Forgetting astrocytes – marijuana, memory, and the brain

My favorite thing about science are those discoveries that remind us we simply don’t know everything. A recent article by a group of researchers from Canada, China, and France (see original research article in the journal Cell here and a nice summary here) summarizes findings that reveal some surprises about the ways marijuana use affects short term memory.

Neuroscientists know a good deal about the way we form memories – long-term alterations in the way neurons in certain areas of the brain communicate known as long-term-depression and long-term-potentiation that are controlled, to a large extent, by chemicals (neurotransmitters) called GABA and Glutamate.

But as usual in human endeavors, we only know to look where we believe we need to. In the case of marijuana and memory, and after this study likely memory formation in general, we always thought that neurons were the sole players in this game. Like our old beliefs about genetics that stated that most of our genetic material is meaningless only to reveal that material to be crucial for gene regulations in a new science known as epigenetics, it seems that neurons are not the only important players in memory.

The scientists in this recent study were trying to figure out whether GABA or Glutamate were responsible for Marijuana’s (or more precisely THC‘s) effects on memory. To their surprise, they found out it was neither and kept looking, eventually realizing that the real culprits were cells called astrocytes, previously thought to be akin to the brain’s cleaning crew. Apparently, this cleaning crew might also be important for many crucial aspects of our daily functioning… Never assume, right?

The results of this research will no doubt produce some serious changes in the study of memory research as well as in research on the effects of THC and other drugs on memory – it broadens our search for the factors important in the primary and secondary effects of drugs and drug use, both short- and long-term. It could help us produce drugs with less side effects, find ways to counter undesirable effects of drug use, and develop treatments that specifically interfere with illicit drug use mechanisms. Exciting times.

Treating alcohol withdrawal with benzodiazepines – Safe if mindful

Alcohol withdrawal can lead to some pretty horrible side effects

Contributing co-author: Andrew Chen

Alcohol withdrawal can be extremely unpleasant (see here for an overview). Symptoms vary from person to person, but most people will experience some negative symptoms of alcohol withdrawal if they try to stop drinking after long term use.

Mild to moderate symptoms include headache, nausea, vomiting, insomnia, rapid heart rate, abnormal movements, anxiety, depression, and fatigue. Severe symptoms of alcohol withdrawal include hallucinations, fever, and convulsions (known as DT’s or delirium tremens). Most people undergoing alcohol detox do not require hospitalization, but in severe cases, hospitalization may be necessary (1). Since their introduction in the 1960s, benzodiazepines have been the drug of choice for treating severe cases of alcohol withdrawal.

Benzodiazepines, or benzos for short, are a class of psychoactive drugs that work to slow down the central nervous system by activating GABA receptors. This provides a variety of useful tranquilizing effects. Aside from relieving symptoms of alcohol withdrawal, benzodiazepines are also commonly prescribed to treat insomnia, muscle spasms, involuntary movement disorders, anxiety disorders, and convulsive disorders.

The most common regimen for treating alcohol withdrawal includes 3 days of long-acting benzodiazepines on a fixed schedule with additional medication available “as needed.” (2)

The two most commonly prescribed benzos are chlordiazepoxide and diazepam. Chlordiazepoxide (Librium) is preferred for its superior anticonvulsant capabilities while diazepam (Valium) is preferred for its safety against overdose with alcohol. Short-acting benzos like oxazepam and lorazepam are less frequently used for treating alcohol withdrawal (1).

Compared to other drugs, benzos are the safest and most effective method for treating difficult alcohol withdrawal. However, benzodiazepines do come with their own potential for dependence and abuse. Ironically, symptoms of benzodiazepine withdrawal are quite similar to those of alcohol withdrawal. Tapering off dosage is the best way to prevent serious withdrawal symptoms. To avoid such complications, benzodiazepines are only recommended for short-term treatment of alcohol withdrawal.

In short

Benzos can be very useful for helping long terms alcoholics deal with the difficult withdrawal symptoms that can accompany the detox period. Just be mindful so as not to find yourself right back where you started.

Citations:

1. Williams, D., McBride, A. (1998) The drug treatment of alcohol withdrawal symptoms: A systematic review. Alcohol & Alcoholism. 33(2), 103-115

2. Saitz, R., Friedmn, L. S., Mayo-Smith, M.F. (1996) Alcohol withdrawal: a nationwide survey of inpatient treatment practices. 10(9), 479-87

Heavy alcohol users Vs. Addicts – Stress response

I can’t even count how many times I’ve talked about the difference between alcohol or drug users and alcoholics or addicts (see here, here, and here for some examples and keep reading). The quick summary: Many people use drugs and many abuse them at times, a small percentage meet criteria for addiction at some point in their life and an even smaller percentage is the type of addict we’ve been taught to think of – chronically relapsing and seemingly incapable of quitting no matter how crappy their life gets.

One of the main reasons we study drug and alcohol abuse is because of the huge health impact of this stuff – we spend billions and billions of dollars every year on health-care that is directly or indirectly related to the abuse of nicotine, alcohol, and pretty much every other drug on earth (marijuana can certainly help some conditions but heavy use of marijuana can bring its own consequences). One of the major players in these health problems is the effect of alcohol and drug use on stress in the body. Stress increases death rates in several ways including: Heart attacks, strokes, cancer, and more.

Well, a recent study in Amsterdam looked at alcohol (yes, you read that right, the Dutch care about more than weed) consumption, alcohol addiction (alcoholism) diagnosis, and effects on the body’s stress system, also known as the HPA (Hypothalamic-Pituitary-Adrenal) Axis. If nothing else, the study helped confirm that an alcoholism diagnosis is not necessarily the same as an indication of heavy drinking and that excessive drinking is no bueno, regardless of whether it meets addiction criteria or not.

Alcohol drinking, alcoholism, and stress regulation

A very simple cortisol graph showing reduced levels during sleep with peaks upon wakingI’m not going to go into this in detail (look here and here for more) but just as our brains and bodies have systems for decision making, they also have complex stress management systems. The latter rely heavily on hormones, including Cortisol, to keep our bodies in the right states whether those be fight, flight, or reading a book before sleep (see figure on left for over-simplified cortisol levels throughout the day in a normal person). We’re supposed to have the most cortisol right upon waking with constant reductions throughout the day until we fall asleep, and back again. Individuals with mental health disorders like anxiety and depression have substantially different cortisol level patterns throughout the day and are less effective at regulating cortisol (in case you needed another reason why our biology affects our states of being and behavior).

The dutch study tested cortisol levels at 7 different times throughout the day after giving their subjects a 4 hour battery of tests. They also assessed their cardiac functioning by assessing different measures related to heart beat regulation that allows for adapting across challenging situations by affecting the sympathetic nervous system (excitatory processes) and parasympathetic nervous system (inhibitory processes).

They looked at these measures as a way of assessing the relative functioning of the HPA Axes’ of different groups. Specifically, they looked at:

  1. Non-drinkers
  2. Moderate drinkers (less than 3 drinks per day)
  3. Heavy drinkers (more than 3 drinks per day)
  4. Non alcoholics
  5. Remitted alcoholics (met criteria for alcoholism previously but not in past 12 months)
  6. Current alcoholics.

One of the most interesting findings, as far as I’m concerned, was that among remitted alcoholics the average amount of drinking was around 1.3 drinks per day with a lot of variability, a little higher than that of moderate drinkers (0.8 drinks per day) but lower than that of heavy drinkers (4.0 drinks per day). I see this as a little more proof that people who met criteria for alcoholism at one point don’t necessarily abstain forever and don’t necessarily continue to have drinking problems (per Moderation Management, spontaneous remission, or some other means of stopping their alcoholic drinking).*

You can blame improper diagnostic criteria, a continuum of addiction severity, or anything else as far as I’m concerned but as I pointed out in my first paragraph, we’ve talked about this topic repeatedly and I see no end coming soon. The bottom line is that meeting criteria for alcoholism at one point in life tells me something, but far from everything, about a person’s drinking habits or drinking problems later in life.

But back to stress. As you might have already guessed, since it is heavy drinking that causes serious dysregulation of the body’s stress response, what the researchers found was that meeting criteria for alcoholism now, or in the past, didn’t have any major effect over their participants’ HPA functioning. Instead, all that mattered was how heavy their drinking was now. Heavy drinkers had higher waking cortisol levels, higher night-time cortisol, and increased sympathetic (excitatory) control. In short – heavy drinkers were less able to regulate their stress and excitation response, likely leading to increased stress on their bodies.

As a side note, this study also found that if anything, moderate drinking conferred health benefits when it came to stress over not-drinking at all – far from the first study to note this but another set of reinforcing evidence that drinking alcohol is not in itself bad for you while over-drinking is.

So – Drinking a lot of alcohol causes disruptions to your body’s stress regulation system that will likely increase the likelihood of heart problems, depression, anxiety, and more. Those disruptions are there whether you meet criteria for alcoholism or not.

Obviously, there are many alcoholics who drink a lot of alcohol, but there are also people who meet (now or in the past) criteria for alcoholism who are binge drinkers and therefore don’t drink daily and have lower “drink numbers.” As we mentioned before, addiction is not about quantity, in fact, the criteria for addiction barely mentions quantity – when it states that addicts consume “more than intended” or that tolerance creates a state where an person needs greater quantity to reach the same effect of the drug. Drinking or using a lot of drugs or alcohol does not an addict make.

*Note: Given the variability in the remitted-alcoholics groups their is little doubt that some of them had stopped drinking while others drank to excess. Additionally, it should be pointed out that alcohol abuse was not assessed in this sample, so it could still be a problem for at least some of those now-drinking past-alcoholics.

Citations:

Lynn Boschloo, Nicole Vogelzangs, Carmilla M.M. Licht, Sophie A. Vreeburg, Johannes H. Smit, Wim van den Brink, Dick J. Veltman, Eco J.C. de Geus, Aartjan T.F. Beekman, Brenda W.J.H. Penninx (2011). Heavy alcohol use, rather than alcohol dependence, is associated with dysregulation of the hypothalamic-pituitary-adrenal axis and the autonomic nervous system. Drug and Alcohol Dependence 116, 170–176.

Heather M. Burke, Mary C. Davis, Christian Otte, David C. Mohr, (2005).  Depression and cortisol responses to psychological stress: A meta-analysis, Psychoneuroendocrinology, Volume 30, Issue 9, Pages 846-856.

Are violent drunks giving the rest of us a bad name? Alcohol consumption and violence

We all know that drinking alcohol changes the way people think and can make them act strangely right? We also know that alcohol is involved in more than 50% of violent crimes and about 75% of partner violence. The question is, why the connection?

A recent paper I published suggests that drugs and alcohol can not themselves be thought to cause violence. Still, the relationship exists, so what gives?

(Before you go any further, if you’re unclear about the difference between causation and association, I suggest you read this article)

Your brain and alcohol abuse

The thought altering effects of consuming alcohol, and most drugs, can be said to affect something called executive functioning (EF). What exactly makes up this type of functioning is a source of some debate, but let’s just say that it refers to attention, strategic planning, reasoning, thought flexibility, and the ability to process information in working memory (an important type of memory used in learning).

You can probably already tell that this type of brain function is extremely important and that different people possess different levels of it. I can also tell you that alcohol consumption has  been shown to reduce overall executive functioning. If you drink alcohol, or have ever seen someone drink, this probably doesn’t come as a huge surprise.

The thing is that alcohol consumption messes up everyone’s EF, though obviously, the more you drink, the more affected you become. Still, given the fact that more than 50% of Americans report at least one binge drinking episode a year and less than 7% are involved in violent crime, something else must be at play, right?

Aggressive personality and irritability

As I mentioned earlier, I published a paper showing that aggressive personality, which I measured using 5 different tests, contributes far more to violent behavior than drug use alone. Still, a recent study found that irritability alone could account for some aggressive behavior. Still, the more interesting finding had to do with alcohol-related EF problems and irritability together. The experiment was pretty interesting, so let’s go over it for a bit.

Researchers at the University of Kentucky took more than 300 students and gave them a whole bunch of tests assessing their EF and their overall level of irritability. Afterward, half of the students were given alcohol to drink (about 3-4 drinks per person) and the other half was given a similar number of drinks that contained no alcohol but were sprayed before being handed to smell the same. The students were then asked to play a game that pitted them against another person. The secret was that there was no game and no other person, the winner and loser in each round was pre-determined. Every time the student “won” they got to give the other player a shock, but every time they lost, they themselves got shocked. As the game went on, the shocks the participants got increased in intensity. The researchers wanted to see how the students would react and how large the shocks they would give back would be.

The results showed that the more mistakes people made in their initial EF testing (and therefore the less overall EF capability they showed) the more aggressive they were. This makes sense, as people who are less able to plan, think ahead, and control their behavior would be more likely to engage in things that would hurt them, or misjudge events and think react inappropriately. Irritability was also shown to affect aggression, but this time only for men and intoxicated women.

The effect of alcohol abuse on aggression and violence

When the whole thing was put together the researchers found that for drunk men only, reduced EF and increased irritability worked together to generate even more aggression that was shown for all the other participants. For the simplest example think back to anyone you know who is pretty quick to react anyway and is a little too easily pissed-off. Chances are they become a pretty mean drunk who likes to get in fights.

Obviously this makes sense if you know someone like that, but in terms of helping us make decisions about who should be considered dangerous and who shouldn’t, especially when consuming alcohol, this research helps further explain why we see such a strong connection between alcohol abuse and violence or aggression.

The way I see it there’s a relatively small number of people (mostly men) who is normally pretty aggressive, irritable, and lacking in judgment and self-control, who often get violent when they drink alcohol. For them, many alcohol drinking episodes end badly, and since they’re the most visible of the aggressive drinkers, their behavior produces an association between alcohol consumption per se and violence. For the rest of us, alcohol consumption rarely leads to violence, but violence rarely occurs without drinking alcohol either, so we hardly ever enter the equation at all. That’s why the pattern holds.

Citations:

Godlaski, A. J., Giancola, P. R. (2009). Executive function, Irritability, and Alcohol-Related Aggression. Psychology of Addictive Behavior, 23, 391-404.

Jaffe, A. et al., (2009). Drug Use, Personality and Partner Violence: A Model of Separate, Additive, Contributions in an Active Drug User Sample. The Open Addiction Journal, 2.

Saving lives made easy – Treating opiate overdose with intranasal naloxone

oxycodone-addiction-big1Contributing co-author: Andrew Chen

Imagine that you and your friend have been using heroin (or another opiate). A few hours go by and you notice your friend is progressively becoming more and more unresponsive. You check on him and find that his breathing is shallow, his skin is cold, and his pupils are constricted. You recognize these as signs of opiate overdose and call for help. Now what?

Well… If you had some naloxone around, you might be able to treat the overdose and save your friend’s life before the paramedics even arrive.

Naloxone hydrochloride (naloxone) is the standard treatment for opioid overdose. Naloxone works by blocking opioid receptors, thereby removing opioid agonists, such as heroin or oxycodone, from those same receptors. As a result, the overdose is reversed and death is prevented.

What makes naloxone great is that it has no potential for abuse. In fact, it makes the user feel pretty crappy.

Naloxone is typically delivered through an injection, which makes it pretty much useless in many situations. However, it can also be delivered using an intranasal spray device. This intranasal form of naloxone is getting lots of attention recently because it is relatively easy to administer.

In 2006, The Boston Public Health Commission (BPHC) implemented an overdose prevention program, providing training and intranasal naloxone to 385 individuals deemed likely to witness an overdose. These individuals were often family members of opiate users or drug-using partners.

15 months later, the BPHC conducted a follow-up:

  • Contact was made with 278 of the original participants.
  • 222 reported witnessing no overdoses during the 15-month span.
  • 7 had their naloxone stolen, lost, or confiscated.
  • 50 reported witnessing at least one overdose during the 15-month span. Together, these 50 individuals reported a total of 74 successful overdose reversals using intranasal naloxone!

The BPHC program is not the only example of successful use of naloxone in opiate overdose prevention programs. Similar programs have popped up in Chicago, New York, San Francisco, Baltimore, and New Mexico.

Unlike injections, using a nasal spray isn’t rocket science. All of the participants in the BPHC program were trained by non-medical public health workers, which makes the idea relatively cheap. As the data shows, the participants were able to effectively recognize an opiate overdose and administer intranasal naloxone. By targeting at-risk populations and providing proper training, distribution of intranasal naloxone can help in saving lives.

For more information, check out our post Addiction and the brain part IV – Opiates

Citation:

Doe-Simkins, M., Walley, A.Y., Epstein, A., & Moyer, P. (2009) Saved by the nose: Bystander-administered intranasal naloxone hydrochloride for opiod overdose. American Journal of Public Health. 99(5)

Influential factors in college drinking

Co-authored by: Jamie Felzer

What influences students’ college drinking decisions?

  • Do friends peer pressure them?
  • Do they do it because they are bored?
  • Do they drink to relieve depression or anxiety?

Researchers recently tried to answer these questions by surveying college students…

65% of the participants reported having at least one drink in the past three months. It was astonishing that the typical number of drinks in a week was 10.5 and on a weekend was 7.3 average drinks. These numbers included drinkers and nondrinkers and was the average (meaning around half the people had more drinks as those had less). This indicates that college drinking is far more extreme than drinking happening outside of the college setting.

3 main influential factors for someone’s decisions in college drinking and to what extent:

  • If their close friends were drinking,
  • How drunk they thought they were, and
  • Their drinking intentions.

Interestingly enough, the more students thought others on their campus approved of drinking, the less they tended to drink. We recently reported similar misconceptions about students, their peers and marijuana use. Typically, if people intend to get drunk they use less protective factors (see here for a previous post about these) such as pacing or eating or keeping track of what they were drinking. Friends’ drinking was the best predictor of drinking habits in all cases.

You can tell a lot about a person by watching their friends, so watch who you surround yourself with. Those who think favorably of drinking tend to think they can drink more before reaching intoxication and also tend to hang out with others who do the same. However, these people are the ones that need the most intervention yet are the most difficult to change.

Those who socialize with a wide variety of people typically are lighter drinkers and tend to respond better to treatment immediately as well as have fewer problems further down the line. The heavier drinkers benefit more from motivational interventions focusing on their attitudes toward drinking.

Regardless of stereotypes, ethnicity, weight and gender did have an effect on any of these findings. It was peoples’ closest friends that were the most significant factor in influencing all aspects of college drinking.

Citation:
Examining the Unique Influence of Interpersonal and Intrapersonal Drinking Perceptions on Alcohol Consumption among College Students. Journal of Studies on Alcohol and Drugs. Volume 70, 2, March 2009

Promising new medical treatment options for drug addiction!!!

Researchers are attacking the issue of drug addiction from multiple angles, and the results seem to be more and more ways to help. Some promising new developments in pharmacological (as in medication) therapies include a new cocaine-vaccine, as well as expanded use of Buprenorphine, for the treatment of opiate (heroin, morphine) addiction.

  • These medications are best used along with behavioral treatment in order to increase to probability of treatment success.
  • By reducing cravings, as well as reducing the effects of the drugs themselves, these medications can increase the length of time that patients will stay in treatment, which is the most reliable way of producing better treatment outcomes.

What else is new aside from medications?

There are also some exciting developments in the behavioral treatment, including Contingency Management (CM), a treatment method that tries to reteach addicts positive, drug-free behaviors by reinforcing those over the use of drugs. While some people still have problems with programs that use CM because of the notion of rewarding drug addicts for not using drugs, I say use whatever works!

Lastly, as early as 2003, researchers have noted that proper drug treatment may take longer than the 14-30 day programs that are currently being offered (1). In fact, while the article I’m referring too speaks specifically about methamphetamine addiction, we now know that the long use of many drugs, including cocaine, leads to long lasting brain changes that can take up to a year to show significant recovery.

I personally think that proper drug treatment for long time addicts (anyone with more than a year or so of heavy use) should take on the order of 6 months to a year, and should be supplemented by some outpatient post-care for an extended period of time (I’m far from the only one calling for this, see article 2). It’s the only sensible thing to do given the long term changes that such drug use creates in the brain…

I think it’s about time that insurance companies step up the plate and recognize that the huge cost of drug problems for our society (estimated at more than $100 billion annually) can be vastly reduced by providing sound, scientifically based, medical treatment options for those who need it.

citations:
(1) Margaret Cretzmeyer M.S.W, Mary Vaughan Sarrazin Ph.D., Diane L. Huber Ph.D., R.N., FAAN, CNAAc, Robert I. Block Ph.D. & James A. Hall Ph.D., LISW( 2003) Treatment of methamphetamine abuse: research findings and clinical directions. Journal of Substance Abuse Treatment Volume 24.
(2)
A. Thomas McLellan, PhD; David C. Lewis, MD; Charles P. O’Brien, MD, PhD; Herbert D. Kleber, MD (2000). Drug Dependence, a Chronic Medical Illness: Implications for Treatment, Insurance, and Outcomes Evaluation. Journal of the American Medical Association, Volume 284, pp. 1689-1695.

Question of the day:
Do you know anyone who’s been through residential drug treatment?
How long were they in for?
How many times?
Did it help?