discussed above before taking regulatory action?

02/20/17

Listening to Marijuana Research

© Mohammed Anwarul Kabir Choudhury

Would it surprise you to know that only .6% of all participants in medical marijuana programs are getting any ongoing medical oversight? Williams et al. assessed medical marijuana programs for Health Affairs according to seven components of traditional medical care and pharmaceutical regulation. The authors found that of the initial 23 states and the District of Columbia who had approved medical marijuana, 14 programs were nonmedical, according to those standards. These fourteen programs collectively enrolled 99.4% of all nationwide participants in medical marijuana programs.

One of the study’s coauthors, Dr. Silvia Martins said: “When you’re allowing someone to have access to a certain product as a medication, it needs to be overseen by good medical practices and medical rules.” And that is necessarily based on a clear understanding of the risks and benefits of any medicinal product.

With that in mind, the MIND project at McLean Hospital in Boston is researching medical marijuana (MMJ).  MIND stands for: Marijuana Investigations for Neuroscientific Discovery. Currently MIND is conducting a longitudinal study of MMJ. The first phase of the MIND project assesses subjects at baseline, before beginning their MMJ treatment. They then track their use of marijuana (MJ) and are in touch with researchers biweekly. Follow up visits occur every three months for two years in order to assess the potential impact of MMJ on cognitive function and related brain and quality of life measures.

The second phase is an FDA-approved clinical trial of high-CBD sublingual tincture for treating anxiety. A third and final phase will examine the clinical state and cognition in veterans who are using cannabinoids to treat various conditions, including PTSD, insomnia and pain. The MIND website noted how policy has gone too far ahead of science, so there is little data available on the impact of MMJ on cognitive functioning.

Given the considerable difficulty with cognitive function and disrupted mood experienced by patients with severe medical disorders, the addition of MJ, which has shown promise in alleviating a range of symptoms, could potentially improve cognitive performance. Equally critical, data showing a loss or impairment of cognitive function following the use of MMJ could inform alternative courses of treatment, staggered dosing, and ultimately prevent unjustified exposure to harm. As the number of states who have passed MMJ laws continues to grow, the ‘need to know’ has never been more important, relevant or timely, and has significant implications for public health policy.

Staci Gruber, who is the director of the MIND project, has been doing research into the effects of MJ since the early 1990s and has documented some interesting neurological effects from MJ. She led a 2013 study that found there were differences in the brain’s white matter and impulsivity between teenagers and young adults smoked an average of 25.5 joints of MJ per week and a control group who did not smoke MJ. Their research suggested that in some individuals who begin smoking MJ at an early age, differences in brain function and structure emerge during development. The study sample was small and it was not clear if the brain changes resulted from MJ use or predated MJ use. The changes could have occurred as the result of either chronic MJ use or reflect a delay in brain development in MJ smokers.

These data represent the first report of significant alterations in frontal white matter fiber tract integrity that are associated with self-report measures of impulsivity in chronic, heavy MJ smokers, and appear to be related to age of onset of MJ use. . . . Future investigations should include additional measures of behavioral impulsivity and their relationship to age of onset of MJ use to more fully explore the potential neurodevelopmental aspects of white matter changes in MJ smokers. Findings from this study suggest that changes in white matter microstructure may be predictive or associated with increased impulsivity, and may ultimately contribute to the initiation of MJ use or the inability to discontinue use.

A follow up study done by Gruber and others was published that same year, 2013. The study confirmed that heavy MJ smokers had lower levels of white matter in the corpus callosum region of the brain; and that earlier age of MJ use was associated with these lower levels of white matter. MJ smokers also had higher levels of impulsivity.

Taken together, these findings reinforce the idea that early onset of MJ use negatively impacts white matter development and is associated with behavioral impulsivity, a combination that may have enduring negative effects, particularly on the developing brain. Data from this study highlight the importance of early identification of MJ use among emerging adults and the need for efforts aimed at delaying or preventing the onset of MJ use.

Then a third study by Gruber and her research team at MIND published in the March 2016 issue of the Journal of Studies on Alcohol and Drugs found that MJ smokers had poorer executive brain function than the control group. The difference seemed to be primarily the result of early onset of MJ use, before the age of 16. The differences remained even after the frequency and amounts of MJ used were controlled. Additionally, the early MJ use and the greater amounts of MJ used predicted poorer performance and errors on the Wisconsin Card Sorting Test (WCST), which is used to assess abstract thinking. “The WCST is also considered a measure of executive function because of its reported sensitivity to frontal lobe dysfunction.”

These findings underscore the impact of early onset of marijuana use on executive function impairment independent of increased frequency and magnitude of use. In addition, poorer performance on the WCST may serve as a neuropsychological marker for heavy marijuana users. These results highlight the need for additional research to identify predictors associated with early marijuana use, as exposure to marijuana during a period of developmental vulnerability may result in negative cognitive consequences.

STAT News highlighted Dr. Gruber’s research with MIND in an August 2016 article. She commented there on the commitment of some of her research participants, how they drive two to three hours to be part of the MIND study. “They’re really committed. They really want to know what effect this will have on them.”

After reviewing some of the comments on the STAT article, it seemed to me that several of the pro marijuana readers either missed or ignored a few of her comments in the article. One of her comments was: “There’s a lot we don’t know about long-term effects, and that’s what I’m here to find out.” In a second remark Gruber pointed out that the cannabinoids she studies aren’t the ones that get you high. “But whether you’re for medical marijuana or against it, what we really need is information.”

SAMA (Science and Management of Addictions) president, Kim Bracket, said Staci Gruber has a talent for translating scientific information so that non-scientists can understand. This leads to a third and telling comment by Gruber in the article: “In science, you can have all the findings in the world, but if you can’t communicate them, what good are they?” So far, I think she is communicating her findings clearly and concisely to scientists and non-scientists, legalization activists and opponents to legalization. And we need to continue to listen to what she says.

02/10/17

Guns and Needles

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Reporting for The Washington Post, Christopher Ingraham gleaned some grim facts from the recent CDC data on drug and opioid deaths in the U.S. Opioid deaths surpassed 30,000 in 2015; an increase of 5,000 from 2014. Deaths from synthetic opioids like fentanyl rose by over 70% from 2014 to 2015. For the first time since the late 1990s, heroin deaths surpassed traditional opioid painkillers like hydrocodone and oxycodone. The grimmest reality is that more people died in 2015 from heroin-related causes than gun violence. “As recently as 2007, gun homicides outnumbered heroin deaths by more than 5 to 1.”

The above linked Washington Post article graphs and discusses CDC data showing the surge in opioid deaths from 8,280 in 1999 to 33,092 in 2015. You will also find graphs of the death rate increases by three classes of opioids. And there is a graph showing the rapid increase in heroin deaths over the last five years or so to 12,989 in 2015, surpassing gun homicide deaths in 2015 by 10 (12,979).

The CDC MMWR—Morbidity and Mortality Weekly Report—indicated that the rate of drug overdose deaths increased in 30 states and DC; and remained stable in 19 others. Opioid death rates increased by 15.6% from 2014 to 2015. The report suggested the increase was most likely driven by illicitly manufactured fentanyl. These increases were also concentrated in eight states. According to another CDC MMWR from August 26, 2016, those states were: Massachusetts, Maine, New Hampshire, Ohio, Florida, Kentucky, Maryland and North Carolina.

During 2014 to 2015 death rates increased overall, as well as for both males and females in the three different classes of opioids. The following chart gives the CDC death rates by class of opioid, year, sex and overall population. The opioid classes are: natural and semi-synthetic opioids (codeine, morphine, hydrocodone, hydromorphone, oxycodone, oxymorphone and buprenorphine), synthetic opioids (meperidine and fentanyl) and heroin. Heroin is a semi-synthetic opioid, but was assessed separately by the CDC. Methadone is a synthetic opioid but was also assessed separately. See the CDC MMWR for data on methadone deaths.  The “rate” in the chart is the death rate per 100,000 people.

Characteristic

Natural and semi-synthetic opioids

2014

2015

% change in rate, 2014 to 2015

No. (rate)

No. (rate)

Overall

12,159 (3.8)

12,727 (3.9)

2.6%

Sex

Male

6,732 (4.2)

7,117 (4.4)

4.8%

Female

5,427 (3.3)

5,610 (3.4)

3.0%

Characteristic

Synthetic opioids other than methadone

2014

2015

% change in rate, 2014 to 2015

No. (rate)

No. (rate)

Overall

5,544 (1.8)

9,580 (3.1)

72.2%

Sex

Male

3,465 (2.2)

6,560 (4.2)

90.9%

Female

2,079 (1.3)

3,020 (1.9)

46.2%

Characteristic

Heroin

2014

2015

% change in rate, 2014 to 2015

No. (rate)

No. (rate)

Overall

10,574 (3.4)

12,989 (4.1)

20.6%

Sex

Male

8,160 (5.2)

9,881 (6.3)

21.2%

Female

2,414 (1.6)

3,108 (2.0)

25%

From 2014 to 2015, the combined opioid death rates increased by 15.6%. The most radical increases were with synthetic opioids, overwhelmingly from fentanyl. The overall increase was 72.2%, driven primarily by a 90.9% increase in male deaths. Overall heroin deaths in 2015 were higher than the number of deaths from natural and semi-synthetic opioids in 2015. Death rates from natural and semi-synthetic opioids increased as well, but at a more leisurely rate.

Another Washington Post article by Christopher Ingraham, “Where opiates killed the most people in 2015,” again used CDC data to compose a series of maps. These maps illustrated which states in 2016 had the most opioid deaths overall and also by classes of opioids: heroin, synthetic and natural (natural and semi-synthetic). Nationally, there were roughly 10.4 opioid overdose deaths per 100,000 people. But New England, and the Ohio/Kentucky/West Virginia had the highest rates. Ohio, West Virginia and Connecticut had the highest death rates from heroin overdoses, between 20 and 36.

Synthetic opioid deaths were primarily located along the East Coast. The national death rate from synthetic opioids is 3.1 per 100,000. In Rhode Island it’s 13.2; in Massachusetts it’s 14.4; and in New Hampshire it’s 24.1. Ohio and West Virginia weren’t far behind. Deaths from natural and semi-synthetic opioids were concentrated in West Virginia and Utah. There is also a table of raw data by state in the article.  The following map, taken from the article, is for overall opioid deaths in the U.S. for 2015.

The following chart, taken from the 2016 National Drug Threat Assessment Summary, combines CDC data for deaths by drug poisoning, homicide, firearms and motor vehicle crashes between 1999 and 2014. You can clearly see how overdose deaths have risen, outpacing the other causes of death. The 2016 NDTA Summary said drug overdose deaths are at the highest level ever recorded. “In 2014, approximately 129 people died every day as a result of drug poisoning.” Since 2010, there has been a 248% increase in heroin overdose deaths.

The U.S. has seen a dramatic increase in the availability of heroin in the last ten years, allowing the heroin threat to expand exponentially.  The increases with heroin production in Mexico have guaranteed a steady supply of low-cost heroin, despite the increases in the number of users over the past decade. While heroin from four source areas (Mexico, South America, Southwest Asia, and Southeast Asia) can be found somewhere in the U.S., Mexico is the main source of heroin. South America is the second most common source. Mexican heroin accounted for 79% of the total weight of heroin analyzed by the Heroin Signature Program.

The domestic supply of Mexico-sourced heroin is more than sufficient to satisfy current U.S. market demand. Moreover, Mexican heroin traffickers are able to keep the supply steady and reliable. This is evidenced by high availability levels in U.S. heroin markets and low retail-level prices.

The number of individuals who used heroin in the month prior to a National Survey on Drug Use and Health (NSDUH) increased by 154% between 2007 and 2014. There was a 51% increase in just the last year of the survey; 27% reported lifetime heroin use. “The estimated number of new heroin initiates doubled between 2007 (106,000) and 2014 (212,000).” See the following graph for more information on current heroin users between 2007 and 2014 from the 2016 NDTA Summary.

So far we’ve looked at the opioid epidemic from the perspective of national statistics and surveys. But I want to close with a more up-close-and-personal look at the issue. During the summer of 2016, I read Gun, Needle, Spoon by Patrick O’Neil. Gun is a compelling look at the life of a “current heroin user.” Patrick has over fifteen years clean now, but gives you a clear-eyed, non-blinking look into the abyss of heroin addiction in his memoir. What follows are a couple of paragraphs of life in that nightmare. Read Gun, Needle, Spoon for more.

Technically, kicking heroin takes three days. Every junkie’s kick is slightly different, yet the symptoms are the same. For me it starts out with an unpleasant familiar taste in the back of my throat. My nose begins to run, I sneeze a lot, and my eyes water. Then the aches arrive, followed by vomiting and diarrhea. There’s no sleeping. I’m either cold and shivering or hot and continually sweating. My muscles cramp, my head feels thick, and all I think about is doing more dope in order to not be in such misery. . . .The digital clock on the desk in the living room read 11:55 PM. I light a cigarette and stare at the gun. Before I can really think about it, I pull on a pair of jeans and get dressed. Digging through a pile of dirty clothes, I find a black bandana and tie it loosely around my neck. I slip the gun into my waistband, button my overcoat, and quickly open the front door.

P.S. There is good new here. Patrick just wrote that he received a pardon from the governor of California for his past crimes. You can read about the day he received his pardon here. And take the time to congratulate him, will you?

01/31/17

Curiouser and Curiouser with Chantix

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In Lewis Carroll’s Alice in Wonderland, Alice famously said: “It would be so nice if something made sense for a change.” Since Carroll wrote this, many people have cited it to refer to one thing or another that puzzles them. I can now add my name to that list, as it does a spot-on job of expressing my thoughts on the recent FDA reversal in removing its black box warning for the smoking cessation drug Chantix.

On December 16, 2016, the FDA issued a drug safety announcement regaring Pfizer’s request that the black box warning be removed from Chantix. The FDA announcement said the decision was consistent with the recommendations of the September 2016 FDA Advisory Committee meeting. Essentially, their rationale was that the benefits of potential smoking cessation outweighed the health risks with Chantix. The conclusion of the committee was that an FDA ordered clinical trial (the EAGLES study) demonstrated “the risk of serious side effects on mood, behavior, or thinking [for Chantix] is lower than previously thought.” These side effects were what led to the black box warning (Given when there are serious or life-threatening risks when using the medication) on Chantix in the first place.

The risk of these mental health side effects is still present, especially in those currently being treated for mental illnesses such as depression, anxiety disorders, or schizophrenia, or who have been treated for mental illnesses in the past. However, most people who had these side effects did not have serious consequences such as hospitalization. The results of the trial confirm that the benefits of stopping smoking outweigh the risks of these medicines.

Notice the FDA is acknowledging the risks are still there and should be noted in the medication guide. However this assertion is debateable when evidence like that on the website RxISK in “Chantix and Violence” is considered. The cases there were originally reported in the FDA database for adverse drug events.

The results of the EAGLES study were published in the journal Lancet here. As Ed Silverman reported for STAT News, this action resulted in renewed efforts by Pfizer to have the black box warning removed. An earlier attempt in 2014 failed when an FDA panel voted to keep the warning intact. The chief medical officer for Pfizer thought removing the warning would more accurately reflect the neuropsychiatric safety profile for Chantix and allow patients and prescribers make informed decisions about treatment options. Despite the rhetoric here, the real reason was money:

The side effects have plagued the drug ever since it was approved a decade ago and endured horrendous publicity about violent or suicidal behavior. As a result, Pfizer spent hundreds of millions of dollars to settle numerous lawsuits and sales for the pill — once pegged to become a blockbuster — have plateaued, sliding from $846 million in 2008 to $671 million in 2015.

Alan Cassels, a pharmaceutical policy researcher at the University of Victoria, British Columbia, pointed out that the FDA action in December 2016 was unprecedented. Most of the drugs removed from the U.S. market over the past 20 years first carried a black box warning. Remember that according to the FDA, those risks ARE STILL PRESENT with Chantix, The EAGLES study concluded those risks are lower than previously reported and the FDA pragmatically agreed the potential benefit from Chantix outweighed the risks.

Not everyone on the FDA Advisory Committee that recommended the removal agreed. Of the 19 panel members, 10 voted to remove the black-box warning. Four wanted to see changes in the wording, while five others recommended the warning remain.

Thomas Moore, a senior scientist with the Institute for Safe Medication Practices, has also voiced concerns with the EAGLES trial itself, used by the FDA to justify removing the Chantix black-box warning. Critical of the study’s design, Moore and the ISMP thought the trial “was greatly underpowered, used a novel, unvalidated measurement scale, required subjective judgements from study investigators, and detected no meaningful differences among eight treatment arms because of a defective design.”

The ISMP letter to the FDA indicated Chantix (varenicline) was suspected to be the primary drug in 17,900 serious injuries from psychiatric adverse events reported to the FDA, 43% of which were done by health professionals. The cases described a series of behaviors ranging from suicidal and homicidal thoughts to delusions, suicidal behavior and bizarre and reckless aggression. These effects were documented in peer-reviewed studies. And Pfizer paid around $300 million in compensation—to over 2,500 varceline victims—for serious injuries that occurred BEFORE the boxed warning was required.

Moore and ISMP were not alone in expressing concern with the EAGLES trial.  Ed Silverman of STAT reported that Sammy Almashat of Public Citizen pointed out how the study had composite outcomes of both serious and milder symptoms, such as irritability and agitation, that normally occur when people are trying to quite smoking. Almashat was concerned with the precedent in this reversal; black box warnings are usually not reversed, especially on such equivocal evidence.

This could set an ominous precedent. If the FDA rescinds, a company can now go to the agency with a substandard post-marketing trial, point to Chantix and demand the same outcome. We’re worried that if the FDA follows through with the recommendation, that this will become a new standard for removing a black box.

The concluding statement from the ISMP letter may be a forewarning of what is to come:

An ambiguous warning can be worse than no warning at all because not only does it render the warning ineffective, it undermines the value of all warnings and the credibility of the FDA. A clear warning does not restrict the access of any patient or physician to this treatment.

“Curiouser and Curiouser,” as Alice would say if she heard about the back-and-forth actions by the FDA. There is more on this topic in another article, “Chantix Tug-of-War.”

01/20/17

Marijuana Use and the Heart

© Andrija Markovic | 123rf.com

Research was presented in November of 2016 at the American Heart Association’s Scientific Sessions that connected marijuana use and a heart muscle problem that can mimic the symptoms of a heart attack. “Stress cardiomyopathy is a sudden, usually temporary, weakening of the heart muscle that reduces the heart’s ability to pump, leading to chest pain, shortness of breath, dizziness and sometimes fainting.” Younger marijuana male users were twice as likely as non-users to experience this heart condition, which usually occurs in older women. They were also significantly more likely to go into cardiac arrest and need an implanted defibrillator to detect and correct the dangerously abnormal heart rhythms.

None of the people in the study who had used marijuana died after they were admitted to the hospital; so this study did not link marijuana use to sudden death. But some reports, discussed below, do report such a link. Nevertheless, one of the study’s co-authors said the link between smoking marijuana and stress cardiomyopathy in younger patients suggests the need for further investigation, especially with the growing legalization of recreational and medical marijuana in the U.S. “If you are using marijuana and develop symptoms such as chest pain and shortness of breath, you should be evaluated by a healthcare provider to make sure you aren’t having stress cardiomyopathy or another heart problem.” See the article on Live Science and the press release from the American Heart Association for more information.

The above heart condition is a rare occurrence, as is sudden cardiac death with marijuana use, but the incidence rate is not zero. Thomas, Kloner and Rezkalla published an article in the January 2014 issue of The American Journal of Cardiology describing a series of marijuana-related heart problems. Thomas et al. noted that published reports describe a temporal relationship between marijuana use and developing heart problems such as: acute myocardial infarction (a heart attack), cardiomyopathy, and sudden cardiac death. Careful evaluation of the cardiovascular effects of marijuana are complicated by the fact that it is often combined with other drugs, such as alcohol or tobacco.

The mechanism underlying the association between marijuana use and myocardial infarction is currently unknown. But it seems possible cannabis has a negative effect on coronary microcirculation. One reviewed report demonstrated how marijuana use made a 34-year-old man susceptible to ventricular tachycardia. After he stopped his marijuana use, his coronary flow returned to normal. A 2010 case study by Karabulut and Cakmak in Kardiologia Polska documented the existence of slow coronary flow in an individual who consumed marijuana regularly over a long period of time.

In “Triggering Myocardial Infarction by Marijuana,” Mittleman et al. interviewed 3,882 individuals an average of four days after the onset of myocardial infarction. The risk of myocardial infarction was 4.8 times higher in the sixty minutes after marijuana use. The risk rapidly decreased afterwards. They were less likely to have a history of angina or hypertension. Showing the presence of the above noted complicating factors, they also tended to be current cigarette smokers and obese.

Thomas, Kloner and Rezkalla noted where most case reports described relatively young patients in their 20s or 30s with normal coronary arteries or minimal atherosclerosis. This suggested that marijuana does not lead to or accelerate atherosclerotic damage in healthy adults and might explain the rarity of reports of marijuana-associated myocardial infarction despite the widespread use of the drug.

Marijuana use may also precipitate the development of myocardial infarction in patients with coronary artery disease. After myocardial infarction, mortality is signiifcantly higher in marijuana users than in the general population. In a study of 1,913 adults after hospitalization for myocardial infarction, Mukamal et al found a 4.2-fold increased risk for mortality in marijuana users who reported consuming the drug more than once per week before the onset of the infarction compared with nonusers.

Reports of marijuana use and sudden death are rarer than those of myocardial infarction, but nevertheless still evident. Most patients were abusing other drugs along with marijuana, precluding an accurate conclusion about the role played by marijuana in the cause of death. Yet there was a case report in the December 2001 issues of Forensic Science International by Bachs and Morland, “Acute cardiovascular fatalities following cannabis use,” of six possible cases of acute cardiovascular death in young adults, who had very recent cannabis use. This was confirmed by the presence of THC in post mortem blood samples; no other drugs were present. The article abstract noted where similar cases have been reported, but the toxicology reports were absent or limited to just urine samples.

The authors also speculated on the underlying mechanisms to these adverse effects. They acknowledged that currently relatively little is known about the underlying mechanisms at this point in time. Yet they noted several features of marijuana use that may explain the potential for an adverse effect on patients with known coronary artery disease. For example, marijuana is known to increase heart rate.

Supporting these findings, the American College of Cardiology described the following effects of marijuana on the cardiovascular system. In “Marijuana and Coronary Heart Disease,” the cardiovascular effects of marijuana included: elevated systolic and diastolic blood pressure, tachycardia,elevated sympathetic stimulation, decreased time to angina, increased risk of myocardial infarction for one hour after marijuana use.

A 2006 study based on data from The Coronary Artery Risk Development in Young Adults (CARDIA) study showed that marijuana use was associated with increased appetite, high caloric diet, and acute increase in blood pressure. “Although marijuana was not independently associated with cardiovascular risk factors, it was associated with other unhealthy behaviors … which all have long-term detrimental effects on health.”

There seems to be a consensus with the following remarks by Thomas, Kloner and Rezkalla to cardiologists and their patients alike:

In conclusion, the potential for increased use of marijuana in the changing legal landscape suggests the need for the community to intensify research regarding the safety of marijuana use and for cardiologists to maintain an awareness of the potential for adverse effects.