05/7/19

Psychedelic Renaissance?

Spravato (esketamine), a chemical cousin of ketamine (Special K), was recently approved by the FDA as a fast-acting antidepressant. MDMA is now in a Phase 3 clinical trial for PTSD. Psilocybin has received a breakthrough therapy designation for treatment-resistant depression by the FDA. Clinical research into the therapeutic effects of psychedelics has resumed for a variety of conditions, including depression, substance abuse and individuals living with serious medical conditions like cancer. This has led to calls for increasing the availability of psychedelics by loosening the regulatory restrictions that currently limit the drugs’ use for research.

In his book, How to Change Your Mind, Michael Pollan said beginning in the 1990s, a small group of scientists, psychotherapists and so-called “psychonauts,” have sought to resurrect what they saw as a wrongful termination of research into the therapeutic value of psychedelics. “A new generation of scientists, many of them inspired by their own personal experience of the compounds, are testing their potential to heal mental illnesses such as depression, anxiety, trauma and addiction.” Others are using psychedelics in conjunction with brain-imaging technology to explore the links between brain and mind. “The hoary 1960s platitude that psychedelics offered a key to understanding—and ‘expanding’—consciousness no longer looks quite so preposterous.”

Psychedelics are currently classified as Schedule I controlled substances, meaning they have a high abuse potential; no accepted medical use; and have safety concerns, even under medical supervision. Some advocates are calling the DEA to place them into Schedule III, along with ketamine, anabolic steroids and buprenorphine. Writing for Scientific American, Rick Strassman described his own research with DMT in the 1990s. One of the most difficult impediments he faced was DMT being Schedule I.

After nearly two years of close work with FDA and DEA, an effective system developed allowing our studies to proceed. My subsequent applications to use psilocybin and LSD were much more quickly and easily approved. The New Mexico project’s success established the current American regulatory framework that has allowed for the current burgeoning of human studies with psychedelics.

Psychedelics have unique characteristics that make it difficult to fit them into the criteria used to define schedule placement. “Their safety and efficacy exist only within highly structured specialized treatment settings.” Outside of that structure, psychedelics retain their ability for abuse and are capable of debilitating, psychological damage. “How one understands the psychedelic drug state determines the assessment of risks and benefits, and thus drives recommendations for rescheduling.” William Richards, the clinical director for the John Hopkins University psychedelics research program, publicly advocates for the increased availability of the drugs, referring to their ‘inherent spirituality’ in lectures and talks.

Glorifying psychedelics’ benefits and rendering innocuous their adverse effects therefore may explain the Hopkins group’s recent publication of a paper suggesting rescheduling psychedelics into Schedule IV—the most liberal recommendation yet to appear.

Strassman suggested a new category—IA—that would acknowledge psychedelics’ abuse potential, while allowing for their use. “The security requirements established by the DEA for possession of psychedelics for clinical research—background checks of those handling the drugs, secure storage, regular inventory, etc.—would be the same as for Schedule I substances.” Significantly, only those with specialized training would be permitted to administer psychedelics to humans. With such a regulatory structure in place, He thought the clinical promise of psychedelic drugs could be realized without exposing patients to unnecessary risk. “It would also ensure that we maintain scientific rigor, intellectual honesty and high ethical standards as we continue investigating how these drugs produce their fascinating effects.”

One study published in the Journal of Psychopharmacology did produce some interesting effects with psilocybin. Two randomized controlled trials with late-stage cancer patients suggested that a single, high dose of psilocybin had “clinically significant and long-lasting effects on mood and anxiety.” There were no serious adverse events; no participants abused psilocybin; no cases of prolonged psychosis or hallucination. “No participants required hospitalization.”

Single moderate-dose psilocybin, in conjunction with psychotherapy, produced rapid, robust, and sustained clinical benefits in terms of reduction of anxiety and depression in patients with life-threatening cancer. This pharmacological finding is novel in psychiatry in terms of a single dose of a medication leading to immediate anti-depressant and anxiolytic effects with enduring (e.g. weeks to months) clinical benefits. Even though it is not possible to attribute causality of the experimental drug (in terms of sustained clinical benefit) after the crossover, the post-crossover data analyses of the two dosing sequences suggest that the clinical benefits, in terms of reduction of cancer-related anxiety and depression, of single-dose psilocybin (in conjunction with psychotherapy) may be sustained for longer than 7 weeks post-dosing, and that they may endure for as long as 8 months post-psilocybin dosing. The acute and sustained anti-depressant effects of psilocybin in this trial are consistent with a recently published open-label study of oral psilocybin treatment in patients with treatment-resistant depression (TRD) in which psilocybin (25 mg) was associated with 1 week and 3 months post-psilocybin anti-depressant effects.

Reflecting on the results of the study, Stephen Ross, MD, the director of Substance Abuse Services at the Langone Medical Center, said it possibly provides a new model in psychiatry. “This is potentially earth shattering and a big paradigm shift within psychiatry.” David Nutt, MD, PhD, of the Imperial College London said the studies were the “most rigorous controlled studies to date” using psilocybin. Others urged caution applying and interpreting the results. Jeffrey Lieberman, MD, from Columbia University said:

[W]e cannot tell if the anxiolytic and antidepressant effects of the drugs are direct results of their serotonergic effects or secondary to the mystical altered state of consciousness that they produce. Since other serotonergic agonists (eg, lisuride) do not produce this psychedelic experience it has been suggested that psychedelic drugs must bind to the 5-HT2A receptors in a special way or exhibit functional selectivity or receptor bias.”

A study of the abuse potential for psilocybin confirmed low abuse and no physical dependence potential. The study used all 8 factors required to guide the FDA and DEA recommendations for the Controlled Substance Act (CSA). They suggested placement as a Schedule IV Controlled substance. There was “no clear evidence of physical dependence and withdrawal in preclinical or clinical studies, or among those who chronically used illicit products.” The authors said the lack of therapeutic and mechanistic studies of psilocybin and other psychedelics stems from the lack of federal funding for the research and the barriers imposed by a Schedule I classification, not a lack of interest among researchers.

While some psychedelics like psilocybin may be viable therapeutic options, there simply isn’t enough modern controlled trials. James Rucker, MD, MRCPsych, PhD, of the King’s College London Institute of Psychiatry, said: “Psychedelics deserve to be investigated in modern, controlled trials if we are to know whether they are useful treatments in psychiatry, or not . . . At the moment there isn’t enough high-quality evidence to make that judgment.”

The biggest barrier to their wider use likely stems from the lack of research. Buy there are additional obstacles in doing the research. Most pharmaceutical companies aren’t interested because of the legal obstacles with Schedule I substances and because it’s not profitable to develop treatments with these drugs. The FDA approval of esketamine as a new molecular entity (NME) is the exception. Another problem is the impossibility of using a placebo control or blinding because of the identifiable effects from psychedelics. Finally, there is the challenge of obtaining sources of psilocybin that meet the standards required for the clinical trials. Rucker said:

I think everyone in this field is interested in one thing — that psychedelics get a fair hearing by Western medicine by undergoing well-funded, well-designed controlled trials . . . Then we will know whether they have any benefit, and we can judge whether this benefit is suitably balanced against any harm they might do. Until then we won’t know, and that is a worse state of affairs than knowing.

Benjamin Bell, from John Hopkins University, wrote “The psychedelic renaissance is here.” He is a proponent of psychedelic medicine, and gave a clearly biased history of how research into psychedelics was “turned off,” after Timothy Leary made the phrase “turn on, tune in, drop out” famous. “Researchers in the field are posed at the precipice of progressing forward with revolutionary studies and may conscientiously move our culture forward with them. But moving the culture will require awareness and action from scientists and citizens.” Researchers believing that psychedelics are important and useful need to recognize how that faith is a double-edged sword “and we must remain truly willing to reconsider beliefs in light of new evidence, or it will be impossible to convince the broader public to do the same.”

Researchers have the opportunity and responsibility to properly communicate their findings and recommendations to the public. He thought this was vital if psychedelics were to be integrated into medical use within the wider culture. Meaningfully, he then said: “It is important to remember psychedelics are not the ultimate panacea for treating mental health concerns.” With time and reams of further research, they may become invaluable components of the medical and mental health toolkit. If the research is carefully and systematically done, I’d cautiously agree.

Let’s not repeat the mistake made with marijuana—failing to reschedule it so research into its risks and benefits is easier to do. The science—not the rhetoric—should be the deciding factor in the medicalization and the legalization of psychedelic substances. Rescheduling psychedelics as suggested by Rick Strassman seems reasonable and would permit the researchers holding back from doing psychedelic research to forge ahead. Some psychedelics, like psilocybin, appear to have potential while ketamine and the ketamine knockoff Spravato increasingly ring alarm bells for me because of their abuse potential and the quickness with which their effects seem to fade. For more information on ketamine and esketamine, see: “Hype and Concern with Esketamine” and “Is Ketamine Really Safe & Non-Toxic?”

01/2/18

What is the Future for Kratom?

Kratom is back in the news as the FDA issued a public health advisory related to mounting concerns regarding the risks associated with its use. The FDA Statement from Scott Gottlieb about kratom singled out its use to treat opioid withdrawal as a particular concern. Gottlieb said: “There is no reliable evidence to support the use of kratom as a treatment for opioid use disorder.” Individuals who use kratom are playing doctor, as there are no dependable instructions for its use and there is no consultation with a healthcare professional about the product’s dangers, adverse effects or interactions with other drugs. “There’s clear data on the increasing harms associated with kratom.”

Calls to U.S. poison control centers about kratom increased 10-fold from 2010 to 2015. There are reports of 36 deaths from kratom or kratom-containing products, according to the advisory. Not surprisingly, given the opioid cocktails appearing on the streets, kratom has been reportedly laced with various opioids. “The use of kratom is also associated with serious side effects like seizures, liver damage and withdrawal symptoms.” There are no currently FDA-approved therapeutic uses of kratom.

Before it can be legally marketed for therapeutic uses in the U.S., kratom’s risks and benefits must be evaluated as part of the regulatory process for drugs that Congress has entrusted the FDA with. Moreover, Congress has also established a specific set of review protocols for scheduling decisions concerning substances like kratom. This is especially relevant given the public’s perception that it can be a safe alternative to prescription opioids.

Gottlieb pointed out that kratom is already a controlled substance in 16 countries, “including two of its native countries of origin, Thailand and Malaysia.” Australia, Sweden and Germany are among the other countries listing kratom as a controlled substance. Several states have banned kratom: Alabama, Arkansas, Indiana, Tennessee, Vermont and Wisconsin. Several others, Florida, Georgia, New York, North Carolina and Oregon have pending legislation to ban it. Gottlieb encouraged supporters to conduct the research that will help to better understand kratom’s risk and benefit profile. “In the meantime, based on the weight of the evidence, the FDA will continue to take action on these products in order to protect public health.”

In response to the FDA advisory on kratom, The American Kratom Association (AKA) has asked the FDA to “review and correct” it. It claimed the advisory was based on “discredited, incomplete, and mischaracterized scientific claims” and as a result, it should be rescinded. Medscape reported the AKA has filed a formal dispute resolution petition with the Department of Health and Human Services challenging what it claimed was the “weak scientific basis” of the FDA advisory.

For years, the FDA has published scientifically inaccurate information on the health effects of consuming kratom, directly influencing regulatory actions by the DEA [Drug Enforcement Administration], states, and various local government entities. AKA believes the FDA health advisory on kratom will lead to more state and local bans, all based on discredited, incomplete, and mischaracterized scientific claims.

The AKA disputed the FDA claim that kratom has opioid-like abuse potential, arguing it is primarily used because it is beneficial, and not as a means to get high. The organization also downplays the overdose risk with kratom, saying: “The handful of possible kratom-associated deaths in the US involved people taking multiple drugs, with apparent causes of death varying widely, quite unlike what is seen with narcotic-like opioids.” Reversing the FDA concern that unrestricted kratom use could increase the opioid crisis, the AKA claimed the ban would increase it. The AKA claimed kratom consumers are afraid they will be forced to seek out illegal opioids if kratom was banned. “It would be an outrageous and unacceptable public health outcome if the effect of the FDA assault on kratom backfires and leads to more opioid addiction and death.”

Despite the claims by the AKA, the FDA public health advisory does not seem ill advised. A CDC Morbidity and Mortality Report in 2016 described a study of U.S. poison centers between 2010 and 2015. During the study poison centers received 660 calls about reported exposure to kratom. The number of calls increased tenfold, from 26 in 2010 to 263 in 2015. See the figure below.

Among the calls, 90.2% reported ingestion of the drug. Isolated exposure, use of kratom alone, was reported by 64.8% of cases. “Among calls reporting use of kratom in combination with other substances (multiple exposures), the most commonly reported other substances were ethanol, other botanicals, benzodiazepines, narcotics, and acetaminophen.”

Medical outcomes associated with kratom exposure were reported as minor (minimal signs or symptoms, which resolved rapidly with no residual disability) for 162 (24.5%) exposures, moderate (non-life threatening, with no residual disability, but requiring some form of treatment) for 275 (41.7%) exposures, and major (life-threatening signs or symptoms, with some residual disability) for 49 (7.4%) exposures.

There was one death reported in the CDC Report, but the person had also ingested paroxetine (Paxil) and lamotrigine (Lamictal) in addition to the kratom. While the FDA advisory said it was aware of 36 deaths associated with kratom products, it did not provide further information. The August 2016 DEA announcement to schedule kratom, which was later rescinded, said the DEA was aware of 15 kratom-related deaths between 2014 and 2016; but again did not provide any further information.

An article in BioMed Research International, “Following ‘the Roots’ of Kratom” described several short term adverse effects from kratom, including nausea, constipation, sleep problems, itching, sweating, erectile dysfunction. Long-term adverse effects include: anorexia, dry mouth, darker skin and hair loss. Withdrawal symptoms can include: hostility, aggression, muscle and bone aches, jerky limb movements, anorexia and weight loss, and insomnia. Kratom could be a deadly substance when mixed with other compounds. Multiple fatalities with a kratom product known as “Krypton” have been reported. See “Following ‘the Roots’ of Kratom,” for more particulars on the reported deaths. For more information on Krypton, see “Krypton Can Kill You.”

Table 1 of the article listed several substances found mixed with kratom in fatalities, including antidepressants, a mood stabilizer and a hypnotic sleep aide: O-desmethyltramadol (a metabolite of tramadol); propylhexedrine (an analog of methampheamine); over-the-counter cold medications and benzodiazepines; venlafaxine (Effexor), diphenhydramine (Benadryl), and mirtazapine (Remeron); zopiclone (Zopiclone), citalopram (Celexa), and lamotrigine (Lamictal).

According to preclinical data and case reports published in scientific literature as well as anecdotal experiences posted online, kratom is not a safe drug. Its consumption is associated per se with drug dependency, development of withdrawal symptoms, craving, serious adverse effects, and life-threatening effects, especially in a multidrug-intoxicating scenario.

Another article in the International Journal of Legal Medicine, “The Pharmacology and Toxicology of Kratom,” said there was growing international concern for the kratom’s effects and safety due to “an increase in hospital visits and deaths in several countries that are said to have been caused by extracts of the plant.” The abuse potential of kratom “requires careful evaluation of its benefits and potential toxicities.”

So what is next with kratom? When the DEA reversed its decision to temporarily classify kratom as a Schedule I Controlled Substance in October of 2016, it said it would solicit public comments (which it did) and review the FDA’s “scientific and medical evaluation” of the proposed scheduling. The FDA public health advisory for kratom indicates the agency concluded there was cause for concern in keeping it unregulated. I’d guess that further action by the DEA to schedule kratom will be delayed, pending the outcome of the AKA’s suit against the FDA.

Gottlieb’s public encouragement of research into kratom’s possible use as a therapy for “a range of disorders” may suggest room for a scheduling of kratom other than as a Schedule I Controlled Substance. If kratom were to be placed even temporarily as a Schedule I controlled Substance, further research into its potential medical benefits would be difficult to conduct. Funding for kratom research is also hard to come by. Obtaining kratom of the quality needed for research is difficult as well. A researcher referred to the FDA requirements to develop a clinical trial for kratom as a “bureaucratic nightmare.” Edward Boyle, a kratom researcher, said: “Is it an effective treatment for opioid withdrawal, or is it another pathway to addiction? I don’t think anybody has a defined concept of where it actually lies on that continuum.”

See “The Secret of Kratom” and “Kratom: Part of the Problem or a Solution?” for more information on kratom.

12/15/17

Head of a Snake

As a result of a Washington Post and “60 Minutes” investigation, Representative Tom Marino withdrew his name from consideration for the position of “drug czar,” Director of National Drug Policy. As the investigation showed, Marino had been the primary force behind what became the “Ensuring Patient Access and Effective Drug Enforcement Act of 2016.” Marino spent several years trying to get the legislation through Congress, and was finally successful when Senator Orin Hatch negotiated a final version of the bill with the DEA. What wasn’t readily apparent by the title of the bill—and sunk Marino’s chances of approval as the new drug czar—was that instead of ensuring effective drug enforcement, it hobbled the DEA’s ability to go after the drug companies suspected of enabling the widespread distribution of prescription pain medication.

The law was the crowning achievement of a multifaceted campaign by the drug industry to weaken aggressive DEA enforcement efforts against drug distribution companies that were supplying corrupt doctors and pharmacists who peddled narcotics to the black market. The industry worked behind the scenes with lobbyists and key members of Congress, pouring more than a million dollars into their election campaigns.

The DEA had opposed the legislation for years, but was finally outmaneuvered by the nation’s major drug distributors and a few members of Congress. The new law made it effectively impossible for the DEA to stop suspicious narcotic shipments from the companies. Despite being fined, some drug distributors had repeatedly ignored warnings from the DEA to shut down suspicious sales. “Overall, the drug industry spent $102 million lobbying Congress on the bill and other legislation between 2014 and 2016, according to lobbying reports.” Through various political action committees, the drug industry contributed over $1.5 million dollars to the 23 lawmakers who sponsored or co-sponsored four versions of the bill. Marino received $100,000; Hatch $177,000. See the following chart from the Washington Post article.

The drug industry, the manufacturers, wholesalers, distributors and chain drugstores, have an influence over Congress that has never been seen before,” said Joseph T. Rannazzisi, who ran the DEA’s division responsible for regulating the drug industry and led a decade-long campaign of aggressive enforcement until he was forced out of the agency in 2015. “I mean, to get Congress to pass a bill to protect their interests in the height of an opioid epidemic just shows me how much influence they have.

Besides the sponsors and co-sponsors, few lawmakers knew what the impact of the bill would really be. Apparently, the same was true for the White House as President Obama signed it into law without any comment. “It sailed through congress and was passed by unanimous consent, a parliamentary procedure reserved for bills considered to be noncontroversial.” Michael Botticelli, who was the drug czar at the time, said neither the DEA nor the Justice Department objected to the bill at the time, which removed a major obstacle to the president’s approval. All this suggests there was some serious behinds-the-scene maneuvering going on. “Neither the DEA nor the Justice Department informed OMB about the policy change in the bill.”

The DEA’s top official at the time, Chuck Rosenberg, declined repeated requests for interviews by the Washington Post and “60 Minutes”; as did Loretta Lynch, then the attorney general and Tom Marino. A spokesperson for former President Obama referred reporters to Botticelli’s statement. Additionally, the DEA and Justice Department repeatedly denied or delayed over a dozen requests filed by the Washington Post and “60 Minutes” under the Freedom of Information Act for public records that could give additional information on what happened. “Some of those requests have been pending for nearly 18 months.”

Another key player in the “Ensuring Patient Access and Effective Drug Enforcement Act of 2016” was a former associate chief counsel for the DEA, D. Lindon Barber. While working for the DEA, he helped design and implement the early phases of the agency’s enforcement campaign against drug companies that were failing to report suspicious orders of opioids. Barber was also one of dozens of DEA officials recruited by the drug industry over the past decade. He brought first hand knowledge of the DEA’s strategy and how it could be countered when he went over to the drug industry in 2011. According to an internal Department of Justice email, Barber has a central role in crafting early versions of the legislation. “’He wrote the Marino bill,’ the official wrote in 2014.”

With a few words, the new law changed four decades of DEA practice. Previously, the DEA could freeze drug shipments that posed an “imminent danger” to the community, giving the agency broad authority. Now, the DEA must demonstrate that a company’s actions represent “a substantial likelihood of an immediate threat,” a much higher bar. “There’s no way that we could meet that burden, the determination that those drugs are going to be an immediate threat, because immediate, by definition, means right now,” Rannazzisi said.Today, Rannazzisi is a consultant for a team of lawyers suing the opioid industry. Separately, 41 state attorneys general have banded together to investigate the industry. Hundreds of counties, cities and towns also are suing.“This is an industry that’s out of control. If they don’t follow the law in drug supply, and diversion occurs, people die. That’s just it, people die,” he said. “And what they’re saying is, ‘The heck with your compliance. We’ll just get the law changed.’”

Sadly, the limitations placed upon the DEA by the “Ensuring Patient Access and Effective Drug Enforcement Act of 2016” were reported by the LA Times soon after the law was passed in 2016, but no consequences occurred until the Washington Post and “60 Minutes” investigation led to Marino withdrawing his name for the position of drug czar. The LA Times noted how the law was backed by some of the same wholesalers, manufacturers and pharmacy chains targeted by the DEA for not doing enough to monitor and restrict the overflow of pills. The stalled legislation also moved through Congress after the resignation of Joseph Rannazzisi from the DEA in October of 2015. He left, in part, because of his view that the bill was “misguided and would worsen the epidemic.” He said: “They are taking the word of industry rather than the government’s expert in diversion control.”

In 2012 the DEA took action against a major national wholesaler of pharmaceuticals and medical products, Cardinal Health, Inc. Data had shown enough pain medication was supplied to two CVS pharmacies in Sanford FLA for every person in the small city to have 59 doses. The DEA accused Cardinal and CVS of failing to maintain “effective controls” against diversion. “Cardinal was banned from shipping prescription drugs from a Florida facility for two years and CVS paid a $22-million settlement.” Note that CVS lobbying expenditures above were $32.5 million, second only to PHRMA, a trade group representing companies in the pharmaceutical industry.

The above are only the most notable and recent actions of the venomous pharmaceutical lobby. The Milwaukee Journal Sentinel published a two-part article on how drug makers work behind the scenes fighting against measures aimed at fighting the tide of prescription painkillers flooding our nation. Part 1 said there is a state level strategy where “hundreds of lobbyists and millions of dollars in campaign contributions” are used to weaken or kill measures aimed at turning back the opioid epidemic. The Associated Press and the Center for Public Integrity found they often use funded advocacy groups to fight limits of drugs such as OxyContin, Vicodin and fentanyl.

Between 2006 and 2015, drug makers spent more than $880 million nationwide on lobbying and campaign contributions — more than 200 times what those advocating for stricter policies spent. For comparison, it’s also more than eight times what the formidable gun lobby recorded for advancing its agenda through similar activities during that same period.

There have been hundreds of opioid-related bills introduced at the state level over the past few years. The few groups fighting for tighter prescription restrictions are primarily grass roots organizations formed by family and friends of individuals killed by opioids. “Together, they spent about $4 million nationwide at the state and federal level on political contributions and lobbying from 2006 through 2015 and employed an average of eight state lobbyists each year.” Compared to estimated lobbying of drug companies, they are being outspent 220 to one.

Part 2 of the Journal Sentinel article highlighted the efforts of a little-known group called the Pain Care Forum. The organization has worked at both the national and state level to communicate the message of the vital role played by painkillers in the lives of millions of Americans. The Pain Care Forum is a loose coalition of drug-makers, trade groups and nonprofits supported by industry funding. A 2012 Pain Care Forum “Meetings Schedule” listed about 64 participating organizations, a mix of medical organizations, advocacy groups and pharmaceutical companies. Among the pharmaceutical companies were: Abbott Laboratories, Allergan, Eli Lily & Company, Endo Pharmaceuticals, Johnson & Johnson, Merck, Purdue Pharma LP, and Teva.

From 2006 through 2015, participants in the Pain Care Forum spent more than $740 million lobbying in the nation’s capital and in all 50 statehouses on an array of issues, including opioid-related measures, according to an analysis of lobbying filings by the Center for Public Integrity and the AP.The same organizations reinforced their influence with more than $140 million doled out to political campaigns, including more than $75 million alone to federal candidates, political action committees and parties.

Purdue’s Washington lobbyist co-founded the Pain Care Forum and coordinates the group’s meetings. The Pain Care Forum doesn’t have an online presence or a physical address, yet it hosts high-ranking officials from the White House, the FDA and other agencies at its monthly gatherings. While Forum members maintain it does not take policy positions, the AP and Center for Public Integrity have shown where the group’s participants worked together “to push and draft federal legislation, blunt regulations and influence decisions around opioids.” A major talking point is the false assumption of a conflict between reducing our dependence on opioids and improving care for patients with pain. “It’s an artificial conflict, but there are lots of vested interests behind it.”

Tom Marino will not be the new “drug czar,” and hopefully the media attention recently received by “Ensuring Patient Access and Effective Drug Enforcement Act of 2016” will result in Congress restoring the enforcement power to the DEA that the legislation removed. But since some legislators have been seduced by pharmaceutical money and influence, Congress may not have the collective will to resist the lobbying influence of Pharma companies. Therein lies the problem: how can you cut off the head of a snake if you depend on the snakes?

11/10/17

Here’s Some Gray Death

The fact-checking website Snopes looked into a report from Indiana claiming there is a new and dangerous drug called “Gray Death.” The report claimed Gray Death could cause the overdose or death of a drug user if it was accidentally inhaled after it became airborne or if it was absorbed through the skin after contact. Their investigation found the report was true. A local Indiana TV station, WDRB, was the source for the Snopes investigation, saying the Indiana Department of Homeland Security announced Gray Death was found in the Hoosier state beginning in May of 2017. But it seems Indiana was late to the Gray Death party.

Gray Death is a drug cocktail of heroin, fentanyl, carfentanl, and often U-47700 known on the street as “Pink” or “U4.” Heroin is two to three times as powerful as morphine. Fentanyl is about 50 to 100 times more powerful than heroin. Carfentil is about 100 times more powerful than fentanyl. U4 is the weakest drug in the mix after heroin, at only 7. 5 times the strength of morphine. The drug cocktail looks like concrete mix, thus the nickname of gray death.

Russ Baer of the DEA told NBC News on May 5, 2017 that Gray Death was initially limited to the Gulf Coast and states like Georgia and the mid-West state of Ohio. But it’s also been spotted in places like Chicago, San Diego, and Lexington. A “Pink”-free precursor to Gray Death was spotted in the Atlanta area back in 2012. “We are more routinely seeing deadly cocktails of heroin, fentanyl, various fentanyl-class substances, along with combinations of other controlled substances of varying potencies including cocaine, methamphetamine, and THC. . . . No one should underestimate the deadly nature associated with these cocktails.”

CNN noted that not only do the ingredients of Gray Death vary from sample to sample, some are present in such low concentrations (because of their strength) they may not show up on tests. Donna Ula, director of forensic chemistry at a biochemical company working with state and federal officials to identify unknown street drugs, said “It’s going to constantly vary, and it’s going to keep the chemists and the medical examiners on their toes.” She said Gray Death is “a fast-track route to the morgue.” A forensic chemist with the Georgia Bureau of investigation said even its gray color is a mysterious. “Nothing in and of itself should be that color.”

There have been several overdoses and overdose-related deaths in Georgia and Alabama linked to Gray Death. The Georgia Bureau of Investigation issued a public safety alert on May 4, 2017 about illegal synthetic opioids (Gray Death). The GBI Crime Lab has received about 50 cases of suspected Gray Death this year. Many contain three or four different opioids. One Metro-Atlanta law enforcement agency seized around 8 kilograms of a substance that when field-tested, didn’t identify what the mixture was. Further analysis at the GBI Lab found furanyl fentanyl and U-47700, two of the opioids regularly found in the Georgia Gray Death cocktail.

On May 10, 2017 The Morning Call reported there is Gray Death in the Lehigh Valley of Pennsylvania. After making two undercover drug buys at a woman’s home in Bethlehem PA, investigators had the drug packets tested because of their off-white color. They suspected they might contain fentanyl. But the preliminary results showed the packets contained a mixture of heroin, fentanyl and U4—Gray Death. After the preliminary identification, a search warrant was quickly issued: “We wanted to get it off the street as fast as possible.”

The woman’s three children, between the ages of 3 and 9, were living in the home with their mother. Police found some of the drug in a cup sitting on the shelf of a kitchen cabinet” within east reach of the children. The woman was arrested and charged with endangering the welfare of children, drug possession and possession of drug paraphernalia. She was freed after posting $5,000 bail. No word was reported on the children, but they were likely not in their mother’s custody given her charges.

According to Healthline News, the combination of synthetic opioids and/or heroin making up Gray Death varies widely. Given that the drugs or their precursors are created in unregulated labs, domestic drug dealers don’t always know how strong a batch is. “The potency can change from one batch to the next.” Dr. Seonaid Nolan, a clinical scientist in addiction medication at the University of British Columbia said: “Because it’s so potent, a small misstep in the preparation of the drug can lead to lethal consequences.”

This high potency also means it’s more difficult for customs and law enforcement to make searches and seizures, as it allows the drug syndicates to ship less physical product across the border. Sometimes the drugs are even shipped directly through the postal system. “Drug traffickers can move a high quantity or high volume of the product in a fairly small package.”

Traditional opiates like heroin are derived from the poppy plant, meaning the poppy plants have to be grown, harvested and then processed before heroin can be manufactured. “However, synthetic opioids can be produced entirely from chemical precursors.” This makes their production much simpler than heroin, since the entire manufacturing process can be done in a lab.

Fentanyl and its analogues have a high lipid solubility, meaning they readily pass through fatty tissues in the body. So fentanyl is used in transdermal patches and even lollipops, allowing it to enter the blood stream without having to be digested in the stomach. Since it doesn’t get metabolized, you need smaller amounts of fentanyl because it can go directly to the brain through the blood system. This also explains its danger if it becomes airborne or comes in contact with exposed skin. Edward Bilsky, a professor of Biomedical Sciences at Pacific Northwest University said:

[These drugs] are very fast acting and produce profound depression of respiration and other central nervous system functions leading to many deaths. . . . First responders and others around the victim need to be careful due to secondary exposure.

According to the DEA, fentanyl analogs, like acetyl fentanyl and furanyl fentanyl are manufactured in China by clandestine labs, and then smuggled into the U.S. through established drug smuggling routes in Mexico. Mexican drug traffickers also manufacture their own analogs of fentanyl. In the past, the Chinese government denied they were the source of illicit fentanyl being smuggled into the U.S. But DEA officials and others met with Chinese officials in 2016, which prompted China to regulate four fentanyl-related substances in an effort to help stem the flow of these opioids into the U.S. in action that went into effect in March of 2017.

Carfentanil was one of these substances. Because of its off-the-charts strength, it was receiving a lot of press coverage in 2016. See “Fentanyl: Fraud and Fatality” and “The Devil in Ohio.” But unless you followed news on the death of Prince, you may not have heard of “Pink” (U-47700 or U4) before. In addition to fentanyl and Percocet (oxycodone-acetaminophen), Pink was found in his system. In November of 2016, the DEA temporarily classified U-47700 as a Schedule I controlled substance, due to its “immanent threat to public health and safety.” The DEA received at least 46 confirmed reports of deaths associated with U-47700—31 in the state of New York and 10 in North Carolina. “This scheduling action will last for 24 months, with a possible 12-month extension if DEA needs more data to determine whether it should be permanently scheduled.”

In addition to Georgia, Pennsylvania and Ohio, drug busts in multiple states are reporting they have seized quantities of Grey Death. Traffic stops in Greenville County South Carolina found 17 pounds of heroin and one pound of Grey Death. There have been two reported seizures of Grey Death in Virginia. Grey Death has been reported in Florida since November of 2016. It’s been found in Alabama. In a video from WCPO in Cincinnati, Ohio, Detective Jim Larkin of the Lorain County Sheriff’s Department wondered why anyone would try something called Grey Death. “Here’s some Grey Death. Now what do think is going to happen to you? Why do you think it’s called Grey Death?”

09/22/17

Be Careful Out There

Recently, around 6 a.m. on a Wednesday, several law enforcement agencies executed federal search warrants at three locations in the West End area of Pittsburgh. In one home, when the SWAT team members entered, one of the suspects was trying to escape through a back window. Another one of the suspects knocked over a table where they had been bagging drugs, “causing the powder narcotics to become airborne” and exposing the SWAT officers to the airborne drug. Eighteen of them were taken to the hospital suffering from various symptoms.

According to Brenda Waters of KDKA, the CBS Pittsburgh affiliate, all eighteen were medically cleared. “None of the … law enforcement officers taking part in the early morning raid were adversely affected by the drugs.” The agencies participating in the raid included Pittsburgh Police, Pittsburgh SWAT, U.S. Immigration and Customs, state police and Homeland Security. In addition to the airborne substance, they found more than 1,000 stamp bags, 250 grams of unpackaged drugs and a “significant quantity of white powder” on a plate in the kitchen. The airborne substance was probably fentanyl; maybe carfentanil.

Dr. Tureurro, the chief of Emergency Services at UPMC Mercy Hospital, where the officers were treated, said they were fortunate to get out of the situation quickly, thus minimizing their symptoms. They had burning sensations in their throats; some became lightheaded; others were nauseous. “The big thing that we did for them is we basically decreased the chance that they could be exposed to anything that was laying on their bodies or on their clothes.” By removing their clothes, then showering and decontaminating themselves, the officers decreased their chances of exposure to any of the substance. The Justice Department press release said:

Fentanyl exposure is an all too real risk to law enforcement as we learned this morning. Quick and professional action by first responders helped avert a potential catastrophe.

The Pittsburgh Post-Gazette reported that the raid originated from a May investigation by Customs and Border Protection when agents intercepted a fentanyl package marked as “plastic fittings” that was shipped from Hong Kong. The accused leader of the drug operation had a history of repeated arrests for felony drug convictions and disregarding bond conditions in his repeated arrests for drug related charges. He had been initially arrested for possession and distribution on June 1^st in relation to the intercepted package of fentanyl from Hong Kong. He was rearrested on July 20^th, discarding a brick of fentanyl on the floor of a police car taking him to jail, and then again on August 2^nd. Each time he was released on bond he resumed his criminal activities. This time he did not receive bail.

This is not an isolated or freak occurrence. In September of 2016, The Washington Post reported on a raid in Harford Connecticut when 11 SWAT officers were exposed to airborne fentanyl and heroin. The powder may have blown into the air after the tactical team tossed a flash-bang grenade, or the suspects could have swept the table where they were packaging the drugs. The officers moved through a “cloud of dust in the air.” Several officers were lightheaded, nauseous; they had sore throats and headaches. As a precaution, the entire team went to a local hospital for treatment.

Jim Pasco, executive director of the National Fraternal Order of Police, said this has been an inherent risk for law enforcement for decades, beginning with “The granddaddy of all problems—being exposed to meth labs.” A DEA spokesperson said law enforcement officers are concerned with protecting themselves and the public.

Law enforcement officers do carry a bigger burden than ever — we are fighting to protect the American public from poisons that bring death and destruction to our communities — but we are also faced with challenges of educating the public as to the deadly risks of these substances and about the inextricable links between misuse of prescription opioids to heroin and fentanyl use and addiction.

Kelly Burch reported for The Fix that in May of 2017 when an East Liverpool Ohio police officer helped in the arrest of drug suspects, they tore open bags of the drugs in an attempt to destroy evidence. Back at the station, the officer noticed a white powder on his uniform and tried to brush it away. “I had placed my thumb, and index finger in it and tried to brush it off. I don’t know if it went through my skin or if it became airborne when I wiped it off, or a combination of both.” Within a few minutes, he didn’t feel like himself. The last thing he remembered was falling backwards into the door.

He received a dose of Narcan at the station and a few more at the hospital. “Never in a million years did I think I would be in the hospital for something that serious, for overdosing.” He knew the job was dangerous and might encounter guns and knives. But “you’re not thinking that a particle of dust or drug killing you.” The experience made him even more determined to keep these powerful drugs off the streets: “I am not letting drug dealers win, you may have almost killed me, but you’re not going to win, you’re not going to come to this city and bring that poison.”

Another Ohio encounter with fentanyl took place in early August of 2017 in Massillion, about 50 miles south of Cleveland. Three nurses at the Affinity Medical Center in Massilon lost consciousness while they were cleaning a room where an overdose victim had been treated. All three were treated with naloxone and are said to have recovered. The nurses union at the hospital wanted to meet with hospital officials to discuss protocols for environmental contamination, but the hospital declined, saying it already has effective policies. Hmmm … with three nurses becoming unconscious, it seems a review of the policies woudn’t hurt.

CTV Vancouver reported in October of 2016 that the CBSA, Canada’s Border Services Agency advised its officers to avoid contact with a package they suspect contains fentanyl. The president of Canada’s Customs and Immigration Union said: “What we’re telling our officers at this time, from a health and safety point of view, is that if there’s a package and they think there could fentanyl, they shouldn’t touch it. They shouldn’t approach it.” If an agent believes a package contains the drug, they are advised to give it to supervisors. “We need to approach this so our officers have the right tools, right training and the right equipment.”

In a June 2016 press release, the DEA announced they had released a short Roll Call Video to all law enforcement agencies about the dangers of improperly handling fentanyl. You can watch the video here. The press release said the DEA was concerned about law enforcement coming in contact with fentanyl on the streets in the course of enforcement activities, such as buy-walk or buy-bust operations. “Officers should be aware that while unadulterated fentanyl may resemble cocaine or heroin powder, it can be mixed with other substances which can alter its appearance.” The report noted the current outbreak involved not just fentanyl, but fentanyl compounds (like carfentanil) as well.

Universal precautions must be applied when conducting field-testing on drugs that are not suspected of containing fentanyl. Despite color and appearance, you can never be certain what you are testing. In general, field-testing of drugs should be conducted as appropriate, in a well ventilated area according to commercial test kit instructions and training received. Sampling of evidence should be performed very carefully to avoid spillage and release of powder into the air. At a minimum, gloves should be worn and the use of masks is recommended. After conducting the test, hands should be washed with copious amounts of soap and water. Never attempt to identify a substance by taste or odor.

The DEA published “A Briefing Guide for First Responders” on fentanyl. It contained a history of fentanyl, a description of illicit forms of fentanyl and fentanyl-related substances, the risks of exposure and treatment, as well as decontamination recommendations.

Fentanyl was first synthesized in 1959 by a Belgian chemist. Other forms of pharmaceutical fentanyl were developed for pain management, including a transdermal patch, a nasal spray, a sublingual tab and a flavored lollipop—yes a fentanyl lollipop. While pharmaceutical fentanyl is diverted on a small scale, the current problem is due to transnational criminal organizations competing for the U.S. market.

China and Mexico appear to be the main source countries for illicit fentanyl smuggled into the United States for domestic‐based processing and distribution. Seizures indicate that China supplies lower volumes of high‐purity fentanyl, whereas fentanyl seizures from Mexico are higher volume but lower in purity. Fentanyl is also routed and smuggled through Canada. China‐based trafficking organizations have also been known to use the internet to distribute fentanyl, fentanyl‐related substances, and synthetic opioids globally.

Among the current fentanyl-related substances on the illicit market are: 4‐fluoroisobutyryl fentanyl, furanyl‐fentanyl, acryl‐fentanyl, acetyl‐fentanyl, carfentanil, and 3‐methylfentanyl, and other synthetic opioids such as U‐47700. I’ve written previously on this website about the fentanyl-related substance, carfentanil (“The Devil in Ohio”). Recently I received an unsolicited email from a “company” in Shanghi offering to send me a free sample of carfentanil. The DEA “Briefing Guide for First Responders” warned that some organizations are distributing pure fentanyl.

During the first quarter of 2017 the DEA indentified 230 instances of fentanyl, fentanyl-related substances and other synthetic opioids in seized drug evidence. The following graphic illustrates the results of their analysis. Fentanyl accounted for about 58% of the identifications. Of those 134 fentanyl identifications, 61% of the samples were combined with heroin; 28% were fentanyl alone. Carfentanil was found in six identifications. U-47700, alprazolam (Xanax) and cocaine’s were found in others.

Because of their hazardous nature, fentanyl and fentanyl-related substances are a serious threat to the health and safety of law enforcement officers and other first responders, such as EMTs. As little as 2-3 milligrams of fentanyl could bring on respiratory depression and possibly death. “When visually compared 2 to 3 milligrams of fentanyl is about the same as five to seven individual grains of table salt.” See the above photo of a penny.

The “Briefing Guide for First Responders” went on to describe treatment for any exposure to fentanyl, repeating some of the actions taken in the above situations:

seek immediate medical attention.
remove the person from the contaminated environment, preferably where there is fresh air.
If a suspected fentanyl-related substance has been inhaled, move the person to fresh air.
If there are overdose symptoms, immediately administer naloxone, which can quickly reverse an opioid overdose.
Multiple doses may be necessary, depending upon the drug’s purity and potency. Continue to administer a dose of naloxone every 2-3 minutes until the individual is breathing on their own for at least 15 minutes or until EMS arrives.
Someone who entered a badly contaminated area or was otherwise exposed to a suspected fentanyl-related laboratory or milling operation without wearing the proper protective clothing should undress and shower with soap and water as soon as possible.
If a suspected fentanyl-related substance was ingested through the mouth or eyes and the person is conscious, rinse their eyes and mouth with cool water.
When there has been any skin contact, wash the exposed area immediately with soap and water.
Do NOT use hand sanitizer, as it may contain alcohol, which is a skin penetrant. This may increase the absorption of fentanyl through the skin.

So if you are a first responder or law enforcement officer—or if for some reason you find yourself exposed to fentanyl—remember the above advice. And first responders and law enforcement officers, remember the safety call given by Michael Conrad, who played the role of Sergeant Phil Esterhaus in Hill Street Blues: “Let’s be careful out there.”

08/8/17

Kratom: Part of the Problem or a Solution?

In August of 2016 the DEA announced that it would temporarily classify kratom as a Schedule I substance. The public outcry against this plan influenced the DEA to reverse itself and delay scheduling kratom in October of 2016. The DEA announcement said before taking further action, it would solicit public comments and review the FDA’s “scientific and medical evaluation” of the proposed scheduling of kratom. Once the DEA has received and considered the information, it would decide how to proceed. But while we await the DEA’s decision, kratom is being sold in vending machines.

Advocates for kratom were overjoyed with the DEA’s decision. Chris Ingraham reported for The Washington Post that researchers welcomed the decision to delay scheduling kratom, but were concerned that the future of their research was still up in the air. After its October 2016 announcement, the DEA set a period for public comments on the potential scheduling of kratom until December 1^st of 2016. As of August 6^th, 2017, there has not been a public announcement about its decision or its review of the FDA report on kratom.

Since the DEA delayed a decision on kratom, it is still unregulated and will remain available for anyone to use without a prescription. And research into the risks and benefits of kratom can continue unhindered by a temporary Schedule I classification.

Andrew Kruegel of Columbia University is working to develop new painkillers from compounds contained in kratom. He commented: “I am encouraged that they will now be having more serious input on this important policy decision.” While the DEA announcement might be good news for now, studies with the methodology of rigorous, controlled trials typical of FDA evaluations don’t exist for kratom. So will the DEA wait for the months or years it could take to complete rigorous kratom studies before deciding whether or not to schedule it?

According to the American Kratom Association (here) and PinneyAssociates (here), Jack Henningfield did an “8-factor analysis” with kratom, which is the legal framework used by the FDA to assess the abuse potential of substances. Henningfield concluded that kratom had a low toxicity level; and that scheduling it as a controlled substance was not warranted.

It’s important to understand that although kratom has some mild effects similar to opioids, its chemical make-up is different, and it appears overall much safer, with apparently relatively small effects on respiration. In fact, kratom’s analgesic effects and impact on energy, combined with its favorable safety profile supports continued access by consumers to appropriately regulated kratom products while research on its uses continues.

STAT News identified another person doing research with kratom, Edward Boyer, who is currently at UMass Memorial Medical Center and Boston Children’s Hospital. Boyer has been interested in kratom since 2006. Even then there was a Catch-22 of sorts when trying to get government funding for kratom. “The National Institute on Drug Abuse didn’t want to fund kratom projects, saying it was a complementary and alternative medicine, while the National Center for Complementary and Integrative Medicine didn’t want to fund them because it was a drug of abuse.”

In 2008, Boyer and two colleagues filed a patent to use kratom or its chemical compounds as a new treatment method for opioid withdrawal, one of the ways it is currently used informally and non-medically. Two large freezer bags of kratom he obtained still sit in a cabinet of the UMass Memorial Medical Center’s toxicology office. Boyer said the bureaucratic nightmare of running the FDA gauntlet to do a clinical trial stopped them cold.

Andrew Kruegel’s research has had some promising initial results. His team was able to demonstrate that the main components of kratom primarily stimulated the painkilling response, while having minimal effects on the proteins that caused other side effects. But these findings need to be repeated in mice and then humans, “before they could claim that they have used kratom to create an opioid-like painkiller without as many risky side effects.” But there is a problem obtaining kratom of the quality needed for his research and the red tape involved in the process of obtaining it. “There is nowhere to buy the plant unless I am going to go to Indonesia and contact plantation owners.”

In the mean time, you can order kratom on the Internet from several vendors. And if you live near the East Coast Super Subs shop in Tucson Arizona, you can buy it out of a vending machine. Eric Boodman reported for STAT News that the vending machine there attracted five customers in an hour. The servers at the sub shop said it gets even busier around opening and closing time. Using cash or a credit card, a customer can buy as little as 10 grams for $5, or up to 120 grams for $50.

The almost-scheduling of kratom seems to have been good advertising for the herbal product. Drew Pickett, the owner of a second kratom vending machine company, Arizona Kratom, said many people discovered kratom because of the bad publicity. “People were like, ‘Wow, if the government doesn’t want me to have it, I want to try it.’” He estimated the aborted ban triggered a 400% boost in his sales.

One person said kratom helped him stop using heroin six years ago. Last year he relapsed, and was back using heroin for several months before he used kratom to wean himself off heroin for the second time. He found the Tucson Kratom vending machine when the kratom he used to get from head shops became too pricey. Now he wants to wean off of kratom as well. “I start with a lot of it initially … and then I taper down. I’ve been doing it very gradually and probably in the next two or three months, I’ll be done with it.”

But things aren’t all sunshine and happiness with the kratom vending machine. Dr. Mazda Shirazi, the medical director of the Arizona Poison and Drug information Center first heard about the machine when a patient of his began to show signs of liver toxicity from using kratom from the machine on a daily basis. He’s worried about the lack of regulation with kratom, meaning you can’t be sure of the purity of what you are buying. He’s also concerned that using kratom to wean off of opioids will give some addicts false hope. “I think it actually prolongs the addiction cycle and puts the patient in a dangerous situation, whereas by getting help they might be better off.”

Susan Ash, the founder of the American Kratom Association, saw the vending machine as a sign of how pervasive the opioid epidemic has become. “Maybe a person who is going to walk into that sandwich store and has never heard of kratom — maybe that will be their first day off of opiates.” She liked the idea of people not having to wait a day or longer for their kratom to arrive in the mail. But she worried the vending machine made kratom available to children under 18. “There’s not enough research to know how the substance affects developing brains.”

And there’s the rub: there simply isn’t enough reliable, replicated research with kratom to make an informed decision on how to use it or whether to schedule kratom. Henningfield’s study is suggestive of a good safety profile for kratom, but can’t be regarded as conclusive since it was funded by the American Kratom Association. In contrast to Henningfield’s safety assessment of kratom, others have said there is a real probability of becoming addicted with kratom.

The National Institute on Drug Abuse (NIDA) noted how two compounds in kratom, mitragynine and 7-hydroxymitragynine, interact with opioid receptors in the brain, and produce the same effects of sedation, pleasure and decreased pain as opioids. There are symptoms of withdrawal when an individual stops using kratom and some users have reported becoming addicted to kratom. Adverse health effects from kratom use include: sensitivity to sunburn, nausea, sweating, loss of appetite, and sometimes psychotic symptoms. Chronic use of kratom has been linked with liver problems, as noted above. Kratom by itself hasn’t been linked with deaths, but if mixed with other substances, it has been part of a fatal drug cocktail. See “Krypton Can Kill You” and “The Secret of Kratom” for more on this.

While it isn’t a federally controlled substance at this time, six U.S. states and three cities have listed kratom as a Schedule I substance. Globally, several countries have either regulated or banned kratom. In Europe, kratom is a controlled substance in Denmark, Latvia, Lithuania, Poland, Romania, Sweden and the UK. It is a controlled narcotic in Australia and New Zealand. Possession of kratom is illegal in Thailand and its use is prohibited in Malaysia. Canada has made it illegal to market it for human consumption.

What is clear is the need for reliable, replicated research with kratom. Edward Boyer said: “Is it an effective treatment for opioid withdrawal, or is it another pathway to addiction? I don’t think anybody has a defined concept of where it actually lies on that continuum.” Nevertheless, it seems there is growing anecdotal evidence of some level of dependence or addiction with kratom. If the DEA delays its decision to regulate kratom much longer, it might become part of the problem instead of a solution to the opioid epidemic.

04/14/17

An Opioid Shell Game

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

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.

09/9/16

The Dragon Threat

The DEA released its updated “National Heroin Threat Assessment Summary” on June 27, 2016 and the news is not good. Chuck Rosenberg of the DEA called the death and destruction from heroin and opioids “unprecedented and horrific.” The number of users, treatment admissions, overdose deaths, seizures from heroin traffickers all increased since the 2015 Summary. The increased demand and use of heroin is being driven by greater availability of heroin in the U.S. and prescription opioid users switching to heroin because it’s cheaper. “The problem is enormous and growing, and all of our citizens need to wake up to these facts.”

There were three big takeaways in the 2016 Summary: 1) the number of people currently using heroin almost tripled between 2007 and 2014. 2) Deaths due to heroin more than tripled between 2010 and 2014. 3) Deaths due to synthetic opioids, like fentanyl, increased 79% between 2013 and 2014. You can access a pdf of the full report here.

In 2014, 10,574 American died from heroin-related overdoses. Geographic areas of the country particularly hard hit are in the Northeast and the Midwest. See Map 2 in the 2016 DEA Summary. Not surprisingly, availability levels are the highest in these areas as well. Possible reasons for the increase in overdoses and deaths include: more heroin users, especially those who are new to heroin, who are young and inexperienced; the higher purity of heroin found in certain areas and the use of adulterants like fentanyl.

Twenty to thirty years ago, the average retail-level purity of heroin available in the U.S. was about 10%. By 1999, the average purity was 40%. While the purity increased, the price decreased. The average price per gram in 1981 was $3,260 in 2012 US dollars. By 1999, the price for a gram of heroin had dropped to $622. Heroin prices have remained low since then. With an increase in purity, heroin can be snorted or smoked, which broadens its appeal. “Many people who would never consider injecting a drug were introduced to heroin by inhalation.”

Beginning in late 2013, several states started reporting overdose death due to fentanyl and acetyl-fentanyl. There were 5,544 reported synthetic-opioid-related deaths in 2014. But the DEA speculated it was much higher because of a lack of standardization in reporting; and because coroners and state crime labs don’t initially test for fentanyl or its analogs unless they have a reason to do so. The eastern U.S. is the area most effected by this, because white powder heroin from South America predominates. Fentanyl, also a white powder, is mixed with heroin or sold disguised as white powder heroin. The following chart is from the 2016 DEA Summary.

The Mississippi River has historically been a geographic dividing line with Mexican, “black tar” and brown powder heroin more common west of the Mississippi and white powder heroin, now supplied from South America, common east of the Mississippi. But that is changing. Mexican traffickers are making inroads into major eastern cities. Mexican organizations are now the most prominent wholesale-level traffickers of heroin in Chicago, New Jersey, Philadelphia, and Washington DC. Increased trafficking of Mexican heroin means more heroin is entering the U.S. across the Southwest border from Mexico. Black tar heroin is popping up more frequently in the Northeast, although it still comprises a small percentage of the heroin seized.

Mexican traffickers have taken a larger role in the U.S. heroin market, increasing their heroin production and pushing into eastern U.S. markets that for the past two decades were supplied by Colombian traffickers. This is notable because Mexican traffickers control established transportation and distribution infrastructures that allow them to reliably supply markets throughout the United States

The DEA also noted the increase in counterfeit prescription pills, many which contain deadly amounts of fentanyl. Small-scale local drug entrepreneurs can buy the materials and equipment to produce the counterfeit drugs online and set up their own operation, ala Breaking Bad. “Fentanyl pill press operations have been identified in the United States, Canada, and Mexico, indicating a vast expansion of the traditional illicit fentanyl market.” Oxycodone and other opioid painkillers are the main counterfeited medications, but traffickers are also packaging fentanyl as Xanax and other benzodiazepines. See “Buyer Beware Drugs” for more information.

When comparing heroin use to other drugs in the U.S., we find that the population of heroin users is slightly smaller than the estimated population of methamphetamine users and significantly smaller than individuals reporting current cocaine use. However, the number of individuals reporting current use of prescription pain relievers non-medically was about TEN TIMES the size of heroin users. So although a rather small percentage of prescription drug abusers (4%) will try heroin, this represents a significant increase in the number of heroin users because the size of the prescription drug abuse population is so much larger. See the following chart taken from the 2016 DEA Summary.

Behind all these statistics are real people, some living and some now dead. And despite all the law enforcement efforts over the past several decades, the problem seems to be getting worse. So two federal law enforcement agencies decided to combine their efforts and try a different tactic. They thought they’d try to address the problem from the demand side instead of the supply side.

Back in February the FBI and DEA released a documentary film addressing the growing epidemic of prescription drug and heroin abuse. “Chasing the Dragon: The Life of an Opiate Addict” is intended as an educational film for high school and above. Educational materials have had mixed effectiveness with decreasing drug usage. But the value of this film is in its portrayal of the real people who chased the dragon and became part of the above statistics. You can watch the film here.

07/29/16

Be Careful of Where You’re Going

On July 9, 2015 eight Senators sent a letter to the Department of Health and Human Services (HHS), Office of National Drug Control Policy (ONDCP), and the Drug Enforcement Administration (DEA) asking for information on their efforts to facilitate scientific research into the benefits of medical marijuana. The Senators asked for answers to a series of questions, stating that relevant federal agencies had to play a leadership role in coordinating and facilitating research into medical marijuana. This began a process culminating in the administrators of the three agencies sending a detailed reply to their questions in an April 4, 2016 response … 26 pages long. And so speculation began that the DEA would decide whether or not to change the controlled substance status of marijuana “in the first half of 2016.”

This was part of the inquiry made by the Senators’ letter, in noting the need to remove “extraneous regulatory barriers for researchers who wish to perform scientific studies on the sue of marijuana for various diseases.” They pointed to the need of the federal government to make a concerted effort to understand how marijuana works and what the appropriate doses and methods of treatment are, “like any prescribed medicine.” Within Appendix C of the HHS, ONDCP, DEA response, was the following graphic and text delineating the process to schedule or re-schedule any drug.

The Controlled Substance Act requires eight factors as part of its scientific review: 1) the actual or relative potential for abuse; 2) the scientific evidence of its pharmacological effect; 3) the state of current scientific knowledge regarding the substance; 4) the history and current pattern of abuse; 5) the scope, duration and significance of abuse; 6) the risk to the public health; 7) the psychic or physiological dependence liability; and 8) the immediate precursor of a substance already controlled.

Writing for the Huffington Post in April 2016, Matt Ferner noted the FDA completed its review of the medical evidence of the safety and effectiveness of marijuana, and forwarded it to the DEA. But the FDA recommendations are still not public. In the Washington Post, Christopher Ingraham interviewed John Hudak of the Brookings Institution, who said the small amount of researchers currently working with marijuana is not due to the government turning down applications to do the research. Rather, it is a function of the application process itself. “People just aren’t applying because of all the headaches involved. . . . It’s a huge disincentive for the academic community.”

The bureaucratic hurdles also mean that colleges and universities are often hesitant to fund marijuana research for fear of running afoul of complex federal regulations. One ongoing study on the use of marijuana to treat veterans with PTSD has been struggling to get off the ground for more than five years, for instance.

There was an unconfirmed rumor by an “anonymous” DEA attorney that the DEA planned to reschedule marijuana as a Schedule II controlled substance and make medical marijuana legal with a doctor’s prescription in all 50 states. This is simply not true. Rescheduling would merely make it easier to get permission to do research with marijuana, not make it legal for doctors in all 50 states to prescribe marijuana. If that were the case, why can’t doctors prescribe cocaine legally? It is a Schedule II Controlled Subtance. Writing for The Fix, McCarton Ackerman noted the skepticism about the validity of the source.

In response to the rumors, DEA staff coordinator Russ Baer would not confirm the rumored rescheduling by August 1st in an interview with aNewDomain. Baer pointed out the complexity of what is referred to as “medical marijuana.” While THC and CBD are the two main cannabinoids, there are an estimated 480 compounds in cannabis. “What is under-reported right now is how complex the marijuana plant is.”

Baer said the DEA wants to remove the roadblocks to further research into the effectiveness of medical marijuana. However, he said the DEA doesn’t support decisions made on anecdotal evidence.

We want there to be research on marijuana and its component parts, there needs to be (more) studies about both the benefits and the adverse effects about marijuana. . . . We want to know more about cannabis— we need rigorous scientific research — the DEA stands behind the scientific process.

He added that safe medical cannabis requires rigorous peer-reviewed studies. He singled out current research into the benefits of cannabinol (CBD). “We are told by NIDA, also, that there are medical studies out there also preliminarily indicate CBD is beneficial.” But the opioid crisis has captured most of the DEA’s attention. “Marijuana is important, but our efforts are mainly focused on the nation’s growing opioid crisis. . . . We’re focusing on fentanyl, fentanyl compounds and on preventing the deaths caused by opioid addiction.”

A June 24th article by Kate O’Keeffe for the Wall Street Journal said Baer didn’t expect an answer by June 30th, but the agency was in the final stages of deciding whether to reschedule marijuana. He added that a decision is expected sometime soon.

On July 13, 2016 Dr. Douglas Throckmorton of the FDA appeared before the Judiciary Subcommittee on Crime and Terrorism. In his written statement to the committee, he reiterated its standing 2006 recommendation that marijuana remain as a Schedule I controlled substance because of a high potential for abuse; no currently-accepted medical use; and that it lacks accepted safety for use under medical supervision. However, “DEA is currently in the process of evaluating a number of other Citizen Petitions regarding the scheduling of marijuana.”

He noted there are three drugs approved for human use that contain active ingredients present in or similar to those in botanical marijuana: Marinol Capsules, Syndros and Cesamet Capsules. These products have undergone the FDA’s approval process and have been determined to be safe and effective for their respective indications. The future of medical marijuana lies in “classical drug development.”

If there is any future for marijuana as a medicine, it lies in its isolated components, the cannabinoids and their synthetic derivatives. Isolated cannabinoids will provide more reliable effects than crude plant mixtures. Therefore, the purpose of clinical trials of smoked marijuana would not be to develop marijuana as a licensed drug but rather to serve as a first step toward the development of nonsmoked rapid-onset cannabinoid delivery systems.

Throckmorton pointed to three Fast Track designations for Savitex (April 2014), Epidiolex (June 2014) and a CBD formulation of Insys Therapeutics to treat Dravet syndrome (February 2015). All three are drugs derived from marijuana. He said the FDA is working with researchers who are conducting studies on the development of potential new drugs derived from marijuana.

FDA encourages and supports medical research into the safety and effectiveness of marijuana products through adequate and well-controlled clinical trials conducted under an IND [Investigational New Drug] and consistent with DEA requirements for research on Schedule I substances. FDA has provided scientific advice to representatives from several states considering support for medical research of marijuana and its derivatives, including CBD, to help ensure that their research is rigorous and appropriate.

Another date floated on the rumor pond for a DEA decision on rescheduling marijuana was August 1st, which is fast approaching. Will there be an answer? Who knows? According to Russ Baer, the DEA is not bound to give its answer within some artificially determined timeframe. So I suggest those anxious for an announcement by the DEA (senators and marijuana activists alike) apply a mash up of a famous Yogi-ism here: “Marijuana ain’t re-scheduled till it’s rescheduled.” Perhaps the DEA is just trying to be careful in its decision making process about the rescheduling. Yogi Berra has some further words of wisdom to apply there: “You’ve got to be very careful if you don’t know where you are going, because you might not get there.”

Faith Seeking Understanding

Charles Sigler, D.Phil.

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