How Alcoholism Causes Muscle Weakness

It’s a mitochondrial thing.

Chronic alcohol intake weakens muscles. This condition can take the form of numbness or shooting pains in arms and legs, muscle cramps, fatigue, heat intolerance, and problems urinating. In some cases it can lead to diarrhea, nausea, vomiting, spasms, muscle atrophy, and movement disorders, even chronic pain and long-term disability. Leg symptoms are the most common. Alcohol-related neuropathy of this kind generally develops over time and gradually worsens. But until recently, the mechanism behind alcoholic neuropathy has remained obscure.

As it turns out, it’s a mitochondrial thing. Mitochondria, as we all remember from 10th grade biology, are little structures known as the “power plants” of cells. They are constantly changing tubular organelles that form networks inside of cells to convert oxygen into energy used in cellular processes. But if the proper enzymes that trigger the process go missing, less energy gets produced for activities like muscle function.

Patients with certain forms of mitochondrial disease, in which mitochondria fail to self-repair, show pronounced muscle weakness as a symptom. In some cases, this is due to a mutation for a particular mitochondrial fusion protein, leading to “late onset myopathy.”

Muscle tissue repairs itself through a process known as mitochondrial fusion, through which a broken mitochondrial cell component can repair itself by fusing with healthy mitochondria and exchanging bodily fluids, so to speak. It had previously been thought that the tightly packed fibers of muscle cells might not allow for normal fusion among the mitochondrial organelles found in skeletal muscle. Not so, according to a recent paper for the Journal of Cell Biology. Principle author Gyorgy Hajnoczky in the Department of Pathology, Anatomy and Cell Biology at Philadelphia’s Thomas Jefferson University writes that the animal study shows how chronic alcohol exposure “suppresses mitochondrial fusion in muscle fibers.” The problem worsens over time due to “lesser metabolic fitness of the mitochondria, which progressively hinders calcium cycling during trains of stimulation.” What this means is that, in cases of prolonged heavy drinking, mitochondria have less “reserve capacity” for supporting calcium regulation in cells.

The researchers began with the known finding that “mitochondrial ultrastructure damage is apparent in the skeletal muscle of alcoholics, and mitochondria and their quality control are considered to be a primary target of chronic alcohol exposure.” Furthermore, “mitochondria represent a major target of alcohol and loose their normal shape upon persistent alcohol exposure.”

The study, funded by the NIAAA, demonstrated that mitochondrial fusion is the key to repair in skeletal muscle, as it is in other muscle tissue. In the study, researchers color-tagged mitochondria in the skeletal muscle of rats, and demonstrated that mitochondrial fusion occurs, and is governed by key players called mitofusin 1 fusion proteins (Mfn1). Chronic alcohol abuse interferes with this repair process. In the study, alcoholic rats showed a decrease in Mfn1 levels of up to 50 percent, while other fusion proteins were not affected.

“That alcohol can have a specific effect on this one gene involved in mitochondrial fusion suggests that other environmental factors may also alter specifically mitochondrial fusion and repair,” Hajnoczky said in a prepared statement.

The study has provided insight “into why chronic heavy drinking often saps muscle strength,” which could also “lead to new targets for medication development,” according to Dr. George Koob, head of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

Eisner V., Lenaers G. & Hajnoczky G.  Mitochondrial fusion is frequent in skeletal muscle and supports excitation-contraction coupling, The Journal of Cell Biology,    DOI: 10.1083/jcb.201312066

Photo Credit: http://mda.org

Marijuana Dependence and Legalization

Making best guesses about pot.

One essential question about state marijuana legalization continues to dog the debate:  Namely, as marijuana becomes gradually legal, how do we estimate how many people will become dependent? How can we estimate the number of cannabis users who will become addicted under legalization, and who otherwise would not have succumbed?

Back in 2011, neuroscientist Michael Taffe of the Scripps Research Institute in San Diego, writing on the blog TL neuro, referenced this common question, noting that “the specific estimate of dependence rate will quite likely vary depending on what is used as the population of interest… Obviously, changing the size of the underlying population is going to change the estimated rate….”

But change it how, and by how much? The truth is, we don’t know. We can’t know in advance. There are sound arguments for both positions: Legal marijuana will lead to increased rates of cannabis addiction because of lower price and greater availability. On the other hand, almost everybody likely to become addicted to marijuana has probably already been exposed to it, including teens.

What we can start attempting to find out with greater rigor, however, is this: How many chronically addicted marijuana users are out there right now?

In The Pathophysiology of Addiction  by George Koob, Denise Kandel, and Nora Volkow (2008), the base rate of cannabis dependence was estimated to be 10.3% for male users and 8.7% for female users. Their data came from the National Survey on Drug Use and Health, and the rate is similar to common estimates for prescription stimulant addiction. The dependence rate for cigarettes is at least three times as high. However, an overall dependence rate of 9.7%, when men and women smokers are combined, is the origin of the highly contested figure of 10%.

Since then, other databases have been tapped for estimates of existing cannabis dependence. In October of 2013, using the Global Burden of Disease database maintained by the World Bank, British and Australian researchers, along with collaborators at the University of Washington in the U.S., published revised estimates in the open-access journal PLOS ONE, based on numbers from 2010.  The scientists culled and pooled a series of epidemiological estimates and concluded that roughly 11 million cases of cannabis dependence existed worldwide in 1990, compared to 13 million cases in 2010. This boost can be accounted for in part by population increases.

Are these dependent users distributed evenly across the globe? They are not. The PLOS ONE paper demonstrates that marijuana use is markedly more prevalent in certain regions: “Levels of cannabis dependence were significantly higher in a number of high income countries including Australia, New Zealand, the United States, Canada, and a number of Western European countries including the United Kingdom.” High income equals high marijuana usage and dependence—“Cannabis dependence in Australasia was about 8 times higher than prevalence in Sub-Saharan Africa West.” But there may be major holes in the epidemiological database: “This is particularly the case for low income countries, where there is typically limited information on use occurring, even less on levels of use, and usually no data on prevalence of dependence.”

In conclusion, the researchers found an age and sex-standardized cannabis addiction prevalence of 0.2%. “Prevalence was not estimated to have changed significantly from 1990, although increased population size produced an increase in the number of cases of cannabis dependence over the period.”

In another 2008 study, this one published in the Journal of Clinical Psychiatry, scientists at Columbia University and the New York State Psychiatric Institute looked at a set of 2,613 frequent cannabis users, using the development of significant withdrawal symptoms as the leading indicator. About 44% of regular dope smokers experienced two or more cannabis withdrawal symptoms, while about 35% reported three or more symptoms. The most prevalent symptoms in this study were fatigue, weakness, anxiety, and depressed mood. “Over two-thirds smoked more than 1 joint/day on days they smoked during their period of heaviest use; mean joints smoked/day was 3.9. About one-fifth had primary major depression….”

Age of onset was not predictive of withdrawal symptoms in this large study. The investigators suggest that “irritability and anxiety may receive great clinical consensus as regular features of cannabis withdrawal because they are subjectively and clinically striking compared to fatigue and related symptoms.” The researchers also speculate that somatic symptoms of weakness and fatigue might be attributed to varying levels of THC, compared to the presence of other cannabinoids such as CBD. The study is further evidence supporting an “association of primary panic disorder or major depression with cannabis depression/anxiety withdrawal symptoms,” suggesting a “possible common vulnerability, meriting further investigation.”

One of the reasons this matters is because of the very tight relationship between marijuana addiction and major depressive disorder. A 2008 study of young adults in the journal Addictive Behaviors  found that participants with comorbid cannabis dependence and major depressive disorder, the most commonly dependence symptom was withdrawal, reported by more than 90% of the subjects in the study. 73% of the subjects experienced four symptoms or more. After that, the most common symptoms were irritability (an underreported but significant behavioral problem), restlessness, anxiety, and a variety of somatic symptoms, including gastrointestinal problems, loss of appetite, and sleep disturbances, including night sweats and vivid dreaming. The authors, affiliated with University of Pittsburgh School of Medicine, concur with the conclusion of earlier researchers:  “Given the weight of evidence now supporting the clinical significance of a cannabis withdrawal syndrome, the burden of proof must rest with those who would exclude the syndrome….”

Clearly, cannabis does not contribute to the world disease burden in the same way that alcohol, nicotine, and opiods do. However, it’s fair to say that for a minority of users, cannabis dependence causes disabilities and liabilities that are not always trivial.

Mark A. R. Kleiman, a Professor of Public Policy at UCLA and a consultant to the state of Washington on marijuana legalization, told PBS:

The couple of million who stay stoned all day, every day, account for the vast bulk of the total marijuana consumed, and thus the total revenues of the illicit marijuana industry. That's typical. The money in any drug, including alcohol, is in the addicts, not the casual users. There was a big fuss during the 80s about how much casual middle-class drug use there was and how respectable folks were supporting the markets. It's certainly true that most people who are illicit drug users are employed, stable respectable citizens. But it doesn't follow that if we could get the employed, stable respectable citizens to stop using illicit drugs, the problem would mostly go away.

Tips For Dating a Person in 12 Step Recovery

Would you let your daughter go out with an addict?

In the title of her book, Girlfriend of Bill, author Karen Nagy riffs on the time-honored public code for mutual AA recognition: “Are you a friend of [AA co-founder] Bill?” Nagy says she was unable to find any material written “specifically for someone who is new to such a relationship or who is thinking about dating someone in recovery.” So she wrote one, and the publishing arm of Hazelden brought it out. People in Hazelden-style recovery (Nagy calls them “PIRs”) can present challenges, since, as Nagy learned by dating several of them, stopping drinking or using is not necessarily the end of the matter.

Readers should know that the book is written from the perspective of a member of Al-Anon, who is also a firm believer in the 12 Steps. But if dating people who participate in AA or NA is not your thing, than Nagy suggests dating people from SMART recovery, Secular Organizations for Sobriety, church, mental health peer support programs, therapy groups, and so on. Her own experience, however, appears mainly limited to men in and out of 12-Step recovery programs.

While the controversial disease model of addiction continues to provoke heated debate, Nagy discovered that “knowing addiction is a disease has helped me to confront and get over my past prejudices about alcoholics and drug addicts, and to better understand why they might think, act, and react the way they do.”

“Change is tough for all of us,” says Nagy, “but it can be especially hard for an addict” because of the strong tendency to rationalize and resist needed change. Addicts, she adds, “are also known for ‘wanting it now,’ a trait that could be related to their brain chemistry and addictive cravings.” (Or, as non-practicing addict Carrie Fisher memorably put it, “instant gratification takes too long.”)

Her summation of the notion behind the AA/NA concept of a higher power is a common one these days: “Some might call their Higher Power God; others might define it as nature, the positive energy of their group, or an unnamed sense of spirit.” While that may sound naïve to some, what the addict must grasp is that white-knuckle notions of triumph through personal will may have to be abandoned along the way, if we are talking about chronic, active addiction. And she correctly points out that the AA Big Book is “written in an old-fashioned style that hearkens back to the 1930s,” when the amateur self-help group known as AA was founded.

It’s easy to forget that there are common experiences that most recovering addicts are heir to. “We who care about a Person in Recovery are also powerless over alcohol and drugs,” Nagy writes. “Try as we might—we can’t control whether or not the PIR uses them.” And non-addicts who are dating them might usefully be forewarned about such things, Nagy believes. In addition, “It can take months for an addict’s body to adjust to abstinence,” she writes. “Aches and pains are common in withdrawal, and so are digestive problems that can include constipation, diarrhea, and loss of appetite… sleep disorders can be a huge problem….”

Nagy also tips boyfriends and girlfriends to the widening and primarily generational dispute over the use of medications for craving or associated mental health disorders. “Believing ‘a drug is a drug is a drug,’ many old-timers in recovery resist taking medications, whereas younger People in Recovery are more open to taking them if they need them.”

Addicts new to recovery may be coming off a period of social isolation, and a sense of being cut off from others. Nagy advises that a summary knowledge of the 12 Steps can be helpful, in particular the business about “making amends” to people one has harmed. Forgiveness is a touchy and ongoing bit of business. It never hurts to say you’re sorry, if in fact you are. Or to say it again.

Perhaps the single most common complaint takes the form of jealousy or irritation: Why is the Person in Recovery spending so much time with those other people, rather than with me? Aren’t I “supportive” enough? Nagy views the essence of AA/NA as a “spirituality of companionship—friends accompanying friends, helping, sharing, daring, celebrating, or grieving.” In the end, Nagy believes, “it’s not about religion; it’s about connection.”