02/13/18

Keep Marijuana Medical in PA

© Jonathan Weiss | 123rf.com

Western Pennsylvania is about to see medical marijuana sales begin. Two dispensaries are scheduled to open on February 15th, 2018. It’s been almost two full years since Governor Tom Wolf signed Senate Bill 3, legalizing medical marijuana on April 17, 2016. As the Governor signed the bill, he said: “I am proud to sign this bill that will provide long overdue medical relief to patients and families who could benefit from this treatment.” At the time, the press release expected implementing the state’s Medical Marijuana Program to take between 18 and 24 months, making it right on schedule. Let’s hope that what’s coming sets PA on a different path than California’s original legalization of medical marijuana did in 1996—despite the hopes of two of the sponsors of the new PA law.

When Proposition 215 was about to be approved in California, Senator Diane Feinstein said: “you’ll be able to drive a truckload of marijuana through the holes in it.” The devil is in the details, and she said that particular bill lacked details. A significant difference between Proposition 215 and the Pennsylvania Medical Marijuana Program is that in PA, dried leaves, plant material and edibles are strictly prohibited. Grower/processors can only manufacture the forms of medical marijuana listed in Act 16. These include: 1) a form medically appropriate to administer by vaporization or nebulization; 2) pills; 3) topical forms, including gels, creams or ointments; 4) tinctures; 5) liquids; or 6) oils. A licensed practitioner or medical professional determines which form is appropriate for the patient.

Cannabis products as they are to be sold in PA will provide medical relief to patients and families within the state without the patent medicine aura in dispensaries hocking different kinds of edibles or plant material for what “ails” you, as in states with less restrictive medical marijuana laws (like California). A medical professional (physician, physician assistant or certified registered nurse) has to be present during all hours a facility is open and offering to dispense or consult with a patient. Additionally, they all have to complete a required four-hour training and be registered with the PA Department of Health. Significantly, “a practitioner or physician may not issue a patient certification at the dispensary facility.”

Patients wanting to participate in the medical marijuana program have to visit the online Patients and Caregivers Registry and create a profile in the Department of Health’s patient and caregiver registry. Then they have to obtain a physician’s certification they suffer from one of the 17 serious medical conditions listed in the graphic below. Returning to the Patients and Caregivers Registry, they pay $50 a year for a medical marijuana ID card. Caregivers for minors or patients unable to travel to a dispensary themselves can also participate in the medical marijuana program. Registered caregivers can have up to five patients. See the YouTube video, “Overview of Medical Marijuana in Pennsylvania” on the webpage for more information on the Pennsylvania Medical Marijuana Program linked above.

Look on the website for other resources such as a list of approved practitioners by state region and county, the Patient and Caregiver Registry, and an Information for Patients Brochure. Under certain guidelines, a parent, legal guardian or caregiver may administer medical marijuana to students with serious medical conditions while on school property. See the website for more information on what is required for this process.

The initial guidelines described above will give patients in Pennsylvania access to marijuana for legitimate medical reasons. If the guidelines are followed as described above, they will help the state avoid its new medical marijuana program morphing into what has happened in California since the approval of Proposition 215 in 1996. But Pennsylvania citizens and government officials need to be vigilant. At least two of the cosponsors of the legislation itself want to see the plant form of marijuana available for sale in dispensaries and to eventually to see the state move towards legalizing recreational marijuana.

In April of 2017 at the World Medical Cannabis Conference & Expo held in Pittsburgh, one of the sponsors of Senate Bill 3 (SB 3), State Senator Daylin Leach, said he expected medical marijuana would be available in plant form in dispensaries sometime during 2018. He noted a section of the bill authorizes an advisory board to make recommendations by April of 2018 about whether to change the permissible forms of the drug. During a panel discussion at the Expo, Margaret Sun for WESA reported Leach said the following about the advisory board:

“But they will [approve sale of the plant form of marijuana], because we’re appointing people to do that,” Leach said as the crowd laughed. “They will recommend that at latest by April 17 (2018), which means when dispensaries open, it is likely that they will have whole plant on their shelves from day one.”

Leach’s statement went over well with his listeners, but his ability to make good on his promise is more bluster than reality. What follows is a description of the members of the Medical Marijuana Advisory Board within the State Department of Health are supposed to include. I don’t see him being able to stack this deck:

Members include the Secretary of Health; the Physician General; State Police Commissioner; Chair of the State Board of Pharmacy; Commissioner of Professional & Occupational Affairs; President of the Pennsylvania Chiefs of Police Association; President of the Pennsylvania District Attorneys Association; members to be appointed by the Governor and the four legislative caucuses who are knowledgeable and experienced in issues relating to care and treatment of individuals with a serious medical condition, geriatric or pediatric or clinical research. One member appointed by the Governor shall be a patient, a family or household member of a patient or a patient advocate.

Also, the Department of Health has the final approval on whether to add the smokeable plant form to the program, but as SB 3 is written—and as it is now described on the website—dried leaves, plant material and edibles are not approved. Leach’s words suggest his intentions in sponsoring the medical marijuana legislation was at least partly as a stepping stone to his intent to pursue full legalization of recreational marijuana. Both Leach and another sponsor of SB 3, State Senator Mike Folmer, said they thought full legalization was inevitable in Pennsylvania. Folmer stated he couldn’t politically advocate for legalization just now, as it was difficult enough getting Republicans on board with the medical marijuana program. He said:

I’d like to see our first dispensaries up, I’d like to see the first grower/processors going, and I think then, on my side, we’ll see that the sky isn’t going to fall, dogs won’t sleep with cats, and the sun will still set in the West and civilization will not crumble.

Civilization won’t crumble with the implementation of the existing PA Medical Marijuana Program. But our inability to trust disingenuous politicians who pragmatically use public sympathy for suffering individuals to further their political agendas will crumble our civilization. SB 3 was apparently a backdoor strategy for these two PA State Senators towards their desire to eventually legalize recreational marijuana. Was there ever any real concern for the needs of medical marijuana patients, or was it just rhetoric to get closer to recreational legalization? Leach is a Democrat from Montgomery County and Folmer is a Republican representing Dauphin, Lebanon and York Counties. Remember this if you live in the areas they represent as their term expires.

The Pennsylvania Medical Marijuana Program as it now exists will provide for suffering individuals within the state. And that is a good thing. Other than THC (the psychoactive cannabinoid in cannabis), there seems to be a significant medicinal potential with CBD (cannabidiol). Further research is needed and the federal classification as a Schedule I substance hampers that research from being done. That needs to change.

There are some serious researchers, like Staci Gruber, who are investigating the medical benefits of cannabis without being blinded to its potential adverse psychoactive harms. PA medical marijuana research would do well to partner with researchers like Gruber and her organization, MIND (Marijuana Investigations for Neuroscientific Discovery). Let’s let research and not rhetoric guide the medical uses of the cannabinoids in cannabis. So far it seems there are limited health benefits from THC. See “Listening to Marijuana Research” for more information on this.

Solevo Wellness is set to open its doors for business in the Squirrel Hill section of Pittsburgh on February 15th. The dispensary’s first shipment is coming from the grower-processor Cresco Yeltrah in Brookville, Jefferson County. Visitors will be greeted by a receptionist and show their necessary legal paperwork to gain access to products and then visit with a pharmacist. “Then they’ll head to a showroom, where cannabis product samples are kept inside glass cases, make a purchase and continue with their day.” The Solevo Wellness dispensary is constantly monitored by security cameras.

CY+ opened its doors with a ribbon cutting ceremony in Butler PA on February 1st. It will begin selling its products on the fifteenth as well. Larry Clark, the Pennsylvania Deputy Director of Medical Marijuana was there. He said: “It’s a medical experience”; not the head shop approach. Kimberly Geyer, the Butler County Commissioner, said: “It defies all the traditional stereotypes associated with this industry.” CY+ is owned by Cresco Yeltrah, which seems to be a subsidiary of Cresco Labs, a company out of Chicago. Charlie Bachtell, the cofounder of CY+, was at the opening in Butler. Bachtell is the CEO and Cofounder of Cresco Labs. They hope to open their second Western Pennsylvania facility in the Strip district by mid-April.

That’s just around the time Daylin Leach thought the state advisory board could approve the sale of plant product in stores. Given the difficulty it seems there was in getting SB 3 passed not only does that seem unlikely, but it would be political suicide for medical marijuana activists. Dispensing marijuana as a medical product in an environment that has the feel of a medical practice or medicine shop rather than a head shop sets the right tone. Trying to force the so-called progressive cause of legalizing recreational marijuana on the back of the recent approval of medical marijuana could sink them both in PA. But Leach may have other things on his mind since his brash claim last year at the World Medical Cannabis Conference & Expo.

Daylin Leach had an event-filled 2017. He temporarily moonlighted as a lawyer for a Philadelphia law firm that lobbies for the marijuana industry from shortly after Governor Wolf signed SB 3 until he announced a run for Pennsylvania’s 7th Congressional District in July of 2017. He then announced the suspension of his campaign in December of 2017 in the midst of accusations of a pattern of inappropriate behavior with several former female staffers. He took this step after a story in the Philadelphia Inquirer appeared in which a series of former campaign and legislative staffers accused him of inappropriate behavior. He said he was taking a step back to focus on his family and work with Senate leaders to address these allegations. “I will continue to do all that I can to advance progressive causes in the Senate and represent my constituents with honor.”

Frankly, I think he’s done enough and needs to move on to another progressive cause besides legalizing marijuana. But I suspect the financial lure of cannabis might be too strong for him to resist. So let’s make other PA state legislators aware of wanting to keep marijuana medical in PA.

02/2/18

Rebirth of the Gateway Hypothesis

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Writing for the journal Substance Use & Misuse in 2015, John Kleinig thought it was time to “retire” the gateway drug theory. The problem as he saw it was “there are too many gateways and ways of going through them, and we do not have an adequate handle on them.” He thought some versions of the hypothesis used an oversimplification of the dynamics of drug use and “developed [it] into a Medusa’s head of hypotheses about progressive drug use.”  The perceived risk leads to the development of  “social policies that prevent the downward passage through a gate or successive gates.”

The term gateway drug was popularized by Robert DuPont in his 1984 book, Getting Tough on Gateway Drugs: A Guide for the Family. DuPont had been the first director of NIDA (National Institute on Drug Abuse) from 1973-1978 and the second drug czar under Presidents Nixon and Ford from 1973 -1977. DuPont was said to have formed the idea of a gateway drug from two observations. First, some young people he came into clinical contact with reported they first used alcohol and tobacco, which was then followed by marijuana use. Second, because marijuana use was illegal, it was more likely other illegal drugs would be tried afterwards. His thesis was primarily used to demonize marijuana as the gateway drug.

DuPont did not, according to Kleinig, take the point of view that the pharmacological properties of some drugs could transport people through gateways. But others did, as we shall see.

If that had been intended, it would have provided a testable (albeit complex) scientific hypothesis and also provided valuable knowledge. It would have provided the kind of testable hypothesis that we have for some addictions—accounts of how, under certain conditions, particular psychoactive substances affect the chemistry and physiology of the brain, and so forth.

Kleinig seems to have been right in naming DuPont as popularizing the term gateway drug. But historically, the origins of the concept itself it should be attributed to Denise Kandel and her 1975 article for the journal Science, “Stages in Adolescent Involvement in Drug Use.” She initially theorized a four stage sequence to drug involvement: beer or wine or both; followed by cigarettes or hard liquor; marijuana; and other illicit drugs. “The legal drugs are necessary intermediates between nonuse and marihuana.”

Over the intervening years Kandel persevered with her hypothesis while others like Kleinig thought it should be abandoned. And she recently coauthored an article with her Nobel Prize winning husband that suggested pharmacological properties of some drugs could transport rats, if not people, through gateways. But I’m getting ahead of myself. Dr. Kandel edited Stages and Pathways of Drug Involvement: Examining the Gateway Hypothesis in 2002. In her introductory essay, “Examining the Gateway Hypothesis,” she acknowledged that while the “Gateway Hypothesis” originated in the mid-1970s, the idea of progression in drug use dates back to the 1930s as the “Stepping Stone Theory.”

She said there was a crucial difference between the two concepts. The Stepping Stone Theory saw the progression in drug involvement to be inevitable, “the use of marijuana invariably leading to heroin addiction.”  Recall that the 1930s was the time of films like: “Reefer Madness” and “Cocaine Fiends.” See “Remembering Reefer Madness” for more on this topic.

In contrast, the Gateway Hypothesis sees a sequence, where the use of certain drugs precedes the use of other classes, but that progression is not inevitable.  Entry into a particular stage may be common and perhaps even a necessary step, but is not a sufficient prerequisite to enter the next higher stage. Notice the modification below in her drug sequencing stages for the 2002 essay.

According to this notion, there is a progressive and hierarchical sequence of stages of drug use that begins with tobacco or alcohol, two classes of drugs that are legal, and proceeds to marijuana, and from marijuana to other illicit drugs, such as cocaine, metamphetamines, and heroin. The basic premise of the developmental stage hypothesis is that involvement in various classes of drugs is not opportunistic but follows definite pathways; an individual who participates in one drug behavior is at risk of progressing to another. The notion of developmental stages in drug behavior does not imply, however, that these stages are either obligatory or universal, nor that all persons must progress through each in turn.

Dr. Kandel pointed out that numerous investigations have documented regular sequences of progression from legal to illegal drugs among adolescents and young adults of both sexes, regardless of the age of their first use, ethnicity and country. The sequence has been observed in France, Israel, Australia, Japan, Spain and Scotland. She also noted there has been a resurgence of interest in the Gateway Hypothesis “as a framework for understanding adolescent drug involvement.”

An interview Dr. Kandel did with the NPR program, “All Things Considered” in 2015 indicated she had received a grant from NIDA in the early 1970s to study marijuana as a possible gateway drug. On her own initiative, she added questions about tobacco and alcohol use in order to look at other factors besides marijuana. Incidentally, this was during Dr. DuPont’s time as the NIDA director.

When I did the analysis, I found that there was a certain sequence that young people seem to be following when they got involved in drugs. They did not start with marijuana, but they started with drugs that are legal for adults in the society, such as beer and wine and cigarettes, other forms of alcohol.

Nearly forty years after her 1975 paper, she coauthored a paper for the New England Medical Journal with her husband, a Nobel Prize winning neuroscientist, “A Molecular Basis for Nicotine as a Gateway Drug.” “What we found is that when an animal was primed by nicotine and then was exposed to cocaine, the effect of cocaine was amplified many times.” Given how well nicotine primes the brain, she’s concerned about reports showing e-cigarette use is increasing among young people.

Although e-cigarettes eliminate some of the morbidity associated with combustible tobacco, they and related products are pure nicotine-delivery devices. They have the same effects on the brain as those reported here for nicotine … and they pose the same risk of addiction to other drugs and experiences.

The Kandels’ work was done in collaboration with Amir Levine and others; and it drew upon the earlier study by Levine et al., which also found how nicotine acted as a gateway drug on the brain. The effect “is likely also to occur when nicotine exposure is from passive and non-smoked forms.” The authors said this emphasizes the need to develop more effective public health prevention programs for all products containing nicotine, which would include e-cigarettes.

In November 2017 Griffin et al. published a study in Science Advances that showed a similar response with alcohol and cocaine. Alcohol was found to enhance cocaine addiction by suppressing two genes that normally inhibited the effects of cocaine, but not the other way around. In addition, their findings suggested that alcohol and nicotine acted through similar molecular mechanisms to increase vulnerability to cocaine. In other words, the use of one or the other gateway drug changed the brain in such a way that using cocaine was more rewarding.

Our findings indicate that a prior history of alcohol use is required for the enhancement of cocaine addiction–like behavior, and that priming by alcohol is a metaplastic effect, whereby exposure to this gateway drug initiates intracellular events that alter the epigenome, creating a permissive environment for cocaine-induced learning and memory, thereby enhancing the addictive potential of cocaine.

The New York Times published an article on the gateway drug theory, “A Comeback for the Gateway Drug Theory?” But it seemed to confuse Kandel’s Gateway Hypothesis and the Stepping Stone Theory without making the crucial distinction between them, as noted above. The Stepping Stone Theory is not an earlier version of the Gateway Hypothesis. Further misunderstanding was apparent in the criticisms of the Gateway Hypothesis the article cited.

The NYT article seemed to assume a version of the hypothesis that infers causation. It quoted an excerpt from a longer quote by Maia Szalavitz in her 2010 Time article on marijuana as a gateway drug. The excerpt in the NYT article was: “there is no conclusive evidence that the drug effects of marijuana are causally linked to the subsequent abuse of other illicit drugs.” Szalavitz was quoting from a report by the Institute of Medicine of the National Academy of Sciences. Below is the NYT quote from her article in context:

In the sense that marijuana use typically precedes rather than follows initiation of other illicit drug use, it is indeed a “gateway” drug. But because underage smoking and alcohol use typically precede marijuana use, marijuana is not the most common, and is rarely the first, “gateway” to illicit drug use. There is no conclusive evidence that the drug effects of marijuana are causally linked to the subsequent abuse of other illicit drugs.

Kandel’s essay, which is linked above, was careful to note the association, not causation inherent in the Gateway Hypothesis. She said the validity of the Gateway Hypothesis was based on two criteria: the sequencing of drug use between classes and the association of drugs, such that using a drug lower in the sequence increases the risk of using drugs higher in the sequence. “Ultimately, association implies causation if all possibilities for spurious associations have been eliminated. Given the difficulties of establishing true causality in the social sciences, the term association rather than causation is emphasized.”

Some of the other criticisms were not even on point to what Dr. Kandel was saying. A critic of the Gateway Hypothesis quoted in the NYT article was Ethan Nadelmann, the founder and former executive director of the Drug Policy Alliance. He said given that the study was on rats, to make claims about people from it was a stretch. Did this guy even look at the title of the Kandel and Kandel paper, “A Molecular Basis for Nicotine as a Gateway Drug,” let alone read it?

He also noted previous studies showing how one drug enhances the effect of another contradicted “gateway theory.” But again, that wasn’t relevant to Kandel’s Gateway Hypothesis. Nadelmann also alluded to research showing how individuals combining marijuana and prescription opioids were not more likely to abuse alcohol or other drugs.

Given the interest of Dr. Kandel in applying her research conclusions to public health concerns and policy issues, Dr. Nadelmann’s criticisms seem aimed at redirecting the attention of politicians like Jeff Session and Chris Christie and others away from seriously considering her research in the context of social and legislation reform of existing drug policy. The Drug Policy Alliance is a non-profit organization whose stated priorities include the decriminalization of responsible drug use. There seems to be dueling political ideologies at work here that either embrace or reject the Gateway Hypothesis.

Some serious political sparks may begin flying over Kandel and the Gateway Hypothesis soon. Dr. Kandel is wrapping up a similar study to those mentioned here on marijuana and hopes it will be ready for publication sometime in the first half of 2018. Given the careful science of Kandel and Kandel, the political firefights could get ugly if it demonstrates a molecular gateway for marijuana as the above studies have for nicotine and cocaine. But we’ll have to wait and see what they found and then concluded from their data. Pro marijuana legalization activists are probably wishing the Gateway Hypothesis had just remained dead.

01/23/18

Opioid Epidemic Price Gouging

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The FDA recently approved Sublocade, the first once-monthly buprenorphine injection in its fight against the opioid epidemic. Indivior, the company which also sells Suboxone film, projected it would be available on the market sometime in the first quarter of 2018. Sublocade is a drug-device combination product. “It is injected by a healthcare professional (HCP) under the skin as a solution, and the delivery system form a solid deposit, or depot, containing buprenorphine.” The initial procedure will to be to start with daily stabilizing doses of Suboxone for at least seven days before the first injection of Sublocade.

After initial formation of the depot, buprenorphine is released by the breakdown (biodegradation) of the depot. In clinical trials, Sublocade provided sustained therapeutic plasma levels of buprenorphine over the one-month dosing interval.

Prescribing information for Sublocade said the recommended protocol was two monthly doses of 300 mg followed by 100 mg monthly maintenance doses. “Increasing the maintenance dose to 300 mg monthly may be considered for patients for whom the benefits outweigh the risks.” Sublocade will come in prefilled syringes of 100 mg and 300 mg. It will carry a boxed warning of the risk of serious harm or death if used intravenously.

The Indivior announcement of Sublocade’s approval indicated Sublocade will be distributed through a restricted distribution system, “which is intended to prevent the direct distribution to a patient.” This restricted release to only healthcare professionals is because of the risk of serious harm or death if someone were to attempt intravenous self-administration of Sublocade. Intriguingly, the boxed warning in the prescribing information wasn’t as clear on the intent of the restricted distribution system to prevent patients from having direct access to Sublocade. The harder it is to get a hold of Sublocade, the harder it will be to figure out a way to hack into the buprenorphine it contains.

The FDA is requiring postmarketing studies to assess four things. First, whether patients would benefit from a higher dose. Second, whether Sublocade can be safely started without a dose stabilization period of Suboxone. Third, to assess the feasibility of administering Sublocade at a longer inter-dose interval than once-monthly. Fourth, to determine a process for transitioning patients stabilized long term on Suboxone film to a monthly dose of Sublocade without the loaded dose in the first two months of treatment.

I assume the study to see if patients would benefit from a higher dose fits into the above prescribing information that maintenance doses could be increased up to 300 mg monthly. But I have this nagging question of whether Indivior felt unsure about the safety risk of maintenance doses above 100 mg. So they wanted to be safe rather than sorry, knowing there was always Suboxone film to supplement Sublocade in a pinch. And postmarketing studies could look at whether higher maintenance doses put people at risk in some way.

The procedure of having an initial “dose stabilization” period on Suboxone before injecting Sublocade helps ensure the individual has really stopped using opioids before their injection. The required postmarketing study will help evaluate whether that’s necessary. My initial thoughts are that given the significant amount of buprenorphine in the depot, clinically the dose stabilization period should remain, especially if this is done when the person is an outpatient. If the person’s pattern of use isn’t stable enough to reach a week of daily Suboxone use, they should probably try inpatient drug treatment to stabilize first before Sublocade.

Depots containing either 100 mg or 300 mg have a significant amount of buprenorphine. So I’m concerned about thoughts of assessing the feasibility of administering Sublocade at longer inter-dose intervals, which would require even higher doses. I guess the thinking behind the longer inter-dose interval study is anticipating of having/keeping Sublocade patients on the treatment for an indeterminate length of time, perhaps years.

Except for the supposed convenience of a once-monthly shot, why would someone who is stable on Suboxone film long term want to switch to Sublocade? If you have demonstrated the discipline, stability and willingness to successfully maintain opioid abstinence with Suboxone, why switch to Sublocade? I do know why Indivior would want you to switch. The average monthly cost for Suboxone is $132, while the average monthly cost for Sublocade is $1,580. The cost for Sublocade puts it in the ballpark for Vivitrol, which costs around  $1,687 per month.

STAT News quoted one addiction professional who said: “It’s potentially a game changer. . . . This could become first-line [medication] for opioid addiction.” But Sublocade is just the first injectable buprenorphine product to be approved. A similar medication, known as CAM 2038, is made by Braeburn Pharmaceuticals and it could be get FDA approval by January 19, 2018. The president and CEO of Braeburn said: “This new technology has the potential to greatly influence the way patients are treated today. . . [It can] free patients from the daily decision and reminder of the disease.” Did this guy ignore or just forget about the Warnings and Precautions on the Sublocade medication guide?

It says: “Buprenorphine can be abused in a manner similar to other opioids; Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with Sublocade.” Pain treatment should be with a non-opioid analgesic whenever possible. “If opioid therapy is required, monitor patients closely because higher doses may be required for analgesic effect.” Sublocade won’t free patients of the daily reminder of the disease, because it is the daily reminder.

STAT said long-acting buprenorphine could make future inroads within the criminal justice system. “In recent years judges, wardens, and health officials have warmed up to Vivitrol, citing fears that daily tablets of buprenorphine can be diverted or abused.” Additionally, the criminal justice system has been more receptive to Vivitrol because Alkermes has been doing targeted marketing with them to promote Vivitrol for a number of years. However, the approval of Sublocade adds a second monthly injectable alongside Vivitrol and potentially could diminish “one of the biggest competitive advantages held by Vivitrol.”

STAT also pointed to another likely financial incentive for Invidior to put Sublocade into the market. Medicaid spending on buprenorphine last year was five times higher than for Vivtrol. But those spending statistics could be partly due to the cost discrepancy between monthly Vivitrol and Suboxone and not the preference for buprenorphine. However, it is likely Invidior will be able to slice off a nice chunk of non-negotiated drug price income for Sublocade from Medicaid.

Another STAT article discussed a study published in The Lancet, Lee et al., that found both Vivitrol and Suboxone had comparable effectiveness outcomes during 24 weeks of outpatient treatment. STAT quoted Dr. Nora Volkow, director of NIDA as saying she hoped the study will change the widespread prejudice patients don’t do as well on naltrexone as they do on buprenorphine.  Apparently it didn’t. In the very same STAT article, two different doctors, not involved in the study, said the study showed buprenorphine was more effective than Vivitrol. However, the lead author of the study, Dr. Joshua Lee told STAT: “Both medications worked quite similarly and, therefore, both should be discussed as treatment options.”

The study findings pointed to by the two doctors included the following: its easier to initiate and patients stay with the treatment (buprenorphine) longer. Fewer participants successfully started Vivitrol treatment, as it required a three day period for detoxification, whereas Suboxone participants could begin as soon as the onset of withdrawal symptoms began. The differences in induction rates were 72% for Vivitrol and 94% for Suboxone.

Naltrexone (Vivitrol) is an antagonist, meaning if there were residual levels of opioids in a participant’s body they would immediately be thrown into acute withdrawal. The delay was medically necessary. Naltrexone is also not an opioid, while Suboxone (buprenorphine) is. The induction period with Vivitrol was expected by the study authors themselves to be more difficult. They didn’t get the easement of acute opioid withdrawal that the Suboxone group did—and yet, 72% were successfully inducted into the study.

Curiously one individual pointed to where many of the overdoses in the study occurred after detox, apparently indicating more occurred with Vivitrol. Yet she failed to comment on the fact that of the five fatal overdoses in the study, THREE were in the Suboxone group!

There were more relapse events (defined as 4 consecutive weeks of any non-study opioid use by urine toxicology or self-report, or 7 consecutive days of self-reported use.) for the Vivitrol group, but “most or all of this difference [was] accounted for by early relapse in nearly all (70 [89%] of 79) XR-NTX induction failures.” The more difficult time intiating patients into Vivitrol treatment effected the over relapse rates. “However, once initiated, both medications were equally safe and effective.”

The Lee et al. study was actually the second study to demonstrate that Vivitrol was as effective as Suboxone in maintaining short-term abstinence. The previous study was a smaller Norwegian study, Tanum et al., that followed its participants for 12 weeks. The bottom line is replicated results are more difficult to rationalize away.

Diversion and abuse of Suboxone has been evident from the time it was approved by the FDA. The approval of Sublocade would hopefully nullify the diversion and abuse problems experienced with Suboxone, if you have the money or insurance for it.

Bringing buprenorphine into the realm of “a restricted delivery system” to prevent direct distribution to patients also seems to be where some justification for the added cost factor comes in. But I wonder to what extent dispensing Vivitrol and Sublocade in a medical setting can justify the high cost. Is there price gouging going on? This is now the second time that technological innovation has extended patent exclusivity for Indivior’s buprenorphine products. Read more about how Reckitt Benckiser, the parent company to Indivior and Indivior itself accomplished this in “The Opioid Buzzard.”

01/12/18

Drunken Monkeys

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In the article, “What does it mean to be human?, the Smithsonian noted how DNA studies have demonstrated that on average, genetic differences between individual human individuals is about .1%. When the same kind of study is done comparing chimpanzees and bonobos with humans, the diversity is about 1.2%. The DNA difference of humans, chimpanzees and bonobos with gorillas is about 1.6%. “The DNA evidence leaves us with one of the greatest surprises in biology: the wall between human, on the one hand, and ape or animal, on the other, has been breached.” Given the close genetic relations we humans have to chimpanzees, apes and monkeys, perhaps it will be no great surprise to hear that researchers have shown they also have a weakness for ethanol. No, really, monkeys and chimpanzees like to get tipsy.

Watch this short BBC video of monkeys stealing alcoholic drinks from unaware, distracted humans at the beach. Keep watching and you’ll also see a suspiciously tipsy monkey who has trouble standing up. The video claims there are even tea totaling monkeys, at around the same percentage as humans. “In line with human habits, most [monkeys] drink in moderation. Twelve percent are steady drinkers and 5% drink to the last drop.” The theory is that like monkeys, we developed a taste for alcohol when we scoured the forest for ripe fermenting fruit.

This behavior also exists in the wild, independent of human drinking and fermentation behaviors. Here is a short video of a chimpanzee drinking fermented, alcoholic plant sap in the wild. The BBC also reported on a 17-year study of wild chimpanzees in the African country of Guinea where the chimpanzees repeatedly ingested naturally fermented palm wine from raffia palm trees. Local humans harvest the “palm wine” by tapping the trees at the crown and gathering the sap in plastic containers. Researchers have then seen chimpanzees—often in groups—climbing the trees to drink the fermented palm sap out of the containers.

The chimps even used drinking tools which the researchers called leaf sponges. They would chew handfuls of leaves and crush them into absorbent sponges. Then they would dip their sponge into the liquid and suck out the contents. In order to measure the extent of the chimp’s drinking, the scientists measured the alcohol content of the wine and filmed the chimps’ “drinking sessions.” Some individuals consumed the alcohol equivalent to of a bottle of wine. “[They] displayed behavioural signs of inebriation, including falling asleep shortly after drinking.”

Dr Catherine Hobaiter, from St Andrews University, said: “It would be fascinating to investigate the [behaviour] in more detail: do chimps compete over access to the alcohol? Or do those who drank enough to show ‘behavioural signs of inebriation’ have a bit of a slow day in the shade the next morning?”

The actual study, “Tools to Tipple: Alcohol Ingestion by Wild Chimpanzees Using Leaf-Sponges,” was published in the journal Royal Society Open Science. It reported that the ethanol in the palm wine varied between 3.1% alcohol by volume (ABV) and 6.9% ABV. Over 17 years the researchers observed 51 drinking events among the chimpanzees. They always used a leaf tool to drink, dipping it into the container with the fermented palm sap. “Individuals either co-drank, with drinkers alternating dips of their leaf-sponges into the fermented palm sap, or one individual monopolized the container, while others waited their turn.”

Some of the chimpanzees at Bossou consumed significant quantities of ethanol and displayed behavioural signs of inebriation. . . . Unlike examples of primates ingesting anthropogenic sources of ethanol elsewhere, such as introduced green monkeys at St Kitts targeting tourist cocktails [seen in the above video], chimpanzee attraction to fermented palm sap at Bossou does not result from former provisioning of ethanol by local people.

In another study, “Hominids Adapted to Metabolize Ethanol Long Before Human-Directed Fermentation,” Carrigan et al. suggested that an enhanced ability to metabolize alcohol in the last common ancestor of living African apes and humans may have resulted from an evolutionary change with an enzyme (ADH4). The changed enzyme enabled them to metabolize ethanol and happened “near the time that they began using the forest floor, about 10 million years ago.”  The researchers thought their findings had implications not only for understanding the forces shaping hominin adaptations to ground-based living, but also for understanding the medical complexities of humans and alcohol today.

There is a short audio on The Academic Minute on “Human Alcohol Consumption” summarizing the above research. In much the same way humans are wired to enjoy sugar, salt and fat Carrigan et al. suggest our genes adapted to promote alcohol consumption. The theory is this gave our ancestors a dietary benefit, as ethanol was present in fermenting fruit that fell from the trees onto the ground.

The results were very clear – the ancestor of humans and our close relatives, the chimpanzee and gorilla, acquired a mutation ~10 million years ago that enable them to metabolize ethanol much more efficiently than previous ancestors.   This coincided with a major global climate change that caused the African forests to shrink, and suggests our ancestors adapted to ethanol in fruit to cope with a dwindling food supply.This does not mean our genomes are adapted to the much higher levels of ethanol found in modern alcoholic beverages … and so much like with sugars, salt and fat, we are now at risk of over-consuming something that was once scarce but important.

Another academic paper by Robert Dudley, “Ethanol, Fruit Ripening, and the Historical Origins of Human Alcoholism in Primate Fruigivory,” made a similar point from his research in the Republic of Panama. “Sustained evolutionary exposure to low-concentration ethanol will favor the evolution of metabolic adaptations that maximize physiological benefits associated with ethanol ingestion while concomitantly minimizing related costs.” Conversely, exposure to higher concentrations of ethanol not naturally encountered may cause harm. Dudley’s 2004 paper led to the publication of his 2014 book, The Drunken Monkey: Why We Drink Alcohol. Dudley’s work was the origins of what is called “The Drunken Monkey Hypothesis,” which proposed that: “A strong attraction to the smell and taste of alcohol conferred a selective advantage on our primate ancestors by helping them locate nutritious fruit at the peak of ripeness.” In the Middle Ages, people learned to distill spirits, concentrating the natural alcoholic content of fermented fruits and grains. “The once advantageous appetite for alcohol became a danger to human health and well-being.”

The last part of the hypothesis suggesting that the development of distillation in the Middle Ages changed the advantageous appetite for alcohol to a danger for human health is not accurate. Hundreds, even thousands of years before that time people understood the dangers of even fermented fruits to human health and well-being. There is a Chinese proverb that says: “To stop drinking, study a drunkard when you are sober.”  An Egyptian proverb says: “Yesterday’s drunkenness will not quench today’s thirst.” The Greek poet Theognis, writing in the sixth century BC, made several comments on the problems with over indulging wine. Here are a few:

“Surely to drink much wine is an ill.”“Wine maketh light the mind of wise and foolish alike, when they drink beyond their measure.”My head is heavy with drink, Onomacritus, and wine constraineth me; I am no longer the dispenser of my own judgment, and the room runneth round. Come, let me rise and try if haply wine possess my feet as well as my wits.  I fear I may do some vain thing in my cups and have great reproach to bear.” “Wine maketh light the mind of wise and foolish alike, when they drink beyond their measure.”“He that overpasseth the due measure of drinking is no longer master either of his tongue or his mind, but telleth reckless things disgraceful to sober ears, and hath no shame in what he doeth in his cups, a wise man once, but now a fool.”

There are also biblical passages condemning drunkenness, such as Proverbs 20:1, which says: “Wine is a mocker and strong drink brawler, and whoever is led astray by it is not wise.” Proverbs 23:29-35 is an extended passage about the negative consequences drunkenness. Verses 31-32 read: “Do not look at wine when it is red, when it sparkles in the cup and goes down smoothly. In the end it bites like a serpent and stings like an adder.” So dividing the history of human appetite for alcohol as advantageous before distillation and dangerous afterwards seems to miss the point.

However, the allure of alcohol as a motive for human tree dwelling ancestors to spend more time on the ground looking for it in fermented fruit fits well with another hypothesis for why humans changed from hunter-gatherers to sedentary farmers in the so-called Neolithic Revolution.

In his paper on the origins of brewing technology in ancient Mesopotamia, Peter Damerow noted where the technique of brewing beer has been discussed as a possible motive for the development of human culture in Neolithic times. The theory suggests that rather than using grain for other foodstuffs like bread, the discovery of the intoxicating effect of ethanol in beer “caused the transition from hunting and gathering to living in stable settlements, domesticating animals, and cultivating the soil.” This happened about 7,000 BC. While there is no conclusive evidence to support this hypothesis, “there can be no doubt that the emergence of agriculture was closely related to the processing of grain after the harvest, and that beer brewing soon belonged to the basic technologies of grain conservation and consumption.”

It is intriguing and somewhat perverse to say the lure of intoxication seems to have guided human development at two crucial crossroads.

01/2/18

What is the Future for Kratom?

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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.

12/22/17

Taliban as an IED

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The President of Afghanistan, Ashraf Ghani said that without drugs, the Afghan war would have been over. “The heroin is a very important driver of this war.” Former President of Afghanistan, Hamid Karzai, said the opium problem was the single greatest threat to the long-term security, development and effective governance of Afghanistan. “Either Afghanistan destroys opium or opium will destroy Afghanistan.” The New York Times reported Afghanistan has consistently produced approximately 85% of the world’s opium, despite more than $8 billion spent by the US to eradicate the trade.

Economic factors are driving opium problem in Afghanistan. The United Nations publishes a yearly Human Development Report that “focuses on how human development can be ensured for every one—now and in future.” It uses a summary measure referred to as the Human Development Index (HDI) which assess progress in three basic dimensions of human development: a long and health life (measured by life expectancy), access to learning and knowledge (measured by expected years of schooling), and a decent standard of living (measured by Gross National Income per capita). Afghanistan’s HDI value for 2015 was 0.479, placing it in the lower section for human development at 169 out of 188 countries and territories.

As one of the poorest countries in the world, its 31 million people have an average per capita income of just $800, with 80 percent of its rural population living in poverty. Only 23 percent of Afghans have access to safe drinking water, and only 6 percent to electricity.

Colonel John Glaze wrote the above quote in a report for the Strategic Studies Institute of the U.S. Army War College titled, “Opium and Afghanistan: Reassessing U.S. Counternarcotics Strategy.” Glaze went to note how the high turn on investment from opium poppy cultivation drove an agricultural shift from growing traditional crops, like wheat, corn, barley, rice, to growing opium poppy. “In recent years, many poor farmers have turned to opium poppy cultivation to make a living because of the relatively high rate of return on investment compared to traditional crops. Consequently, Afghanistan’s largest and fastest cash crop is opium.”

Cultivating opium poppy makes powerful economic sense to the impoverished farmers of Afghanistan. It is the easiest crop to grow and the most profitable. Even though the Karzai government made opium poppy cultivation and trafficking illegal in 2002, many farmers, driven by poverty, continue to cultivate opium poppy to provide for their families. Indeed, poverty is the primary reason given by Afghan farmers for choosing to cultivate opium poppy. With a farm gate price of approximately $125 per kilogram for dry opium, an Afghan farmer can make 17 times more profit growing opium poppy—$4,622 per hectare, compared to only $266 per hectare for wheat.Opium poppy is also drought resistant, easy to transport and store, and, unlike many crops, requires no refrigeration and does not spoil. With Afghanistan’s limited irrigation, electricity, roads, and other infrastructure, growing traditional crops can be extremely difficult. In many cases, farmers are simply unable to support their families growing traditional crops; and because most rural farmers are uneducated and illiterate, they have few economically viable alternatives to growing opium poppy.

Business Insider reported an Afghan farmer could be paid $163 for a kilo of raw opium, which looks like a black sap. When the raw opium is refined into heroin, it can be sold for $2,300 to $3,500 per kilo at regional markets. “In Europe it has a wholesale value of about $45,000.”  In the past, most of the opium harvest was smuggled out of the country as raw opium and then refined in other countries. But now, officials estimate that half or more of Afghan opium is processed at some level within the country.

“Afghanistan’s economy has thus evolved to the point where it is now highly dependent on opium.” In 2006, revenue from opium cultivation was over $3 billion, more than 35% of the country’s total gross national product (GNP). Opium production has become Afghanistan’s top employer and the principle base of its economy. An estimated 10% of the population are involved in some way with opium cultivation. Yet less than 20% of the $3 billion in profits goes to the farmers that grow the opium.

Traditionally, processing of Afghan’s opium into heroin has taken place outside of Afghanistan; however, in an effort to reap more profits internally, Afghan drug kingpins have stepped up heroin processing within their borders. Heroin processing labs have proliferated in Afghanistan since the late 1990s, particularly in the unstable southern region, further complicating stabilization efforts. With the reemergence of the Taliban and the virtual absence of the rule of law in the countryside, opium production and heroin processing have dramatically increased, especially in the southern province of Helmand. In 2006, opium production in the province increased over 162 percent and now accounts for 42 percent of Afghan’s total opium output. According to the UNODC, the opium situation in the southern provinces is “out of control.”

The refining labs are simple, nondescript huts or caves containing maybe two dozen empty barrels for mixing, sacks or jugs of precursor chemicals, piles of firewood, and a press machine. They also have a generator, a water pump and a long hose to draw water from a nearby well. Afghan police and American Special Forces repeatedly ran into them all over Afghanistan in 2017. “Officials and diplomats are increasingly worried that the labs’ proliferation is one of the most troubling turns yet in the long struggle to end the Taliban insurgency.” Afghanistan’s deputy interior minister in charge of the counternarcotics police estimated his forces destroyed more than 100 of the estimated 400 to 500 labs in the country last year. However, “They can build a lab like this in one day.”

The NYT noted the Taliban has long profited by taxing and providing security for producers and smugglers. “But increasingly, the insurgents are directly getting into every stage of the drug business themselves, rivaling some of the major cartels in the region — and in some places becoming indistinguishable from them.” Refining makes the drug easier to smuggle and dramatically increases the profits for the Taliban. Officials estimate that up to 60% of the Taliban’s income now comes from the drug trade.

In country drug seizures suggest more opium is being processed within Afghanistan. Previously, the amount of opium seized would be five times or more than that of morphine and heroin. “In 2015, for example, about 30,000 kilograms, or 66,000 pounds, of opium was seized, compared with a little over 5,000 kilograms, or 11,000 pounds, of heroin and morphine combined.” But so far in 2107, the seizure numbers have reversed. The amount of heroin and morphine seized is double that of raw opium.

And there seems to be a direct relationship between recent Taliban gains territorially and the drug trade. The Southern Afghan provinces of Helmond, Uruzgan and Kandahar are where much of the country’s opium-poppy production occurred in 2016. They are also in the midst of the country’s provinces with the highest security risks. A senior Afghan official said: “If an illiterate local Taliban commander in Helmand makes a million dollars a month now, what does he gain in time of peace?” See the map below originating with the United Nations Department of Safety and Security.

The Taliban seem to be in the midst of changing from a fundamentalist Sunni political movement into a drug cartel. Their mixture of ideology, power and greed has led to a situation in Afghanistan that can be likened to a political and cultural IED. Afghanistan’s deputy interior minister in charge of the counternarcotics police said the Taliban used the growing insecurity over the past two years to establish more refining labs and move them closer to the opium fields. The Afghan deputy minister of counternarcotics said: “We have to merge these two things together — the counterterrorism and the counternarcotics. It has to go hand in hand, because if you destroy one, it is going to destroy the other.”

For more on the Taliban and the drug trade, see “Opium and the Taliban.”

12/12/17

Greed with OxyContin is NOT Good

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The health insurer Cigna announced that effective January 1, 2018, it will no longer cover OxyContin as a preferred medication. The company is in the process of notifying customers with current OxyContin prescriptions and their doctors of the upcoming change. Individuals who have begun using OxyContin for hospice care or cancer treatments will continue to be covered through 2018. If a doctor believes the use of OxyContin is medically necessary, Cigna will consider approving coverage. Needless to say, Purdue Pharmacy, the manufacturer of OxyContin, disagrees with the Cigna decision.

Cigna will offer an oxycodone equivalent medication with abuse deterrent properties, Xtampza ER with Collegium Pharmaceuticals. Collegium signed a “value-based contract” with Cigna, which will hold the company financially accountable if average daily dosage strengths of Xtampza ER prescribed for Cigna customers exceed a specific threshold. If the threshold is exceeded, Collegium will reduce the cost of the medication. “Linking financial terms to dosage metrics may encourage more education to prevent overprescribing.”

The Fix reported a Purdue spokesperson said there were few differences between OxyContin and Xtampza ER. “Unfortunately, Cigna’s decision limits the tools prescribers can use to help address the opioid crisis as both products are formulated with properties designed to deter abuse.” Cigna responded by saying the point is to change prescription practices. “The insurer hopes that doctors will begin to prescribe drugs like Xtampza ER ‘in lesser quantities and for lesser amounts of time.’”

Cigna’s decision comes in the midst of increasing pressure on Purdue Pharmacy for their aggressive, and at times illegal marketing practices of OxyContin. The pharmaceutical company came under scrutiny partly because of a series of investigative reports by the LA Times that noted a series of issues. The issues including how Purdue Pharma knew pain relief with OxyContin did not last the 12 hours as it claimed; but the company continued to insist the drug did last, in part, to protect its revenue. When doctors complained about the duration, Purdue instructed them to prescribe stronger, not more frequent doses. “OxyContin’s market dominance and premium price hinge on its 12-hour duration.” Purdue allegedly knew of this issue for more than twenty years.

For years, Purdue Pharma lied to federal regulators and the public about the addictiveness of OxyContin and countless patients got hooked on this deadly painkiller. We need to know if Purdue once again lied about the longevity of OxyContin’s pain-relieving properties and hold Purdue accountable.

Additionally, Purdue knew OxyContin was being overprescribed and illegally trafficked, but in many cases, did nothing about it. With one such operation, Lake Medical, Purdue did not stop supplying OxyContin and did not tell authorities what it knew for several years until the clinic was out of business and its leader indicted. By that time, 1.1 million pills has been put on the street.

A Los Angeles Times investigation found that, for more than a decade, Purdue collected extensive evidence suggesting illegal trafficking of OxyContin and, in many cases, did not share it with law enforcement or cut off the flow of pills. A former Purdue executive, who monitored pharmacies for criminal activity, acknowledged that even when the company had evidence pharmacies were colluding with drug dealers, it did not stop supplying distributors selling to those stores.

In 2015 Kentucky received $24 million from Purdue to settle the state’s 2007 against the company over their allegedly illegal promotion of OxyContin. As is usual in cases where pharmaceutical companies settle outside of court, they requested the records gathered in the court case be sealed and destroyed. In this case, there were 17 million pages of documents, including a deposition of Dr. Richard Sackler, the former president of Purdue Pharma and a member of the family who owns the privately held company. As part of the agreement, the Kentucky attorney general destroyed its copies of the documents provided by Purdue. However, copies of several key documents, including the Sackett deposition, filed under seal at the Pike County court, were not destroyed.

STAT News learned of the existence of these documents and filed a motion in March of 2016 to unseal the documents. In May of 2016 a Kentucky judge ordered that the documents be unsealed by June 12th. The judge said he would stay the release of the records if there was an appeal filed before then.  As of June of 2017, the documents were still not released. Purdue appealed the ruling to the Kentucky Court of appeals and although the appeals court said it expected to rule on the matter by the end of August, there was still no announcement by the middle of October.

The President of the Kentucky state Senate planned to file a motion to support the efforts by STAT to unseal the documents, saying that shielding the records from public view was “inappropriate.” He acknowledged his request to intervene could be unsuccessful, and it seems that it was. He thought the documents could help evaluate whether the $24 million payment from Purdue was a good settlement for Kentucky. “Two prior attorneys general valued the case at between $100 million and $1 billion.” Senate President Robert Stivers was concerned the state settled for “pennies on the dollar.”

Purdue was already pivoting to go overseas with its marketing strategy by 2011. With the growing concern over the opioid crisis in the U.S. and the awareness of the role OxyContin played in it, prescriptions fell by almost 40% since 2010, meaning billions in lost revenue for Purdue. Again, the LA Times documented this market expansion by Purdue in a December 2016 article, “OxyContin Goes Global.” Using a network of international companies owned by the Sackler family, Purdue Pharma is moving rapidly into Latin America, Asia, the Middle East, Africa and other regions. “In this global drive, the companies known as Mundipharma, are using some of the same controversial marketing practices that made OxyContin a pharmaceutical blockbuster in the U.S.”

In 2011, operations were started in China, Russia, Turkey, Hong Kong and South Africa. 2013 saw activity in Indonesia, Vietnam, Thailand and Taiwan. Dubai, Brazil, Columbia and Spain came on board in 2014. Lebanon and Portugal opened operations in 2015; Argentina in 2016. Chile, Ecuador, Peru, Uruguay and Venezuela plan to launch operations in the near future.  There is an interactive map on “OxyContin Goes Global” that graphically illustrates this expansion.

In Brazil, China and elsewhere, the companies are running training seminars where doctors are urged to overcome “opiophobia” and prescribe painkillers. They are sponsoring public awareness campaigns that encourage people to seek medical treatment for chronic pain. They are even offering patient discounts to make prescription opioids more affordable.

Like the initial marketing of OxyContin in the U. S., some Mundipharma representatives and promotional material minimize the risks that patients will become addicted to opioid medications. While U.S. public health officials were warning of the growing pain killer threat in 2015, a Mundipharma executive in Seoul South Korea was saying doctors there worry too much about addiction: “Many studies have shown that it’s almost impossible for those with chronic or severe pain to become addicted to narcotics, as long as the drug is used for pain relief.” The opioid problem in the U.S. is said to be largely due to recreational abuse of the drugs.

“That is exactly the same thing they were teaching U.S. physicians when they launched OxyContin in this country,” said Sharon Walsh, an addiction expert who advises the FDA on risks from pain medications.

Mundipharma uses consultants (referred to as thought leaders in the U.S.), as did Purdue and other pharma companies, to overcome this opiophobia among doctors reluctant to prescribe narcotics. Top company officials have said their success in new markets depends on defeating this mind-set.

In Spain, Mundipharma used a series of actors, musicians and models in a campaign against chronic pain. “Ebélate contra el dolor (Rebel against the pain).” The ads did not recommend a specific medication, but urged viewers to seek out a healthcare professional (call your doctor?).  “The campaign is part of a strategy to redefine back pain, joint aches and other common conditions as a distinct malady — chronic pain — that doctors and patients should take seriously.” Mundipharma sales were up seven-fold since 2007.

Around the world, Mundipharma companies cite statistics suggesting there is a great unmet need for their products. Opening an office in Mexico in 2014, Mundipharma officials declared that 28 million citizens were suffering from chronic pain. In Brazil, the company cited a figure of 80 million. In Colombia last year, a company news release said 47% of the population — about 22 million people — were afflicted by ‘this silent epidemic.’”

Meanwhile, back in the US, the lawsuits against Purdue Pharma just keep on coming. In May of 2017 the NYT reported Purdue and three current and former executives pleaded guilty in federal court to criminal charges “that they misled regulators, doctors and patients” about the drug’s addiction risk and potential for abuse. In order to resolve criminal and civil charges stemming from the drug’s “misbranding,” Purdue agreed to pay $600 million, one of the largest amount ever paid by a drug company in such cases. Three executives, including its president and its top lawyer pleaded guilty as individuals to misbranding, which is a criminal violation. “They agreed to pay a total of $34.5 million in fines.”

Purdue Pharma acknowledged in the court proceeding today that “with the intent to defraud or mislead,” it marketed and promoted OxyContin as a drug that was less addictive, less subject to abuse and less likely to cause other narcotic side effects than other pain medications.

Reuters reported that New Hampshire announced in the beginning of August of 2017 that it was suing Purdue for engaging in deceptive marketing practices. The lawsuit followed similar cases against Purdue and other pharmaceutical companies by Oklahoma, Mississippi, Ohio and Missouri and several cities and counties in California, Illinois, Ohio, Oregon, Tennessee and New York.

A week later, South Carolina filed suit against Purdue Pharma, according to Reuters. Again the company is accused of unfair and deceptive marketing of opioid painkillers. South Carolina had been part of a 2007 settlement when Purdue and three executives pleaded guilty to federal charges of misbranding OxyContin. In the August 2017 lawsuit, “South Carolina claimed that since the 2007 settlement, Purdue has continued to engage in misleading opioid marketing practices rather than reforming them to conform with the law.”

In the 1987 movie Wall Street, Michael Douglas as Gordon Gekko famously said, “Greed, for lack of a better word, is good.”  He went on to claim that greed captured the essence of the evolutionary spirit. “In all of its forms; greed for life, for money, for love, knowledge has marked the upward surge of mankind.” At the end of his speech, he was applauded. The greed of Purdue Pharma and the Sackett family, which privately owns Purdue Pharma and OxyContin, is not good. Their unrestrained greed has contributed to the current opioid epidemic in the U.S., despite the denials of the company. And now they want to export the same drug and marketing strategy to the world.

12/1/17

Snorting Chocolate

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You probably won’t see any of this product in your kids Trick or Treat stash, but keep a lookout for a tin of Coco Loko in their rooms just in case. Yes, you read that correctly. Coco Loko is snortable chocolate powder. Marketed by Legal Lean, the Florida-based company founded by Nick Anderson, Coco Loko is the first product of its kind in the US. Similar products have been available in Europe for several years. After ordering and trying one, Anderson decided to create his own “raw cacao snuff.” So he invested $10,000 with an Orlando-based supplement company and created Coco Loko.

The Washington Post quoted Anderson as saying the effect is “almost like an energy-drink feeling, like you’re euphoric but also motivated to get things done.” He said he uses his product as an alternative to drinking and at music festivals and in “those types of social situations when you feel anxious.” Rolling Stone reported that Coco Loko promised a “30-minute buzz,” that would lift moods, reduce anxiety and give you a surge of energy. “Legal Lean claims Coco Loko will cause a rush of endorphins and serotonin, boost energy, and bring about a sense of calm. But the company hasn’t provided concrete research to back up those claims.”

However, the company website now refers to its product as “Coco Snuff” and the overt claims noted in Rolling Stone and other media write ups just after its release and attributed to Legal Lean are now not directly attributed to Coco Loko/Coco Snuff. Legal Lean makes no such claims anymore about Coco Snuff. You learn about endorphins, that a serotonin rush produces “an elevated mood and a state similar to the feeling of ecstasy [not the drug ecstasy]. This is the feeling that will make the music sound better and overall happiness.” Gee, isn’t that why the drug ecstasy was used at raves?

Raw cacao is said to give you a steady rush of euphoric energy that helps party goers “Dance the nigh away without a crash.” Then it claims raw cacao can give you a “calm focus,” reducing the chatter in your brain. “It is also known to help with anxiety and to reduce stress.”

The revisions to product description are likely the result of action taken by Senator Chuck Schumer where he called on the FDA to formally launch an investigation into “Coco Loko.” He said the product was a “brazen example of ‘narcotic marketing.’” He said it was like cocaine on training wheels. Schumer, The Washington Post and others (like The Fix) have reported it contains caffeine, guarana and taurine, which are ingredients commonly found in energy drinks. You won’t find that information on their website.

This suspect product has no clear health value. It is falsely held up to be chocolate, when it is a powerful stimulant. And they market it like a drug – and they tell users to take it like a drug, by snorting it. It is crystal clear that the FDA needs to wake up and launch a formal investigation into so-called Coco Loko before too many of our young people are damaged by it. ‘Coco Loko’ isn’t even pure chocolate at all. Instead, it is chock full of concentrated energy drink ingredients masked and marketed under the innocence of natural and safe chocolate candy. Parents and doctors don’t want kids snorting anything at all, especially not dangerous stimulants proven to wreak havoc on the bodies and brains of young kids and teens. That’s why the FDA must formally investigate this dangerous ‘party goer’ fad before it hurts our kids, not after.

The Washington Post reported in July of 2017 the FDA had not decided on how or whether to regulate the product. An FDA spokesperson said: “In reaching that decision, FDA will need to evaluate the product labeling, marketing information, and/or any other information pertaining to the product’s intended use.” Thus the changes in product effects on the website. The company is trying to keep under the FDA’s radar A representative for the DEA said he was not aware of any agency concerns with chocolate inhalants. According to reports mentioned by Schumer, the Legal Lean said the effects were “equal to about two energy drinks.”

Anderson said he didn’t consult any medical professionals when he created Coco Loko, “nor have scientists tested the snortable snuff before it was released to the public,” according to Rolling Stone. A company spokesperson said they used research data on the market in Europe. “There are no health issues … everyone seems fine. . . . It says not to do more than half the container, I think everything is self-explanatory, there are warning labels on it and I don’t think I would be responsible.”

There have been previous concerns raised about the health effects of energy drinks containing the ingredients reported to be in Coco Loko— caffeine, taurine and guarana. There can be increased blood pressure or heart palpitations. Those effects could be magnified when someone inhales these stimulants. The director for the John Hopkins Sinus Center said as yet, there is no data reported on health consequences, but he did have a few concerns.

First, it’s not clear how much of each ingredient would be absorbed into the nasal mucus membranes. And, well, putting solid material into your nose — you could imagine it getting stuck in there, or the chocolate mixing with your mucus to create a paste that could block your sinuses.

Another sinus specialist, Dr. Jordan Josephson, said you could expect more pulmonary problems like asthma or bronchitis. Blocked sinuses could lead to snoring and even sleep apnea, which in some cases could be fatal. There are multiple social media and online reports of trying snortable chocolate products like Coco Loko.

Hopefully, this product will go the way of Palcohol, a powered alcohol product that Senator Schumer took on in 2015. As with Coco Loko, his concern was it would be marketed to teens. One of the voiced concerns then was that powered alcohol could be snorted. According to The Hill, the manufacturer of Palcohol fought back by saying: “Listen, people can snort black pepper … so do we ban it? No, just because a few goofballs use a product irresponsibly doesn’t mean you ban it.” The company reported that although its product was approved on March 10, 2015 for legal sale in the US, it would not be manufacturing Palcohol. Rather, it would be “auctioning off the secret formula and manufacturing process.” Let’s hope Coco Loko ends up with a similar fate. For more on Palcohol, see: “Hype Over Powered Alcohol” or “Down For The Count?”

P.S. On December 11, 2017 the FDA took action against Legal Lean for its marketing and distribution of two of its products, Coco Loco and Legal Lean Syrup. “The warning letter explains how the claims made in the promotional materials for Legal Lean Syrup and Coco Loko demonstrate that the products are intended to be used as alternatives to illicit street drugs and that the products, as labeled and marketed, may pose safety concerns.” The FDA warning letter stated that Coco Loko was labeled as a food and marketed as a dietary supplement on the company website. However, since it is intended for intranasal administration, it is not a food or dietary supplement. “Failure to correct violations may result in FDA enforcement action, including seizure or injunction, without further notice.”

 

11/21/17

Cunning, Baffling, Powerful

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Vincent Dole was one of the three physicians who originated methadone as a maintenance drug treatment for heroin addiction in the 1960s. Rather unexpectedly, he was asked to serve as a Class A, non-alcoholic, trustee for the General Service Board of Alcoholics Anonymous. He thought they had made a mistake so before accepting the position, he discussed his research into “chemotherapy for narcotic addiction” with executives of the A.A. Fellowship. They didn’t see any problem or conflict of interest with his appointment and Dr. Dole served as a trustee for A.A. for eleven years, from April of 1965 until April of 1975.

At one point in his tenure as a trustee, he served as a co-chair for the General Service Board. In his farewell letter to the A.A. GSO, printed in the August-September issue of Box 4-5-9, the newsletter from the General Service Office of A.A., he said he would always remain identified with A.A. “My heart is with the Fellowship.”

Like most in A.A., I have gained more in the association than I have been able to give. Especially, it has been a privilege to witness the power of love when focused and unsentimental. I have seen that: Salvation is found in helping others; help stems from knowledge, humility, compassion, and toughness; success is possible.My greatest concern for the future of A.A. is that the principle of personal service might be eroded by money and professionalism. Fortunately, most of the membership of A.A., especially the oldtimers, know that A.A. cannot be commercialized. It is not a trade union of professional counselors or an agency hustling for a budget. The mysterious wisdom of A.A. will discover how to cooperate in reaching out to sick alcoholics while maintaining its Traditions.

In a 1991 article he wrote for the journal Alcoholism, “Addiction as a Public Health Problem,” Dr. Dole said that throughout his time as a trustee he was puzzled by why he specifically was asked to serve. He ended by assuming he had been “brought in as a smoke alarm, a canary in the mine” to guard against “the Fellowship being distorted by aggressive person with dogmatic opinions.” Then, in the late 1960s, he believed a more specific reason emerged, not long before Bill W.’s death. An excerpt from that article is available here: “The Methadone/AA Link.”

A more specific answer, however, emerged in the late 1960s, not long before Bill’s death. At the last trustee meeting that we both attended, he spoke to me of his deep concern for the alcoholics who are not reached by AA, and for those who enter and drop out and never return. Always the good shepherd, he was thinking about the many sheep who are lost in the dark world of alcoholism. He suggested that in my future research I should look for an analogue of methadone, a medicine that would relieve the alcoholic’s sometimes irresistible craving and enable him to continue his progress in AA toward social and emotional recovery, following the Twelve Steps. I was moved by his concern, and in fact subsequently undertook such a study.

Dr. Dole went on to say he unsuccessfully sought to find that analogue in his laboratory until it closed in 1991. But he thought the work had just begun. Other laboratories and investigators would continue to work on the analogue problem. “With the rapid advance in neurosciences, I believe that Bill’s vision of adjunctive chemotherapy for alcoholics will be realized in the coming decade.”

Since Dr. Dole made that optimistic prediction, several different medications have been used as a harm reduction strategy for individuals with alcohol dependence or alcohol use disorders. Two opioid antagonists, nalmefene and naltrexone and three drugs acting on the gamma-aminobutyric acid (GABA)ergic system (baclofen, acamprosate and toprimate) has been used formally or informally to reduce alcohol consumption or maintain abstinence. Recently in the journal Addiction, Palpacuer et al. did a meta-analysis of 32 double-blind randomized controlled trials of these five medications. The studies were published between 1994 and 2015, and had a combination of 6,036 patients between them. They concluded:

There is currently no high-grade evidence for pharmacological treatment to control drinking using nalmefene, naltrexone, acamprosate, baclofen or topiramate in patients with alcohol dependence or alcohol use disorder. Some treatments show low to medium efficacy in reducing drinking across a range of studies with a high risk of bias. None demonstrates any benefit on health outcomes.

There was no evidence of any significant reduction in serious adverse events or mortality. Studies that sought to assess the efficacy of these medications as maintenance drugs, similar to how methadone is used, “were inadequate to investigate” whether they reduced serious adverse events. “In addition, any pharmacological approach that might benefit patients by reducing their alcohol consumption might also harm them because of safety issues.” As a result, the researchers advocated for long-term mega-trials exploring health outcomes.

To conclude, our results suggest that no treatment currently has high-grade evidence for pharmacologically controlled drinking in the treatment of patients suffering from alcohol dependence or alcohol use disorders. At best, some showed low to medium efficacy in reducing drinking, but across a range of studies with a high risk of bias. Although based on all available data in the public domain, this meta-analysis found no evidence of any benefit of the use of drugs aiming for a controlled drinking strategy on health outcomes. We invite researchers and stakeholders to set up a coherent agenda to demonstrate that pharmacologically controlled drinking can be translated into genuine harm reduction for patients. From the clinical perspective, while this new approach is often presented as a ‘paradigm shift’ in terms of therapeutics, doctors and patients should be informed that the critical examination of the pros and cons of the evidence clearly questions the current guidelines that promote drugs in this indication.

Reporting for The Guardian, Sarah Boseley further noted that one of the reasons for the inconclusive findings in Palpacuer et al. was because of the high drop out rates in the studies. “So many people dropped out of the trials that 26 of the 32 studies – 81% of them – had unclear or incomplete outcome data.” The lead author for the study, Clément Palpacuer, said the report did not mean the drugs weren’t effective. “It means we don’t yet know if they are effective. To know that, we need more studies.” There have also been concerns raised about the drugs by some studies already.

Bosley cited Fitzgerald et al., a review of the trial evidence used to approve nalmefene for use in the NHS. The researchers said at best, there was only modest evidence of efficacy in reducing alcohol consumption. This was despite stacking the deck in how the data was analyzed for approval of the drug.

Important weaknesses in nalmefene trial registration, design, analysis and reporting hamper efforts to understand if and how it can contribute to treating alcohol problems in general practice or elsewhere. The efficacy of nalmefene appears uncertain; a judgement of possible limited efficacy in an unusually defined and highly specific posthoc subgroup should not provide the basis for licensing or recommending a drug.

There are issues noted with baclofen as well. A co-author of Fitzgerald et al. noted one French study raised concerns with the safety of baclofen, with more deaths in the treatment group (7 of 162) than the placebo group (3 of 158). A further study by France’s medicines safety agency drew attention to additional adverse effects: “In particular, the risk of intoxication, epilepsy and unexplained death [on the death certificate] increases with the dosage of baclofen.” See “Sure Cure for Drunkenness” and “A ‘Cure’ for Alcoholism” and “The End of Alcoholism?” Part 1, Part 2 and Part 3 for more concerns with baclofen and nalmefene.

Vincent Dole’s search for a methadone analogue or adjunctive chemotherapy for alcoholism is unlikely to be successful. As Carleton Erickson pointed out in The Science of Addiction, alcohol is different than other drugs. He said: “Unlike other drugs, alcohol has no specific receptor to activate in the brain.” Cocaine works on the dopamine transporter. Heroin and other opioids work on the opioid receptor; and marijuana works on the cannabinoid receptor. “Alcohol is known to affect the GABA receptor, the NMDA receptor, and probably others.”

There isn’t a hand-in-glove fit between a receptor and alcohol as there is with the opioid receptor and heroin or other opioids. So there isn’t a medication that can single handedly block alcohol as there is with heroin and other opioids. As Bill W. knew from personal experience, alcohol is cunning, baffling and powerful.

11/10/17

Here’s Some Gray Death

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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?”