01/10/17

Marijuana Makes You Nauseous?

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Live Science reported on a study published in the August 31, 2016 issue of The Lancet that found more people are using marijuana and they are using it more often.  In 2014, 13.4% of people said they had used marijuana in the previous year, an increase of 3% since 2002. The percentage of people who reported daily or near daily use rose from 1.9% to 3.5%. At the same time concerns about the risks associated with marijuana use dropped. In 2002, 50.4% of adults thought there was a great risk with marijuana use. That fell to 33.3% by 2014. But the perception of lowered risks may be premature.

The authors of the Compton et al. study thought the combination of increased marijuana use and a decreasing perception of the harm suggested there was a need for education regarding the risks of smoking marijuana. One of these health risks is for a medical condition called cannabinoid hyperemesis syndrome, or CHS. It is caused by heavy, long-term use of various forms of marijuana. Its symptoms include cyclic episodes of nausea and vomiting; some people have severe abdominal pain. A CBS Evening News report described a man who struggled with symptoms of CHS for two years before it was correctly diagnosed. Oddly, hot showers or baths seem to provide symptom relief.

CHS was first reported in 2004 by Allen et al. The ten patients were all cyclical vomiters and chronic marijuana users. Nine of the ten also had the abnormal bathing behavior of multiple hot showers or baths. The symptoms of nausea, vomiting and abdominal pain would all settle within minutes of taking a hot bath or shower. Symptoms resolved with abstaining from marijuana use in seven of the ten patients. Three of the abstaining patients resumed marijuana use and relapsed within months.

High Times described CHS as a rare form of cannabinoid toxicity that developed in chronic smokers. The author suggested with CHS, there was generally daily use in excess of three to fives times for several years. CHS is often mistaken for cyclic vomiting syndrome (CVS), because the symptoms are similar. But CVS is not caused by marijuana use. CHS is easily cured by abstaining from cannabis use.

This should not, by any means, hurt marijuana’s reputation for being the safest recreational drug around, but people need to be aware of the syndrome’s existence. If you know anyone with these symptoms tell him or her go to a doctor and stop smoking.

A 2011 review article by Galli et al., “Cannabinoid Hyperemesis Syndrome,” observed how the recognition of CHS coincided with the increased use of cannabis. Their review gave an overview of cannabinoid pharmacology that focused on the properties that seem to contributes to CHS. They also gave a clinical description of CHS and a proposed a method for clinical evaluation, which included differential diagnosis and treatment modalities.

Patients are typically young adults with a long history of cannabis use. They present with recurrent episodes of nausea, vomiting and dehydration with frequent visits to emergency departments. In almost all cases, there was a delay of several years between their chronic marijuana use and the onset of symptoms. One study reported an average duration of 16.3 years of cannabis use before the onset of symptoms. But there have been reports where the time lag was equal to or less than three years.

CHS is a recurrent disorder, with symptom-free periods. There are three phases: pre-emetic, hyperemetic, and recovery. The pre-emetic phase can last for months or years. Patients have early morning nausea, a fear of vomiting and abdominal discomfort. They maintain normal eating patterns and may even increase their marijuana use because its reported relief of nausea.

The hyperemetic phase has spasms of intense and persistent nausea and vomiting, which has been described as “overwhelming and incapacitating.” Patients vomit profusely, often without warning—up to five times per hour.  There can be weight loss. Most patients have diffuse, but relatively mild abdominal pain. They are found to be dehydrated, but hemodynamically stable. The tests and work ups done at EDs are inconclusive in the majority of cases.

During this phase, patients take numerous hot showers throughout the day. As this seems to be the only measure that brings some symptom relief, it rapidly becomes a compulsive behavior. The precise mechanism for this relief is not known. It typically lasts for 24 to 48 hours, but the risk of relapse is high if the patient resumes cannabis use.

The recovery phase can last for days, weeks or months. It’s associated with relative wellness and eating patterns. “Weight is regained and bathing returns to regular frequency.”

Patients with CHS usually are misdiagnosed for a considerable length of time. One problem is that it is often confused with cyclic vomiting syndrome (CVS). “Confusion also exists in the medical literature secondary to a failure to recognize chronic marijuana use as a source of vomiting.” Although there is a close similarity of conditions, there are also significant differences.

A 2015 study by Kim et al. looked at the prevalence of patients presenting for cyclic vomiting in Colorado before and after the liberalization of medical marijuana in 2009. A secondary objective was to describe the odds of marijuana use among cyclic vomiting visits during these same time periods. The prevalence of CVS increased from 42 per 113,262 Ed visits to 87 per 125,095 ED visits after marijuana liberalization. Patients with CVS post liberalization were more likely to have documented marijuana use than patients in the pre liberalization period.

The prevalence of cyclic vomiting presentations nearly doubled after the liberalization of medical marijuana. Patients presenting with cyclic vomiting in the postliberalization period were more likely to endorse marijuana use, although it is unclear whether this was secondary to increased marijuana use, more accurate marijuana reporting, or both.

The study said it does not demonstrate causation of CHS. But it does demonstrate a preliminary association “and should serve as the foundation for future prospective studies on the association between marijuana and cyclic vomiting, the eventual establishment of formal diagnostic criteria for CHS.” Foremost among the interventions for symptomatic treatment should be counseling toward abstinence from marijuana use. The authors saw their study as a crucial first step towards establishing a formal diagnosis of cannabinoid hyperemesis syndrome.

High Times seemed to minimize the present concerns with CHS by referring to it as “a very rare syndrome” that is easily cured. CHS does not reverse marijuana’s reputation as “the safest recreational drug around” at this point. But remember that even High Times agreed the cure for CHS is to stop using cannabis. We are just entering into a time of not only increased marijuana use, but also increased daily or near daily marijuana use. As this trend grows into a population of chronic, heavy marijuana users, the safety profile for marijuana will likely change; and it seems that CHS will be part of that decreasing safety profile.

12/30/16

The “Hotel California” Effect

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Alkermes is a believer in the classic idiom, the third time’s the charm. The pharma company recently announced success on its third-late stage clinical for ALKS 5461, which it hopes will become a new antidepressant blockbuster. In January of 2016 two previous phase III trials failed to achieve their primary endpoints and the company’s stock price took a nosedive. After the positive results of the FORWARD-5 study, shares were up over 30%. Alkermes plans to meet with the FDA in order to argue that despite failing in its two previous phase III clinical trials, the FDA should approve ALKS 5461 and “bring this new medication to patients with MDD [major depressive disorder].”  FDA regulations require a total of two successful phase III trials with statistical significance over placebo. What’s going on here?

The FORWARD-4 clinical trial tested two dose levels of ALKS 5461, 2mg and .5 mg and it failed to meet its initial primary endpoint, “change from baseline in the Montgomery Asberg Depression Rating Scale (MADRS) total score.” Post-hoc statistical analysis done on the FORWARD-4 data indicated the group receiving the higher 2mg dose of ALKS 5461 had a statistically significant difference on the MADRS. Alkermes then decided to “update” their methodology and analysis for FORWARD-5. In other words, Alkermes used statistical analysis of the failed FORWARD-4 trial to uncover a significant result within a subpopulation of the study that was not targeted in their initial study design. They then modified their methodology and analysis of the FORWARD-5 trial to match the post-hoc analysis.

In a previous article on the FORWARD-3 and FORWARD-4 failed clinical trials, “Nearsighted Drug Development,” I expressed the opinion that this seemed a bit like cheating. Nevertheless, it seems that changing the methodology from what was initially proposed for an ongoing trial is permitted. But would it be appropriate for the FDA to reconsider the post-hoc analysis of the FORWARD-4 trial as a “successful” clinical trial? It seems a bit like trying to argue that the FDA should give Alkermes credit for positive results in FORWARD-4 even though those positive results only became apparent after the fact—when they began to fiddle around with the data to see if they could find something positive.

Another disturbing claim by Alkermes is with how they describe ALKS 5461. It is “designed to rebalance brain function that is dysregulated in the state of depression.” As I pointed out in “Nearsighted Drug Development,” the chemical imbalance theory of depression is now said to be an urban myth even by pro drug psychiatrists like Ronald Pies.

If approved, ALKS 5461 is proposed as an add-on, adjunctive medication in the treatment of major depression for patients “with an inadequate response to standard antidepressant therapies.” However, there is a hint that if approved ALKS 5461 could be put forward by the company as a standalone treatment for depression. Elliot Ehrich, the CMO of Alkermes, said the studies in the FORWARD program contributed data useful in assessing the safety and efficacy of ALKS 5461 on a standalone basis and if taken as an adjunct medication.

It also appears that if the FDA does not agree to approve ALKS 5461 as a treatment for MDD based upon the above discussed rationale, Alkermes will drop it. Richard Pops, the chairman of Alkermes, said they are not planning to conduct any additional studies on ALKS 5461. Is this just a cut your losses decision to forego the additional cost of another clinical trial for the company? Or is it a veiled threat to the FDA that Alkermes will shelve any future work on a product that was once approved by the agency for a fast track drug development status? In other words will the FDA permit post hoc analysis of a phase III clinical trial turn a failed trial into a successful one?

What is at stake here is that the active ingredient in ALKS 5461 is a known opioid, with an acknowledged addictive potential—buprenorphine. Buprenorphine is a Schedule III controlled substance.  Combining it with an opioid antagonist (samidorphan) does not lessen its addictive potential. In higher doses buprenorphine is used as a maintenance drug therapy for opioid dependence (Suboxone; Subutex; Zubsolv). Regularly, opioid dependent individuals have told me that getting off of buprenorphine was harder than heroin or methadone.

Higher doses and longer term use of buprenorphine influence the length of time for withdrawal or discontinuation. And guess what, depression is one of the commonly experienced withdrawal symptoms. The Addiction Blog posted some helpful information on “How long does buprenorphine withdrawal last?” Note that the website is not taking an anti-buprenorphine position. It begins by saying “Buprenorphine can be a useful drug prescribed to treat opiate addiction.”

Within the first 24 to 72 hours, physical withdrawal symptoms peak in severity and intensity with common symptoms such as: diarrhea, sweating, nausea, dilated pupils, watery eyes and restlessness. As the first week progresses, aches, stomach cramps, and joint pain will probably continue. General feelings of discomfort and problems sleeping can occur. “Mood swings are also common, with bouts of anxiety or depression.”  After two weeks, the pain and discomfort of acute physical withdrawal should be less severe, but depression and an extreme loss of motivation can set in.

After [the] three to four week mark, most of the physical withdrawal symptoms will be gone, however … intense drug cravings may be present for those addicted to buprenorphine. Depression is also common. This time is very important, as you will be very vulnerable to relapse. . . . However, psychological withdrawal symptoms can last for months after cessation.

Now “relapse” here refers to resuming active opioid use or abuse. But in reviewing the withdrawal symptoms described above, the relapse experienced could just as easily be interpreted as a depression relapse by individuals attempting to taper off of long term ALKS 5461 use.

So someone could add ALKS 5461 to their antidepressant of choice, take it for an extended period of time and see a clear remission of their depressive symptoms. If they were to then attempt a taper off of ALKS 5461, they would likely experience the above described buprenorphine withdrawal symptoms, interpret them as a return of depressive symptoms, and resume using ALKS 5461. If ALKS 5461 is used as a stand-alone treatment for depression, a misinterpretation of withdrawal symptoms as a relapse of depression is also likely occur. Similar to long-term antidepressant users, there could be a “Hotel California” effect—you can taper down any time you want, but you can never leave.

With continued use of buprenorphine, there comes a point where the brain produces an inadequate amount of neurotransmitters in the body. People going through buprenorphine PAWS [post acute withdrawal syndrome] manifest long lasting changes in the brain as a result of long term use. These changes are slower to reverse and can persist for many months, depending on the frequency and amount of past dosing.

I don’t know whether the above concerns will be considered in an FDA review of the Alkermes request to approve ALKS 5461. I hope they are. But if Alkermes is successful in bringing its drug to market, “where new therapeutic options are highly sought after as millions of patients in the U.S. do not respond to standard courses of antidepressant therapy,” be prepared for what seems to be an unavoidable cycle of depression treatment perpetuating depression and further treatment. While the rhetoric appears overblown to some, I do believe there is a “Coming Depression Apocalypse” if ALKS 5461 is approved by the FDA.

12/20/16

The Opioid Buzzard

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The U.S. is in the midst of a health crisis from the use and abuse of opioids. Since 1999, the rate of overdose deaths from opioids—prescription pain relievers and heroin—nearly quadrupled. On an average day in the U.S. more than 650,000 opioid prescriptions are dispensed; 3,900 people begin nonmedical use of opioids; 580 people start using heroin; and 78 people die from an opioid-related overdose. Economically, there is a $20 billion cost in emergency department and inpatient care for opioid poisoning each year; and $55 billion spent on health and social costs related to prescription opioid abuse.

In order to address this opioid epidemic, the U.S. Department of Health and Human Services (HHS) launched an initiative in March of 2015 aimed at improving prescribing practices, expanding the access to and use of medication-assisted treatment and expanding the use of naloxone. So far, the Substance Abuse and Mental Health administration (SAMHSA) has awarded $10.7 million to 11 high-burden states for medication-assisted treatment (MAT). Applications were due in May of 2016 and awards were to be made to an additional 11 states. The above information and statistics were drawn from a Health and Human Services report, “The Opioid Epidemic: By the Numbers.”

Then in July of 2016, the HHS Secretary announced new rules that permit doctors licensed to dispense buprenorphine to see as many as 274 patients per year. The old limit was 100. HHS estimated that change permits as many as 70,000 more people to access buprenorphine. The former limit of 100 was seen by many as a barrier to individuals seeking to access MAT. “The rule aims to increase access to medication-assisted treatment and associated behavioral health supports for tens of thousands of people with opioid use disorders, while preventing diversion.” Clearly buprenorphine products like Suboxone are seen as a crucial element in our attempts to combat the opioid health crisis.

There are issues with this approach to treatment for the opioid crisis that I’ve addressed previously in articles such as: “The Seduction of Opioid Substitution” and “A Double-Edged Drug.” Here I want to look at how the company that brought buprenorphine treatment to market, Indivior/Reckitt Benckiser, tried to position itself as the primary service provider for buprenorphine-based MAT in the U.S. It’s kind of like a buzzard chasing off smaller scavengers from the carcass of an overdose victim. At one point, Reckitt Benckiser had 85% of the U.S. MAT market—almost all of it subsidized by taxpayers.

In 1994 Reckitt Benckiser established the Buprenorphine Business Group to develop buprenorphine as a treatment for opioid dependence. In 2000 legislation (DATA 2000) was passed in the U.S. permitting office-based treatment of opioid dependence. In 2002 the FDA approved Subutex (buprenorphine) and Suboxone (buprenorphine and naloxone) for the treatment of opioid dependence in the U.S. These products came to market in 2003. In 2007 the initial cap of 30 patients was raised to 100 for physicians with at least one year’s experience with buprenorphine. That same year Reckitt Benckiser acquired the rights for the sublingual film version of Suboxone from MonoSol Rx. Then in 2010 Suboxone sublingual film was launched in the U.S. Subutex tablets were discontinued in 2011; and Suboxone tablets met the same fate in 2012. In December of 2014, Reckitt Benckiser spun its specialty pharmaceutical company into a separate business and Indivior was born.

This history was taken directly from the Indivior website, where the company estimated they had treated 5 million individuals in the U.S. with Suboxone film and tablets and Subutex tablets. Here are some additional facts to add to the above timeline from a 2013 article, “Pharma Gamemanship.”

Reckitt Benckiser (RB) knew it only had patent exclusivity for their buprenorphine products until 2009. But they had a plan to circumvent the pending loss. As noted above, they acquired the rights for the sublingual film version of Suboxone in 2008. In October of 2008 they submitted a New Drug Application to the FDA for the film version of Suboxone; and it was approved in August of 2010. Reckitt Benckiser has patent exclusivity on the newer film version until 2023.

In their 2011 annual report (no longer retrievable from its website), RB indicated to their shareholders that competition from generics could take up to 80% of the revenue and profit from the U.S. Suboxone market. But they expected “that the Suboxone film will help to mitigate the impact.” In September of 2012 RB announced that they were voluntarily withdrawing Suboxone tablets from the market because of data they had received from the U.S. Poison Control Centers suggesting there were higher rates of pediatric overdose on the tablet formulation than the film version. They said they would take the tablet form off the market to “protect public health and safety.”

The very same day RB filed a “Citizen’s Petition” with the FDA calling for the agency to postpone the approval of generic version of Suboxone in the interests of public safety. Reporting for The Daily Beast, Christopher Moraff said the “data” they based their withdrawal of Suboxone tablets on was a single study RB had paid for itself. RB reportedly said the study demonstrated the risk factor for accidental ingestion was eight times higher in bottled tablets than for the individually packaged film. Yet its own data told a different story.

Compared to the more than 20,000 deaths in 2012 from prescription opiates and heroin, pediatric poisoning from Suboxone was far from a public health crisis. A preliminary study commissioned by Reckitt Benckiser found just 46 cases of serious injury or death out of more than 2,200 accidental pediatric exposures to Suboxone tablets between 2010 and 2012—which researchers described as not significantly different from poisonings from the film.

The FDA thought the RB study was inconclusive and did not demonstrate any difference in the safety profile or abuse potential of the two formulations. They said the study was poorly designed and conducted. “Reckitt’s own actions also undermine, to some extent, its claims with respect to the severity of this safety issue.” Despite the first report of pediatric death in June of 2010, RB continued marketing the tablets in multi-dose containers for two more years. And it continues to sell them throughout Europe, where Suboxone tablets are still under patent.

In June 2013 the FTC opened an investigation into whether Reckitt Benckiser abused public regulatory processes and fought for nearly two years to obtain more than 20,000 documents the company was fighting to withhold. That case is ongoing. In December of that year, federal agents raided Reckitt Benckiser’s West Virginia offices after the Department of Justice launched a criminal probe into the company’s Suboxone business. That investigation continues.

Public Citizen said that few, if any, companies went as far as RB to pre-emptively withdraw an off-patent drug from the market to make room for a newly patented successor. A year before the withdrawal of the tablets from the market, RB stated in its 2011 report that its goal was to convert as many tablet users as possible to the film version.

To this end, the company initiated a marketing campaign to persuade physicians to switch patients from the tablet to film form. It also employed more direct tactics to complement the marketing push, raising the price of the tablets to levels higher than the film versions. As a result of these efforts, tablet sales fell 19 percent between August 2011 and August 2012, while sales of Suboxone film doubled during the same period. By September 2012, the film version had captured 70 percent of the Suboxone market, clearing the way for the announcement of the withdrawal of the tablets that month.

So it should come as no surprise that a lawsuit has been filed by 35 states and the District of Columbia alleging that Indivior violated antitrust laws by trying to extend its monopoly over Suboxone. Reporting for CNN, Susan Scutti said the lawsuit charges that Indivior/RB and MonoSol Rx “conspired to block generic competitors for Suboxone by switching the drug from a tablet to a dissolving film.” A September 23, 2016 press release on the Indivior website said: “The Company intends to continue to vigorously defend its position.”

The International-Dictionary.com said there are two meanings for the word “buzzard.” The first one is zoological, referring to a bird of prey of the hawk family. The second meaning is “a blockhead; a dunce.” A quote attributed to Goldsmith reads: “It is common, to a proverb, to call one who can not be taught, or who continues obstinately ignorant, a buzzard.” It seems to me that either sense can be applied to Reckitt Benckiser and Indivior.

12/9/16

Channeling Your DXM Personality

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5© ljupco | 123rf.com

June of 2016 was a confusing month for DXM. Alaska became the 11th state to limit the sale of products containing dextromethorphan (DXM) to individuals 18 and older. Representative Charisse Millett of Anchorage thanked her colleagues for passing a bill that will protect Alaska teens. On the other hand, there was a study published in the journal, Substance Abuse Treatment Prevention, and Policy by Spangler, Loyd and Skor that same month which said DXM was a safe, effective cough suppressant, available without a prescription since 1958. The article reported how the annual prevalence of DXM abuse has sharply decreased since 2010. So why would so many states be restricting the sale of a “safe, effective cough suppressant”?

Adding to the issue, there is H.R. 3250, The DXM Abuse Prevention Act, which was sent to both the House and Senate for consideration on April 27, 2016. H.R. 3250 seeks to prevent the abuse of DXM and would restrict its sale to individuals 18 and over. Civil penalties for retailers violating H.R. 3250 would range from a warning for a first offense up to $5,000 for four or more violations. If implemented, the federal law would take precedence over any existing state legislation.

The pro-drug website Erowid noted that while DXM is still unscheduled in the US, and legal to buy, possess and ingest without a prescription, it is becoming increasingly difficult to purchase. “Some pharmacies and mega-stores like WalMart have instituted voluntary procedures to reduce the sale of DXM-containing products to minors.” Erowid listed and commented on the legal status of DXM in 25 different states and was soliciting more information on its status in other states.

In 2007 the DEA requested that the FDA evaluate whether dextromethorphan should be scheduled as a controlled substance. Three years later the FDA held an Advisory Committee meeting on the matter. After hearing presentations on DXM and its abuse potential, the committee voted 15 to 9 against scheduling DXM. An Erowid assessment of the presenters was they did not believe that scheduling was warranted, but were concerned about abuse.

The DXM article by Spangler, Loyd and Skor said that to address reports of abuse, the Consumer Healthcare Products Association (CHPA) initiated a plan to raise awareness of the behavior and “address prevention by focusing on the factors that impact teen behavior.” All three authors were employees of the CHPA, “which represents manufacturers of over-the-counter medicines and dietary supplements.”  And funding for the research, collection of the data, analysis, interpretation, plan implementation, and writing of the manuscript was provided by CHPA member companies. They concluded:

It is noteworthy that the annual prevalence of over-the-counter cough medicine abuse has sharply decreased since 2010. While a true cause-and-effect relationship cannot be assured, the Consumer Healthcare Products Association and its member companies believe that the increased awareness of the issue since the 2010 Food and Drug Administration Advisory Committee meeting, and the subsequent implementation of a well-delivered and targeted abuse mitigation plan that addressed the levers influencing teen decisions is contributing to the observed reduction in abuse. During the period of 2010–2015, reported abuse of dextromethorphan by 8th, 10th, and 12th graders decreased 35 %. The authors believe this reduction supports the view of the Consumer Healthcare Products Association at the outset of the abuse mitigation plan effort and today: Controlled substance scheduling or prescription requirements would result in a reduction in the legitimate use of this medicine that has benefits that far outweigh its risks. Instead, there are more targeted, more effective, and less disruptive interventions to address dextromethorphan abuse.

Writing for The Fix, John Lavitt reported that one in 30 adolescents use DXM to get high because it is cheap and accessible. In 2014 there were six DXM-related deaths, according to the American Association of Poison Control Centers. Non-medical use of DXM leads to around 6,000 ER visits per year. Adolescents account for almost 50% of those visits. The effects range from mild stimulation to euphoria and hallucinations. There can be an out-of-body dissociative state, complete dissociation with unresponsiveness and even overdose.

Medline Plus lists some of the many products that contain DXM, including NyQuil, DayQuil, TheraFlu, Tylenol Cold, Dimetapp DM, Robitussin DM, Triaminic DM, and Alka-Seltzer Plus Cold and Cough.  Some of the symptoms of a DXM overdose listed included: breathing problems, bluish-colored fingernails and lips, blurred vision, coma, Convulsions, drowsiness, hallucinations, heart palpitations, nausea and vomiting, rapid heart beat.

Now here is some DXM history from Erowid. It was approved by the FDA in 1958. In the early 1960s, there were reports that beat poets like Allen Ginsberg and Peter Orlovsky and the author Jack Kerouac were using DXM in the form of Romilar tablets. Incidentally, Romilar was introduced as a replacement for codeine cough remedies in an attempt to cut down on abuse. In 1973, Romilar DXM tablets were removed from the market after an increase in recreational use was noted. DXM continued to be available as a syrup, with the thinking that consuming large quantities of syrup would be deterrent for recreational use. OTC DXM tablets have been back on the market now for number of years. In the late 1980s DXM use was prominent among the punk subculture.

By the way, codeine cough syrup is main ingredient in the concoction “Sizzurp” that sent rapper Lil Wayne to the hospital with multiple seizures. He even wrote a song about his love for Sizzurp, “Me and My Drank.”  Then there’s Justin Beiber and his street-racing-DUI-Sizzrup arrest. Teens and others without ready access to a codeine prescription cough formula can substitute OTC DXM formulas in their Sizzurp knockoff. Add some Jolly Ranchers to make the concoction more drinkable.

So while DXM may be safe and effective when used as recommended, it was being used as a recreational high almost from the time it came onto the market as a substitute for codeine. It has ebbed and flowed in its consideration for classification as a controlled substance. Currently it isn’t one. However, it does seem likely to face restricted sales to anyone under the age of 18. Eleven states have already passed legislation to that effect, and larger chains like WalMart, Walgreens, Target, Rite-Aid and others now require ID and limit sales to two DXM-containing products. And there is pending federal legislation that has a 38% of passing that would make it illegal to sell DXM products to minors. The last word on DXM is from Erowid.

Recreational DXM use continues. A number of deaths have been documented due to the recreational use of DXM although a majority of these have been the result of products (such as Coricidin Cough and Cold) that combine DXM with other substances that become dangerous in high doses.

So if you decide to try and contact your inner beat poet, or channel your punk rock personality through DXM, be careful.

11/29/16

Marijuana & Adverse Health Effects

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© David Castillo Dominici | 123rf.com

In the 2016 election there was another political milestone met besides the presidential election of Donald Trump—four more states voted to legalize recreational marijuana. California, Maine, Massachusetts, and Nevada joined Alaska, Colorado, Oregon, Washington and the District of Columbia. However, the public use of marijuana—recreational or medical—is still not permitted anywhere. Arkansas, Florida and North Dakota approved medical marijuana initiatives and Montana loosened restrictions on an existing medical marijuana law. The executive director of the Drug Policy Alliance was quoted in The Washington Post as saying: “The end of marijuana prohibition nationally, and even internationally, is fast approaching.”

Given the election of Donald Trump and the international position on marijuana, this may be more optimism than reality. Within the U.S. there has been clear momentum towards legalization of some kind, as there are now eight states and the District of Columbia where recreational marijuana is legal; and 28 states and the District of Columbia where medical marijuana is permitted. However, because of the ongoing federal classification of marijuana as a Schedule I drug, reliable research into the benefits and adverse health effects from marijuana use is hard to come by. The public needs to be more aware of the scientific research into the potential adverse effects and medical benefits from marijuana as the U.S. continues to move toward a complicated, patchwork quilt of varied state laws and regulations regarding marijuana.

A good place to start is with an article written by the current director of the National Institute on Drug Abuse (NIDA), Dr. Nora Volkow and three others, “Adverse Health Effects of Marijuana Use.” Volkow et al. reviewed the current state of the scientific findings on the adverse health effects related to the recreational use of marijuana. Their review focused on the areas where the evidence was the strongest. In a table summarizing their confidence in the evidence for adverse effects of marijuana on health and wellbeing, they gave the following assessment of marijuana use, particularly with heavy or long-term use that starts in adolescence.

Effect

Overall Level of Confidence

Addiction to marijuana or other substances

High

Diminished lifetime achievement

High

Motor vehicle accidents

High

Symptoms of chronic bronchitis

High

Abnormal brain development

Medium

Progressive use of other drugs

Medium

Schizophrenia

Medium

Depression or anxiety

Medium

Lung cancer

Low

Long-term marijuana use can lead to addiction; there’s no real doubt. About 9% of those who experiment with marijuana will develop dependence, according to the criteria for dependence in the DSM-IV. This increases to one in six (16.7%) among those who started using marijuana as teens. Daily smokers have a 25% to 50% risk of developing an addiction to marijuana. There is also a cannabis withdrawal syndrome, with symptoms such as: irritability, sleep difficulties, dysphoria (a state of being unhappy or unwell), cravings, and anxiety.

Since the brain remains in a state of active development until around the age of 21, individuals under 21 who use marijuana are more vulnerable to adverse long-term effects from marijuana use. Adults who smoked marijuana regularly during adolescence have impaired neural connectivity (fewer fibers) in certain brain regions.

The impairments in brain connectivity associated with exposure to marijuana in adolescence are consistent with … findings indicating that the cannabinoid system plays a prominent role in synapse formation during brain development.

While regular use of marijuana is associated with anxiety and depression, causality has not been established. Marijuana is also regularly linked to psychosis, especially among people with a predisposition. Heavy marijuana use, greater drug potency, and exposure at a young age can all negatively effect the experience of psychosis or schizophrenia, accelerating the time of a first psychotic episode by 2 to 6 years.

Because marijuana use impairs critical cognitive functions during acute intoxication and for days after use, many students may be functioning below their natural capabilities for long periods of time. “The evidence suggests that such use results in measurable and long-lasting cognitive impairments, particularly among those who started to use marijuana in early adolescence.” A failure to learn at school, even for short or sporadic periods of time because of acute intoxication, will interfere with the capacity to achieve educational goals. This seems to explain the association between marijuana use and poor grades.

Heavy marijuana use has been linked to lower income, greater need for socioeconomic assistance, unemployment’s, criminal behavior, and lower satisfaction with life.

There is also a relationship between THC levels in blood and performance in controlled driving-simulation studies. These studies have been a good predictor of real-world driving ability. “Recent marijuana smoking and blood THC levels of 2 to 5 mg per milliliter are associated with substantial driving impairment.” The overall risk of involvement in an accident increases by a factor of 2 when someone drives soon after using marijuana. Not surprisingly, combining marijuana and alcohol seems to result in greater risks than the use of either drug alone.

The authors noted that most of the long-term effects of marijuana use in the article have been seen among heavy or long-term users. Yet the presence of multiple confounding factors, including the frequent use of marijuana with other drugs, detracts from their ability to establish causality.

They also noted there is a need to improve our knowledge on the potential medical benefits of the marijuana plant. A report by the Institute of Medicine sees the benefits for stimulating appetite and in combating chemotherapy-induced nausea and vomiting, severe pain and decreasing intraocular pressure in the treatment of glaucoma. “Nevertheless, the report stresses the importance of focusing research efforts on the therapeutic potential of synthetic or pharmaceutically pure cannabinoids.” With all of its problems, the existing structure for the approval of new medicines through the FDA is better than the current lack of any safety and regulatory apparatus with medical marijuana. The ongoing failure to confirm or refute the plethora of health and medicinal claims with marijuana use is progressively taking us back to the days of patent medicine claims in state-by-state approval. In conclusion they summarized the results of their review of the literature on adverse effect from marijuana use as follows:

Marijuana, like other drugs of abuse, can result in addiction. During intoxication, marijuana can interfere with cognitive functions (e.g. memory and perception of time) and motor function (e.g. coordination), and these effects can have detrimental consequences (e.g. motor-vehicle accidents). Repeated marijuana use during adolescence may result in long-lasting changes in brain function that can jeopardize educational, professional, and social achievements. . . . . As policy shifts toward legalization of marijuana, it is reasonable and probably prudent to hypothesize that its use will increase and that, by extension, so will the number of persons for whom there will be negative health consequences.

A German review study by Hoch et al., “Risk Associated with the Non-Medical Use of Cannabis,” also sought to summarize the current state of knowledge regarding the physical and mental adverse effects of intensive recreational cannabis use. They came to conclusions similar to the Volkow et al. study. Hoch et al. noted the potential for addiction and withdrawal, mild negative effects on learning capacity, neurocognitive impairments with adolescents, an increased risk of psychosis, and others. “Further research is required to clarify the causal nature of the links between cannabis consumption patterns and adverse events.”

Empirical data have now clearly shown that starting early in life and regularly using high amounts of cannabis for a long period of time increases the risk of various mental and physical disorders and endangers age-appropriate development. Because many studies have failed to control properly for confounding variables, it still cannot be stated beyond doubt that there is a causal connection between cannabis consumption patterns and cognitive damage or the development of comorbid psychic or somatic disorders. The worldwide increase in the THC content of cannabis may increase the health risks, particularly for adolescent users. Further research is required to determine why some people are more affected than others by the unfavorable consequences.

On the other hand, another long-term study of chronic marijuana use among young adult men by Bechtold et al., was published  in the journal, Psychology of Addictive Behavior. The study used data from The Pittsburgh Youth Study, a longitudinal study that followed seventh grade students until they were 36. The study found that chronic marijuana users were no more likely than other groups to experience several physical or mental health problems, including early onset psychosis and heart problems. Some limitations in applying the findings of this study would include the fact that participants were only followed until the age of 36, perhaps too early for many of the health problems to become evident. Another difference was that the heaviest use category for marijuana was “more than 3 times per week,” while Volkow et al. seems to have been looking at daily or almost daily use.

In a postscript addition to the above studies, a 2016 study by Columbia researchers found evidence of a compromised dopamine system in heavy marijuana users. Dopamine levels were lower in the striatum, an area in the brain involved in working memory, impulsive behavior and attention. Previous studies have found addiction to other drugs of abuse, like cocaine and heroin, have similar effects on dopamine release. This was the first such evidence for marijuana.

A press release by the Columbia University Medical Center quoted the lead author as stating that in light of the increasing use and acceptance of marijuana, especially by young people, it is important to look more closely at the potentially addictive effects of cannabis on key regions of the brain. The study was small, with 11 adults who were severely dependent upon marijuana and 12 matched healthy controls. The average age of onset among the marijuana users was 16, with dependence occurring by 20. In the month before the study, all users in the study had smoked daily.

“Compared with controls, the cannabis users had significantly lower dopamine release in the striatum, including subregions involved in associative and sensorimotor learning.” The investigators also explored the relationship between dopamine release in the striatum and cognitive performance on learning and working memory tasks. The bottom line was that long-term, heavy marijuana use could impair the dopaminergic system, which in turn could have a series of negative effects on learning and behavior.

I talked with someone who had been to California a few weeks after the 2016 election when recreational marijuana use was legalized. She reported how employees of her hotel were gathering outside on their break to smoke pot, similar to what cigarette smokers do. If legal recreational use becomes more widespread in the U.S., the adverse physical and mental adverse effects from heavy, regular use will also become more evident. Then marijuana use will take a place beside alcohol use and tobacco use as a public health problem.

11/18/16

National ADHD Epidemic

© kentoh | stockfresh.com

© kentoh | stockfresh.com

The CDC published a study that found 11% of school-aged children in the U.S. between 2003 and 2011 had received an ADHD diagnosis. This statistic meant that 6.4 million children, 1 in 5 boys and 1 in 11 girls, were said to have ADHD. A different CDC report indicated the American Psychiatric Association (APA) estimated in their 2013 edition of the DSM, the DSM-5, that only 5% of children have ADHD. The rates of ADHD diagnosis are increasing over time, from an average of 3% per year between 1997 and 2006, to 5% between 2003 and 2011. The prevalence of children between the ages of 4 and 17 diagnosed with ADHD varied widely by state. In 2011, the lowest reported rates were in Nevada (5.6%); the highest rates were in Kentucky (18.7%). In contrast, the percentage of children diagnosed and medicated for ADHD in France is less than half of one percent—.5%!

You can see the CDC reports cited above here, here and here.

Writing for Psychology Today in 2012, Marilyn Wedge noted in “Why French Kids Don’t Have ADHD,” how the difference seemed to turn on how ADHD was conceived. In the U.S. ADHD is seen as a biological disorder with biological causes. So the go-to treatment method is stimulant medications. Dr. Wedge also pointed that French psychiatrists did not use the DSM system to diagnose childhood emotional problems. Instead they used an alternative classification system that focuses on the underlying psychosocial causes of a child’s symptoms.

French child psychiatrists, on the other hand, view ADHD as a medical condition that has psycho-social and situational causes. Instead of treating a child’s focusing and behavioral problems with drugs, French doctors prefer to look for the underlying issue that is causing the child distress—not in the child’s brain but in the child’s social context. They then choose to treat the underlying social context problem with psychotherapy or family counseling. This is a very different way of seeing things from the American tendency to attribute all symptoms to a biological dysfunction such as a chemical imbalance in the child’s brain.

She commented that the holistic, psychosocial approach of the French allowed for the possibility there could be nutritional factors that worsen ADHD symptoms. “In the U.S., the strict focus on pharmaceutical treatment of ADHD, however, encourages clinicians to ignore the influence of dietary factors on children’s behavior.”

Psychiatrist Robert Berezin commented on Wedge’s report saying that it seemed American boys had contracted some contagion that spread ADHD exponentially. More seriously, he went right to the heart of the problem: if ADHD rates are so drastically different between the U.S. and France, how can ADHD be a brain disease? “Yes there can be symptoms of hyperactivity and concentration. But it is created by psychosocial causes, not biological ones. And the treatments should be appropriate to the cause.” He concluded that the French situation showed that so-called ADHD was a psychosocial problem, not a brain disease.

So if we accept this conclusion, where does this leave us in America with regard to ADHD and the aftermath of decades of conceiving and treating it as a brain disease? A recent investigative report by the Milwaukee Journal Sentinel and MedPage Today pointed out several areas of concern. First is the increase in the diagnosis of Adult ADHD. Twenty years ago ADHD was rarely diagnosed in adult Americans. Now, 1 in 23 adult Americans, around 10 million people, are said to have ADHD. And there has been a fourfold increase among adults 26 and older who use Adderall recreationally.

The reporters cited a 2010 study where 22% of the adults tested for ADHD had exaggerated their symptoms. This finding underscores how college-aged adults increasingly use ADHD medications as  “study aides.” A 2013 study found wastewater samples collected near college dormitories in Tacoma Washington were eight times higher for amphetamines during final exams week than during the first week of classes. Although FDA adverse events indicated there were more reports for children, the adults were reporting more serious adverse events. “Adults accounted for just over one-third of reports, but made up more than half of all hospitalizations and 85% of deaths.”

Experts question whether adult ADHD is truly a widespread condition that needs treatment with the array of FDA-approved prescription medications. A medical historian, Nicolas Rasmussen, was quoted as saying that amphetamines are grossly overused; and that “the streets are awash with Adderall.”

Drug companies counter that ADHD is a real and treatable medical condition that effects millions of Americans. Charles Catalano, a spokesperson for Shire, which manufactures two ADHD medications, Vyvanse and Adderall, said the drugs have been approved by regulators around the world and are safe to use. “Our medications are proven to be effective when used according to prescribing practices of a licensed, trained health care professional.” A spokesperson for Novartis, the manufacturer of Ritalin, said it has been used safely and effectively for more than 60 years. “If used inappropriately, the results could be serious, just like with the misuse of any other medication.”

The DSM-5, published in 2013 by the APA, relaxed the criteria for diagnosing adult ADHD. Previously adults needed to have six of nine possible symptoms. Now they only need five of nine symptoms. Seventy-eight percent of the panel of experts who approved the changes had financial ties to drug companies. The APA minimized the potential conflicts of interest by stating no panel member had made more than $10,000 a year working as industry speakers and consultants.

Moffitt et al. published the results of a forty-year study of individuals in New Zealand in The American Journal of Psychiatry. The study found that found 90% of adult ADHD cases did not have a history of childhood ADHD. “The findings raise the possibility that adults presenting with the ADHD symptom picture may not have a childhood-onset neurodevelopmental disorder.” The authors added that if the findings were replicated, adult ADHD’s place in the DSM should be reconsidered and that research needs to investigate the etiology of adult ADHD.

It also appears that using ADHD medication leads to addiction and abuse problems with some individuals. Some of this is simple common sense. All ADHD stimulant medications are Schedule II controlled substances, meaning that the DEA considers them to have the same addictive potential as cocaine. Yet the research literature presents conflicting accounts. Some studies report that untreated ADHD is a significant risk factor in developing substance use disorders. Others suggest there is no compelling evidence that treating children with ADHD medication leads to an increased risk of later substance use problems.

A Medscape article concluded that the bulk of evidence suggested that treating ADHD with stimulant medication did not increase the risk for developing a substance use disorder, nor did it decrease to risk. At the very end of the article this comment appeared: “This activity is supported by an independent educational grant from Shire.” The author of the article had also received grants and served as a paid consultant for Shire.

On the other hand, Peter Breggin and others have noted there is a high abuse liability with stimulant medications. A 1995 DEA report indicated there was an abundance of scientific literature on the abuse potential of Ritalin and other Schedule II stimulants. A 1998 NIH conference on the “Diagnosis and Treatment of ADHD” stated: “An extensive scientific literature spanning more than 30 years of research unequivocally indicates that MPH [Ritalin] has a high abuse liability.” A 1995 study by Nora Volkow and others found that cocaine and MPH had similar effects on the brain when given intravenously. Breggin commented in his discussion of the study in his book, The Ritalin Fact Book, that the main difference was the longer lasting effect of Ritalin. This was speculated to be why Ritalin was less subject to abuse than cocaine. Breggin said:

What does all of this mean in plain English? Ritalin’s biochemical mechanism of action is essentially the same as that of cocaine, and therefore Ritalin produces similar effects to cocaine. In fact, all of the stimulants, including Ritalin and cocaine, jack up dopamine, serotonin, and norepinephrine chemical messengers in the brain, producing a variety of similar mental abnormalities. If given intravenously, the “high” is the same for all of them.

A study by Schrantee et al. published in the September issue of JAMA Psychiatry found there was a distinct effect of methylphenidate (Ritalin) on the brains of children and young adults. A discussion of this study in an article on Mad in America indicated the lead researcher of the study’s team, Liesbeth Reneman, said given that maturation of several brain regions are not complete until adolescence, drugs given during the sensitive, early phases of life could effect “neurodevelopmental trajectories” and have profound effects later in life.

The adolescent brain is a rapidly developing system that maintains high levels of plasticity. As such, the brain may be particularly vulnerable to drugs that interfere with these processes or modify the specific transmitter systems involved.

The mesolimbic dopamine system (MDS), the reward pathway of the brain, is one of those later maturing brain regions. Incidentally, the MDS is probably the region of the brain where drugs produce dependence. In his book, The Science of Addiction, Carleton Erickson said neuroscientists believe that when the functioning of certain MDS neurotransmitter systems are disrupted from genetic “miswiring” and/or long-term exposure to a drug, “chemical dependence as a bran disease” can develop.

The Schrantee et al. study is the first evidence that using ADHD medications can alter brain development. So studies of the long-term consequences need to be completed. But one of the questions that should be investigated is does the long-term use of stimulant medications effect changes to the MDS of the brains of adolescents and young adults and are those changes related to a greater risk of substance abuse. Hopefully we’ll have some answers before prescription stimulant drugs compete with opioids as a national drug epidemic.

11/8/16

This Stuff Is not Weed

38945846 - illustration of a not allowed icon with a marijuana leaf

© Juan Pablo Gonzalez | 123rf.com

Like a snowball that begins rolling down from the very top of a hill, negative consequences from synthetic drugs have been building momentum for several years. LiveScience posted an article based on a CDC report that highlighted the increase of synthetic-cannabinoid overdoses. Between 2010 and 2015 there were a total of 456 synthetic-cannabinoid intoxications recorded by 101 US hospitals and clinics included in the study. While the overdoses from these substances are still a fraction of all drug overdoses in the US, their percentage has increased every year since 2010.

The CDC report was based on data gathered from the Toxicology Investigators Consortium (ToxIC), a toxicology surveillance and research tool. The ToxIC Registry was established by the American College of Medical Toxicology in 2010. Of the 456 cases of synthetic-cannabinoid intoxication treated by physicians in the ToxIC, 277 reported synthetic cannabinoids were the only substance used. The findings of the CDC report are representative of what doctors in emergency departments from around the country are seeing.

Among the 456 cases, 70.6% were in persons aged 19-65 and 27.4% were in persons aged 13-18; 83.1% were male. The reported adverse effects were primarily cardiovascular-related (17.0%), pulmonary-related (7.6%) or central nervous system-related (66.1%).  The CNS symptoms included agitation, CNS depression or coma, and delirium/toxic psychosis. The annual percentage of cases increased significantly in all four US Census regions, except the South. “The largest overall increases during these periods took place in the Northeast, primarily driven by increases at the New York City sites.” See the chart below which was taken from the CDC report:

toxicThe CDC report mentioned a June 2015 Morbidity and Mortality Weekly Report (MMWR) for June 12, 2015 that found a 300% increase of telephone calls to poison centers related to synthetic cannabinoid use from January 2015 to April 2015. The report suggested that synthetic cannabinoids posed an emerging public health threat. The number of calls spiked dramatically in mid-April. Look at the report for a chart showing the spike from less than 100 calls per week in the third week of March 2015 to over 500 weekly in the third week of April 2015.

Then there are the “bath salts.” The New York Times published an article referring to Brooklyn users of K2, a synthetic cathinone (bath salts), as “zombies.” In an area around the subway station at Myrtle Avenue and Broadway, emergency workers transported 33 people with suspected K2 overdoses to the hospital in ONE DAY. Brian Arthur, who filmed and then posted what he saw on online said: “It’s like a scene out of a zombie movie, a horrible scene . . . . This drug truly paralyzed people.” While responders helped an unsteady man into an ambulance, another man nearby was slumped against a fire hydrant.

Pairs of police officers walked the blocks around Broadway and Myrtle Avenue, checking the vital signs of men they found unconscious. Anyone who was unresponsive was loaded onto a stretcher and taken away in an ambulance.

Keep in mind this was after legislation by The New York City Council last Fall banned synthetic cannabinoids and threatened businesses and owners who sold K2 with closings, hefty fines and jail time. So it seems that the synthetic drug trade in NYC simply switched to synthetic cathinones.

A 2012 article in the Journal of Medical Toxicology, “The Toxicology of Bath Salts,” provides some background information on the emergence of synthetic cathinones as a drug of abuse. Synthesis of cathinone derivatives occurred as early as the late 1920s. Methcathinone was synthesized in 1928 and mephedrene in 1929. While a few of the derivatives have been investigated for medical use, only bupropion (Wellbutrin, Zyban) have been approved for a medical use in the US and Europe. Wellbutrin is approved to treat depression; Zyban is used as a smoking-cessation aide.

Numerous synthetic cathinone derivatives have become popular for use as “legal highs.” Exactly when these derivatives gained popularity amongst club goers and others seeking new drugs of abuse is difficult to pinpoint, but mentions in Internet drug forums began in 2007.

In “Synthetic Cathinones: A New Public Health Problem,” Karila et al. described the major clinical effects of synthetic cathinones and their impact on public health. Together with synthetic cannabinoids they account for more than two thirds of the New Psychoactive Substances (NPS) available. Again, cardiac psychiatric and neurological adverse effects are the most common ones requiring medical care. “These drugs, still not controlled by international laws, are often produced and used to mimic the effects of controlled drugs such as cocaine, methylenedioxymethamphetamine (MDMA, ecstasy), and methamphetamine.”

If you’re skeptical about what I’ve written so far, try this article from High Times, “What’s in Synthetic Cannabis and Why Is It So Dangerous?” In order to study the endocannabinoid system in the body, scientists created these compounds for research purposes. The author is quick to point out that synthetic cannabis does not contain cannabis or synthetic cannabinoids. While the compounds bind to cannabinoid receptors in the brain, they only have a “slight relation” to natural THC. “Doctors do not fully understand how most of these compounds interact with the body, and some can be extremely harmful and even deadly.”

The author suggested they would be better named: synthetic cannabinoid receptor agonists (SCRA). THC is only a partial agonist of CB1 and CB2,the cannabinoid receptors, where SCRAs are designed to bind strongly to the receptors and exert THC-like effects. These effects can be 100 times more potent than cannabis. The unusually strong binding of SCRAs to cannabinoid receptors can produce unforeseen downstream effects in the brain and nervous system.

If you consume any of these chemicals, you are literally performing an experiment on your body, and a dangerous one at that. People have suffered from seizures, cardiac arrest, kidney failure, severe reduction in body temperature, etc. and doctors don’t know how it happens or who is more susceptible.

Not only are there many different classes of these compounds, each one of the general classes of compounds contains dozens of different related compounds. “Regulatory agencies play a game of cat and mouse with designer drug manufacturers as they constantly use different compounds to bypass laws.”  While the Us government continues to make different groups of SCRAs illegal, underground chemists seem to be one step ahead, making newer compounds that tend to be more toxic and harmful than the previous generation.

Steer clear of these dangerous substances, treat them like dangerous addictive drugs on par with methamphetamine, ecstasy pills and prescription narcotics. This stuff is not weed, and when your friends smoke it you should confront them about it and make them understand they are putting their lives at risk. Even if you need to pass a drug test, don’t use this stuff; even one toke of Spice can land you in intensive care and put you on a dialysis machine with kidney failure.

Let the fact sink in that what we just reviewed was a clear warning from High Times to avoid synthetic cannabinoids. Alternately, there are synthetic cathinones that can turn you into a zombie. Think about the consequences before you try some.

10/28/16

Fluctuations in the Heroin Market

© 4designersart | stcokfresh.com

© 4designersart | stcokfresh.com

The 2016 World Drug Report (2016 WDR) is a good-news bad-news source of information on global opiate statistics. The good news is that global opium production fell by 38% in 2015. The decrease was primarily the result of a decline in opium production in Afghanistan, which fell 48% compared to 2014. This was mainly because of poor yields in the country’s southern provinces. Despite this, Afghanistan was still the world’s largest opium producer, accounting for 70% of global opium production.

The bad news is that despite the drop in production, the global number of opiate users has remained relatively stable. And opium production in Latin America, mostly in Mexico, Columbia and Guatemala, more than doubled from 1998-2014. Central and South American production accounts for 11% of the estimated global opium production. Also, in North America, heroin use and heroin-related deaths have continued to rise. In both cases, the increases were roughly three times the 1999 levels. See the following chart from the 2016 WDR.

heroin-deathsIn 2014, the largest seizures of opiates were in South-West Asia, with Europe next in line. The Islamic Republic of Iran reported the largest opiate seizures worldwide, accounting for 75% of global opium seizures and 17% of global heroin seizures. The next largest heroin seizures were from Turkey (16% of global heroin seizures), China (12%), Pakistan (9%), Kenya (7%), the U.S. (7%), Afghanistan (5%), and the Russian Federation (3%). Iran is the first stop on the so-called “Balkan route” of opiate distribution. From there the route travels into Turkey, and onto South-Eastern Europe, where it is distributed throughout Western and Central Europe. “Seizure data suggest that the Balkan route, which accounts for almost half of all heroin and morphine seizures worldwide, continues to be the world’s most important opiate trafficking route.”

The massive decline in opium production of almost 40 per cent in 2015 is unlikely, however, to result in a decline of the same magnitude within a year in either the global number of opiate users or the average per capita consumption of opiates. It seems more likely that inventories of opiates, built up in previous years, will be used to guarantee the manufacture of heroin (some 450 tons of heroin per year would be needed to cater for annual consumption) and that only a period of sustained decline in opium production could have any real effect on the global heroin market.

In 2015 Bloomberg published an article with three maps of global drug smuggling routes. The major opiate producers are: Afghanistan, Myanmar, Laos, Mexico and Columbia. The opiate map illustrates the vast reach of the so-called Balkan route. The Americas are primarily supplied with opiates grown in Mexico and Columbia. More than 70% of all heroin and morphine seizures in the Americas were in the U.S. between 2009 and 2014. Seizures more than doubled from around 2 tons per year from 1998-2008 to 5 tons per year from 2009-2014. Heroin trafficking and use was seen in 2015 as the main national drug-related threat in the US, according to the 2015 National Drug Threat Assessment (NDTA).

The 2015 NDTA reported that heroin was available in larger quantities, used by larger numbers of people, and caused more overdose deaths than 2007. The increased demand and use of heroin is driven by greater availability and controlled prescription drug (CPD) abusers switching to heroin. Cheaper prices for heroin contribute to the switch as well.

Increases in overdose deaths are driven by several factors. The purity of heroin has increased in some areas. New heroin users switching from prescription opioids are used to the set dosage amounts potency of prescription drugs. Illicitly–manufactured drugs can vary widely in their purity, dosage and adulterants. Over the past few years the use of highly toxic adulterants like fentanyl (20 to 40 times stronger than heroin) in certain markets has also added to the increase in overdose deaths. Then there are heroin users who stopped using for a while (from treatment or incarceration) whose tolerance has decreased because of their abstinence.

Most of the heroin in the US today comes from Mexico and Columbia. Columbian heroin is still the predominant type available in the Eastern US. While Southeast Asian heroin, largely from Afghanistan dominates the global market, very little makes its way to the US. Southeast Asian heroin was the dominant supplier of heroin in the US at one time. But it no longer can compete with the transportation and distribution networks of the Mexican and Columbian drug cartels. Se the following chart from the 2015 NDTA.

heroin-seizuresThe Mississippi River has been a dividing line in the US heroin market for the past 30 years, with Mexican black tar and brown powder heroin west of the Mississippi and white powder heroin from South America in the East. There is increasing evidence that Mexican drug cartels are processing their own white powder heroin and mixing white heroin with Mexican brown powder heroin to create a more appealing product to the Eastern US markets. See charts 12 and 13 in the 2015 NDTA for further information on the availability of heroin types purchased in Eastern and Western cities.

The suspected production of white powder heroin in Mexico is important because it indicates that Mexican traffickers are positioning themselves to take even greater control of the US heroin market. It also indicates that Mexican traffickers may rely less on relationships with South American heroin sources-of-supply, primarily in Colombia, in the future. If Mexican TCOs [transnational criminal organizations] can produce their own white powder heroin, there will be no need to purchase white powder heroin from South America to meet demand in the United States. This would also reinforce Mexican TCOs’ poly-drug trafficking model and ensure their domination of all major illicit drug markets (heroin, cocaine, methamphetamine, and marijuana) in the United States.

Mexican TCOs have been increasing their cultivation of opium poppies, to an estimated 17,000 hectares in 2014. This can potentially produce up to 42 metric tons of heroin. Switching to opium cultivation from marijuana cultivation may be at least partly due to the lowered demand for illicit marijuana in the US because of the legalization movement. See “The Economics of Heroin” for more information.

The number of heroin users reporting they used heroin over the past month increased 80% between 2007 and 2012. Of the total number of heroin-related treatment admissions in 2012, 67.4% reported daily use and 70.6% reported their preferred route of use was by injection. Heroin treatment admissions were consistently highest in the New England and Mid-Atlantic states. There are also high rates of repeated treatment among heroin users. Eighty percent of the primary heroin users admitted to treatment in 2012 reported previous treatment; 27% had been in treatment five or more times.

Most opioid users in the 1960s began by using heroin. But that steadily changed until 75% of heroin-users in the early 2000s reported they began by using prescription opioids. The number of people using illicit prescription opioids who switched to heroin was a relatively small percentage of the total number of prescription drug abusers at 3.6%. But it represented 79.5% of new heroin users. Heroin use was 19 times higher among individuals who had previously used pain relievers non-medically.

The reformulation of OxyContin in 2011 is seen as helping to curb the abuse of the drug. In 2011 emergency department visits involving oxycodone declined for the first time since 2004. Overdose deaths from opioid analgesics also began to decrease in 2011. But remember, CPD abusers have been switching to heroin and seem to be contributing to the dramatic increase in overdose deaths from heroin.

The number of heroin overdose deaths increased 244% between 2007 and 2013. Keep in mind that heroin deaths are undercounted. This occurs because of the differences in state reporting procedures for reporting drug-related deaths; and because heroin metabolizes very quickly into morphine. A metabolite unique to heroin, 6-monoaceytlmorphine (6-MAM), quickly metabolizes into morphine erasing the biochemical evidence for heroin use. So many heroin deaths get reported as morphine-related deaths. So what does the future hold for heroin use in the US? The 2015 NDTA concluded the current outlook for the near future is more of the same.

Heroin use and overdose deaths are likely to continue to increase in the near term. Mexican traffickers are making a concerted effort to increase heroin availability in the US market. The drug’s increased availability and relatively low cost make it attractive to the large number of opioid abusers (both prescription opioid and heroin) in the United States.

The United Nations Office on Drugs and Crime (UNODC) publishes a yearly report giving a global overview of the supply and demand of various drugs and their impact on health.

10/18/16

Dancing with the Devil

© choreograph | stockfresh.com

© choreograph | stockfresh.com

I once knew a woman who had an anxiety disorder. She also abused benzodiazepines. She was able to conjure up a panic attack in a doctor’s office and walk out with a prescription for the benzo of her choice. At one time, she had four concurrent prescriptions for these anti-anxiety medications. Another person I know of has a ten-year history of using benzodiazepines at close to the maximum recommended dose. When he had an unexpected short-term hospital stay, the treating physicians were reluctant to continue prescribing benodiazepines at such a high level while he was in the hospital. When he returned home, in case his medical issue resulted in another unexpected stay, he put together an emergency hospital kit with various things—including extra benzodiazepines.

A study published in the American Journal of Public Health in April of 2016 found that benzodiazepines were the second most common drug in prescription overdose deaths for 2013. Given the common knowledge of the potential dangers of benzodiazepines and people becoming more aware of opioids, Marcus Bachhuber and a team of researchers thought that their study would show a steady of declining pattern for prescribing benzodiazepines. But they found exactly the opposite. Between 1999 and 2013 there was an increase of 30% among adult Americans who filled a benzodiazepine prescription. In addition, the amount of medication within a prescription doubled over the same time period.

Bachhuber was quoted by CNN as saying the study’s findings were very concerning. The risk of overdose and death from benzodiazepines alone is said to be generally lower in otherwise healthy adults. But in combination with other drugs like alcohol or opioids, they can be lethal.

Future research should examine the roles of these potential mechanisms to identify effective policy interventions to improve benzodiazepine safety. In particular, as underscored by several recent reports, interventions to reduce concurrent use of opioid analgesics or alcohol with benzodiazepines are needed.

The overdose problem with benzos has been overshadowed by the problems with prescription opioids. Writing for CNN, Carina Storrs said: “The current study could help shine a light on the problem of benzodiazepine abuse and overdose.” Dr. Gary Reisfield, a professor of psychiatry at the University of Florida, referred to the problem with benozdiazepines as a “shadow epidemic”:

Much attention has been paid to the explosion of prescription opioid prescribing and the associated morbidity and mortality. Much less attention has been paid to the shadow epidemic of benzodiazepine prescribing and its consequences.

A 2015 study by Jones and McAninch found that emergency department visits and overdose deaths involving opioids and benzodiazepines increased significantly between 2004 and 2011. Overdose deaths from combining the two classes of drugs rose each year from 18% in 2004 to 31% in 2011. This rate increased faster than the percentages of people filling prescriptions and the quantity of pills in the prescriptions.

As Dr. Indra Cidambi wrote in “Are We Ignoring an Escalating Benzodiazepine Epidemic?”,  she observed with increasing alarm the rising rate of concurrent use/abuse of benzos among opiate users. She pointed to two possible factors driving this trend. First, some opiate abusers use benzos to “spike” the euphoria from their opiates. Second, patients often receive their prescriptions from two different physicians. She said that it is “notoriously difficult” for doctors to refuse to prescribe these two medications.

Unfortunately, and ironically, pain and anxiety are neither verifiable nor quantifiable through medical testing! Consequently, self-reported symptoms by patients are the sole basis on which prescriptions for these medications are written, enabling individuals addicted to these medications to obtain them fairly easily.

Dr. Cidambi recommended the establishment of a national database for physicians to verify whether or not a patient has been prescribed one of these medications before prescribing or filling a prescription for the other. Second, she said physicians should develop limited, short-term treatment plans from the beginning to treat noncancerous pain with opiates and anxiety with benzodiazepines.

Studies have shown the decreasing efficacy of long-term treatment for pain with opioid medications, and evidence-based treatment protocols for benzodiazepines clearly indicate that long-term use of benzodiazepines is not recommended.

In “Benzos: A Dance with the Devil,” Psychiatrist Kelly Brogan described some of her work helping patients taper off of benzodiazepines. A woman who had been placed on Remeron (an antidepressant) and Klonopin (a benzodiazepine) for eight years said of her original prescriber: “He never once told me there might be an issue with taking these meds long-term. In fact, he told me I probably needed them after I tried stopping them cold turkey and felt so sick I thought I was dying.” Brogan said no one ever discussed with this woman or her patients the true risks, benefits and alternatives to psychiatric medications like benzodiazepines, “perhaps because we as clinicians are not told the full story in our training.”

She went on to quote from a paper by another psychiatrist, Peter Breggin, on the risks of benzodiazepines, which include: cognitive dysfunction that can range from short-term memory impairment and confusion to delirium; “disinhibition or loss of impulse control, with violence toward self or others, as well as agitation, psychosis, paranoia and depression.” There can also be severe withdrawal symptoms, ranging from anxiety and insomnia to psychosis and seizures after abruptly stopping long-term larger doses. The person can re-experience their pre-drug symptoms as they taper. These so-called rebound symptoms of anxiety, insomnia and others serious emotional reactions can be more intense than they were before drug treatment began. And don’t forget dependency or abuse.

Psychiatrist Allen Frances, the former chair of the DSM-IV, recently wrote: “Yes, Benzos Are Bad for You.” He introduced his article by saying that he was going to say some very negative things about benzodiazepines in the hope that doctors think twice before prescribing them and patients are discouraged from taking them. Benzos were wonder drugs in the 1960s. Anyone remember the 1966 song, “Mother’s Little Helper,” by the Rolling Stones? These drugs were reputed to be safe, and so were used for a variety of “ills,” such as anxiety, alcohol use disorders (yes, really), to take the edge off of agitation in dementia, and to help people sleep. “Initially we were pretty oblivious to the risk of addiction.” So benzodiazepines quickly became the most prescribed medications in America.

A second craze began in the 1980s with the release of Xanax. Frances said the dose to treat panic disorder was “dangerously close” to the dose leading to addiction. “This should have scared off everyone from using Xanax, but it didn’t.” It remains a best seller, with its own “brand” that now leads to fentanyl be pressed into counterfeit Xanax pills. See “Buyer Beware Drugs” and Paul Gaita’s article on fake Xanax laced with fentanyl.

The real wonder of the benzos is that sales continue to boom, despite their having so little utility and no push from pharma marketeering (because patents have run out – thereby decreasing costs and profits.) Between 1996 and 2013, the percentage of people in the U.S. using benzos jumped more than one-third from an already remarkable 4.1 to 5.6 percent. Especially troubling is that benzo use is ridiculously high (nearly one out of ten) in the elderly, the group most likely to be harmed by them.

Frances said the beneficial uses of benzodiazepines can be counted on the fingers of one hand: short-term agitation in psychosis, mania and depression; catatonia; “as needed” use for times of special stress, like fear of flying, or for sleep. While they should be used very short term, in real life most people take them long term—“in doses high enough to be addicting, and for the wrong reasons. . . . Benzos are very easy to get on, almost impossible to get off.”

In addition to the harm from overdoses, Frances described the painful and dangerous withdrawal symptoms, which he said are a “beast.” Common symptoms are irritability, insomnia, tremors, distractibility, sweating and confusion. “The anxiety and panic experienced by people stopping benzos is usually much worse than the anxiety and panic that initially led to their use.”  Concurrent use or abuse of alcohol or other drugs, like opioids, complicates withdrawal even further.

The most insidious issues with benzos for Frances, is how they effect brain functioning. Especially with the elderly, ongoing benzo use can be devastating. Many elderly begin their downward spiral to death and disability from falls—that happen from their benzo use! He said: “If you meet an elderly patient who seems dopey, confused, has memory loss, slurred speech, and poor balance, your first thought should be benzo side effects — not Alzheimer’s disease or dementia.” See “Sedating Seniors” for more information on this topic. It’s been over 30 years since he last prescribed a benzo for anxiety.

The tough question is what to recommend for those many unfortunates already suffering the tyranny of benzo addiction. Should they stay the course to avoid the rigors and risks of withdrawal or should they make the great effort to detox? This is an individual decision that can’t be forced on someone. But the longer you are on them, the harder it gets to stop, and the cognitive side effects of benzos create more and more dysfunction as your brain ages. The best bet is to stick with a determined effort to detox, however long and difficult, under close medical supervision. On a hopeful note, some of the happiest people I have known are those who have overcome their dependence on benzos.

So it was encouraging to see that the FDA will require class-wide changes in drug labeling to bring attention to the dangers of combining opioids and benzodiazepines. The changes will include boxed warnings on nearly 400 products with information on the risks of combining these medications. The FDA Commissioner, Robert Califf said: “It is nothing short of a public health crisis when you see a substantial increase of avoidable overdose and death related to two widely used drug classes being taken together.” He implored health care professionals to carefully and thoroughly evaluate on a patient-by-patient basis whether the benefits outweigh the risks when using these drug classes together.

Used alone or in conjunction with opiates, benzodiazepines are potentially lethal and addictive. A too sudden withdrawal from benzodiazepines can be fatal, where the same is rarely true with opiates. They work quickly and effectively for anxiety and sleep problems and yet they can have a multitude of side effects, including addiction. Did I say they are addictive? Using benzodiazepines has become a dance with the devil for too many unsuspecting individuals … those that are still alive to regret it, that is.

This article previously appeared on the addiction and recovery website “The Fix” under the title of “Dangerous Dance.”

10/7/16

Sure Cure for Drunkenness

© Volodymyr Baleha | 123rf.com

© Volodymyr Baleha | 123rf.com

Researchers at the University of North Carolina have identified a circuit between two regions of the brain that are thought to control binge drinking. The two areas—the extended amygdala and the ventral tegmental area (VTA)—have been implicated in past studies of alcohol binge drinking.  The results of this study provide the first direct evidence that inhibiting a circuit between two brain regions may protect against binge drinking. Todd Thiele, who directed the research, said: “If you can stop somebody from binge drinking, you might prevent them from ultimately becoming alcoholics. We know that people who binge drink, especially in their teenage years, are much more likely to become alcoholic-dependent later in life.” But so far, the research has only been demonstrated with mice.

Thiele and his team demonstrated that alcohol activates the CRF (corticotropin releasing factor) neurons in the extended amygdala, which in turn act on the ventral tegmental area. Applied to humans, these observations suggest that when someone drinks alcohol, CRF neurons in human brains are activated in a similar manner, promoting continued and excessive drinking. Thiele thought their findings could be relevant for future pharmacological treatments to help curb binge drinking. Although Thiele and his team didn’t connect their research to a particular pharmacological treatment for binge drinking, others did.

Writing for the Telegraph last year, Laura Donnelly connected the dots between the UNC team of researchers and a drug called Selincro (nalmefene).  Selincro was approved by the National Health Service (NHS) in Britain to help individuals cut back on their alcohol intake. It costs £3 ($3.96) and is to be taken as needed to stave off the desire to drink. Writing for the Mirror, Paul Christian’s headline was designed more to catch your attention than communicate truth: “New £3 pill to ‘cure’ alcoholism can stop binge boozing.”

Paul Fuhr was more cautious in his article for After Party Magazine, “Pill Could Cure Alcoholism, Binge Drinking.” His review accurately pointed out that Selincro is recommended for heavy drinkers. “In targeting weekend warriors rather than career alcoholics, the drug becomes less a cure-all than a solid first step toward sobriety.” He thought the implication of using Selincro to treat binge drinking was more intriguing than the reported effectiveness of the pill.

The prospect of a $4 pill that helps binge drinkers from falling down the alcoholic rabbit hole is an intriguing one but, in my opinion, could cause more damage than good. The pill’s very existence would feed the very problem it’s trying to combat, serving as something of a security blanket for people who know they can take a pill. It’s more important that researchers have uncovered the link between brain areas than designing a drug to flip the switch.

I think Fuhr is exactly right in his assessment that uncovering the link between brain areas is more important than a drug designed to “flip the switch.” I also agree that any drug used to turn this neurochemical circuit off and on will likely do more harm than good, aggravating the problem it is supposed to relieve. Its effectiveness is contingent upon the person actually taking the Selincro. And since it will also limit the euphoric effects of the alcohol as well as the cravings, if you don’t want to limit the euphoria, you won’t take it.

It may disrupt cravings and limit the euphoria from drinking, and this could limit how much you drink; but it won’t neutralize the other physiological effects of the alcohol you do drink. Physiological conditions from heavy drinking (anemia, cancer, cardiovascular disease, cirrhosis, gout, high blood pressure, pancreatitis, to name a few) may not improve—and could even progress—with continued drinking. It also won’t limit you blood alcohol level (BAL), so alcohol can still effect your judgment and decision making. Your self-control will still be blunted.

And this isn’t a new drug or a new treatment method, as some of the media seems to imply. The Sinclair Method actually recommends intentionally drinking after taking naltrexone. It conceives alcoholism to be a learned disorder. Limiting the euphoric reward of drinking is alleged to “cure” your alcoholism by systematically extinguishing the high. They should have remembered from behaviorism 101 that intermittent reinforcement (flicking the alcohol euphoria switch off-and-on) makes it more difficult to extinguish a behavior. See “A ‘Cure’ for Alcoholism.”

Another issue lies with the mixed results of research studies done with nalfmefene on humans.

Two French researchers published “Nalmefene: a new approach to the treatment of alcohol dependence” in the journal Substance Abuse and Rehabilitation. They reviewed the recent scientific literature on nalmefene that described its value in reducing alcohol consumption in alcohol-dependent patients. They noted where nalmefene was well tolerated. Its most common side effects were nausea, dizziness, insomnia and headache—which were mild or moderate and of short duration. Now the adverse effects disclaimer:

Selincro® must not be used in people who are hypersensitive (allergic) to nalmefene or any of its other ingredients. It must not be used in patients taking opioid medicines, in patients who have current or recent opioid addiction, patients with acute symptoms of opioid withdrawal, or patients in whom recent use of opioids is suspected. It must also not be used in patients with severe liver or kidney impairment or a recent history of acute alcohol withdrawal syndrome (including hallucinations, seizures, and tremors).

Paille and Martini said the available studies on nalmefene showed it to be more effective than placebo in reducing the number of heavy drinking days and total alcohol consumption. They lamented that the reduction of alcohol consumption in alcohol-dependent patients is not more widely recognized as a treatment objective. They pointed to the February 2013 approval of nalmefene by the European Medicines Agency with the following indications:

Selincro is indicated for the reduction of alcohol consumption in adult patients with alcohol dependence who have a high drinking risk level, without physical withdrawal symptoms and who do not require immediate detoxification.

Selincro should only be prescribed in conjunction with continuous psychosocial support focused on treatment adherence and reducing alcohol consumption.

Selincro should be initiated only in patients who continue to have a high drinking risk level two weeks after initial assessment.

The European Medicines Agency limits the use of Selincro (nalmefene) in patients with a high drinking risk level that continues two weeks after an initial assessment. These patients should not exhibit physical withdrawal symptoms upon decreased alcohol consumption; and should not be in need of detoxification. And it should only be initiated in patients who remained in “continuous psychosocial support” that focused on treatment adherence and reducing alcohol consumption. In others words, use nalmefene as a method to reduce alcohol consumption and not as a method to more effectively control the negative consequences of drinking large amounts of alcohol. Paille and Martini concluded:

Nalmefene appears to be an effective treatment to reduce alcohol consumption in alcohol-dependent patients not wanting to become totally abstinent. It differs from other drug therapies essentially by replacing systematic dosing by “as-needed” dosing adapted to the patient’s clinical situation on a day-to-day basis. Patients therefore take nalmefene when they feel that alcohol consumption is imminent.

This is not the final word in nalmefene as a harm reduction tool with alcohol dependence. Palpacuer et al. published a literature review and meta-analysis of published and unpublished double-blind randomized controlled trials of nalmefene: “Risks and Benefits of Nalmefene in the Treatment of Adult Alcohol Dependence.” Significantly, they used the Cochrane Collaboration tool for assessing the risk of bias in their screening of nalmefene trials for their methodological quality. Five randomized control studies with a total of 2,567 randomized participants were included in the main analysis. So what did the researchers find?

The researchers identified five RCTs that met the criteria for inclusion in their study. All five RCTs (which involved 2,567 participants) compared the effects of nalmefene with a placebo (dummy drug); none was undertaken in the population specified by the European Medicines Agency approval. Among the health outcomes examined in the meta-analysis, there were no differences between participants taking nalmefene and those taking placebo in mortality (death) after six months or one year of treatment, in the quality of life at six months, or in a summary score indicating mental health at six months. The RCTs included in the meta-analysis did not report other health outcomes such as accidents. Participants taking nalmefene had fewer heavy drinking days per month at six months and one year of treatment than participants taking placebo, and their total alcohol consumption was lower. However, more people withdrew from the nalmefene groups than from the placebo groups, often for safety reasons. Thus, attrition bias—selection bias caused by systematic differences between groups in withdrawals from a study that can affect the accuracy of the study’s findings—cannot be excluded. Indeed, when the researchers undertook an analysis in which they allowed for withdrawals, the alcohol consumption outcomes did not differ between the treatment groups.

What do these findings mean?

These findings show that there is no high-grade evidence currently available from RCTs to support the use of nalmefene for harm reduction among people being treated for alcohol dependency. In addition, they provide little evidence to support the use of nalmefene to reduce alcohol consumption among this population. Thus, the value of nalmefene for the treatment of alcohol addiction is not established. Importantly, these findings reveal a lack of information on clinically relevant outcomes in the evidence that led to nalmefene approval by the European Medicines Agency. Thus, these findings also call into question the decisions of this and other regulatory and advisory bodies that have approved nalmefene on the basis of the available evidence from RCTs, and highlight the need for further RCTs of nalmefene compared to placebo and naltrexone for the indication specified in the market approval.

germanPaul Fuhr observed how the idea of miracle cures was as old as time itself, reminiscent of the days of patent medicines, like the German liquor cure sold at one time by Sears Roebuck and company for a buck.

Culturally, we want to believe there is a “cure” for drunkenness in pill form that doesn’t require us to do the hard work of establishing and maintaining abstinence.  My suggestion is to do the hard work.