03/3/17

Shatter and Psychosis

© Birute Vijeikiene | 123rf.com

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

02/20/17

Listening to Marijuana Research

© Mohammed Anwarul Kabir Choudhury

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

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

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

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

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

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

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

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

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

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

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

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

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

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

02/10/17

Guns and Needles

© Roman Legoshyn | 123rf.com

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

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

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

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

Characteristic

Natural and semi-synthetic opioids

2014

2015

% change in rate, 2014 to 2015

No. (rate)

No. (rate)

Overall

12,159 (3.8)

12,727 (3.9)

2.6%

Sex

Male

6,732 (4.2)

7,117 (4.4)

4.8%

Female

5,427 (3.3)

5,610 (3.4)

3.0%

Characteristic

Synthetic opioids other than methadone

2014

2015

% change in rate, 2014 to 2015

No. (rate)

No. (rate)

Overall

5,544 (1.8)

9,580 (3.1)

72.2%

Sex

Male

3,465 (2.2)

6,560 (4.2)

90.9%

Female

2,079 (1.3)

3,020 (1.9)

46.2%

Characteristic

Heroin

2014

2015

% change in rate, 2014 to 2015

No. (rate)

No. (rate)

Overall

10,574 (3.4)

12,989 (4.1)

20.6%

Sex

Male

8,160 (5.2)

9,881 (6.3)

21.2%

Female

2,414 (1.6)

3,108 (2.0)

25%

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

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

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

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

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

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

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

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

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

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

01/31/17

Curiouser and Curiouser with Chantix

© shamian | 123rf.com

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

01/20/17

Marijuana Use and the Heart

© Andrija Markovic | 123rf.com

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

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

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

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

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

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

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

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

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

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

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

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

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

01/10/17

Marijuana Makes You Nauseous?

© Viachaslau Vaitsenok |123rf.com

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

© Visions of America, LLC | 123rf.com

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

© Andrea Izzotti | 123rf.com

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

5© ljupco | 123rf.com

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

© David Castillo Dominici | 123rf.com

© 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.