Marijuana has Long-term Effects on the Brains of Adolescents

(from wikipedia.org)
(from wikipedia.org)

After alcohol, marijuana is the most widely used illegal drug in the United States (I mean seriously, who hasn’t smoked up at least once? According to Pew Research Center, half of the country) But pot laws are rapidly changing in many parts of the country and soon it may be as ubiquitous as alcohol. Four states in the US have legalized marijuana for recreational use and 23 total states have some form of legal marijuana use (including D.C.). While the health effects of alcohol have been well studied and are significant (some 88,000 deaths/year, the third highest cause of preventable death in the US, according to the CDC and NIAAA), little is known how this shifting trend in marijuana use will affect the country. Another important trend is the amount of THC (Δ-9-tetrohydrocannabinol, the chemical that is primarily responsible for the psychoactive effects of marijuana) in marijuana strains has been steadily increasing over the past few decades [1, 2]. The big question that researchers are asking themselves is if legal marijuana use drastically increases, what are the long-term personal and public health consequences of marijuana use? Of course, this is a huge question with many complexities.

Significantly, Marijuana is the also the most widely used illegal substance amongst youths. Adolescence (ages 12-17) is an extremely critical period for brain development [3, 4] yet the effects of marijuana on the brains of kids have not been thoroughly studied. A recent paper out of Dr. Steven R. Laviolette’s laboratory at the University of Ontario sought to answer this question: what happens to brains of adolescent and adult rats that have been exposed to THC?

Renard et al. 2016 abstract

Why was the research done? What is the hypothesis?

 There have been a number of studies published that suggest there might be an association between prolonged marijuana use (especially of high-potency strains) and schizophrenic-like or psychotic-like symptoms [5, 6] although there is disagreement in the scientific community on the evidence [7, 8] (I may write a blog post discussing this issue in the future). It is has even been suggested that youths that smoke marijuana are more at risk for psychotic symptoms as adults [9, 10]. The author’s sought to test this directly by injecting adolescent and adult rats with THC for a number of days, waiting a period of time after the injections, then measuring the long-term effects on the rats. The team hypothesized THC would have induced long-term changes in the brains of adolescent but not adults rats, and subsequent changes in psychotic-like behavior.

How was it done?

Adolescent and adult rats were injected with THC twice daily for 11 days. The dose of THC administered was increased (escalating dose) to account for any tolerance that may occur. As an important control, separate groups of adolescent and adult rats were injected with vehicle (the solution that THC was dissolved in but minus the THC itself). Following a 30-day abstinence period after the last injection, THC-adolescent, control-adolescent, THC-adult, and control-adult rat groups were subjected to number of behavioral and molecular tests to see what effect the drug had on the animals. I need to point out that the 30-day abstinence period is significant in the rat life-span. This is enough time for the adolescent rats to become adults so what the scientists are primarily studying is the long-term effects of THC on adolescents vs adults in adulthood.

In the behavioral neuroscience field, we have devised another of tests to measure various aspects of animal behavior. Obviously we can’t inject humans with THC and see what happens so we have to use rodents and identify behaviors that approximate a similar behavior in humans. Of course, rodent behavior is no where near as complex as humans but rats are remarkably sophisticated animals (ask anyone living in New York) and scientists have developed a number of ways to measure things from motivation to social behavior to anxiety to depression.

In this experiment, a social test was used, two different types of anxiety tests and a motor activity test. The tests measured effects on motivation, exploratory-behavior (another indicator of how motivated rats are), social interaction, and anxiety.

The scientists also measured the activity of dopamine-releasing neurons in the living animal using a technique called in vivo electrophysiology. Recall from my post I am Neuron! that when activated, brain cells (called neurons) conduct an electrical current that results in the release of neurotransmitters onto another neuron. This electrical current is called an action potential and we can measure this by inserting a special probe into the those neurons in the animals brain (the probe measures electrical currents). Therefore, with in vivo electrophysiology we can measure every time a neuron fires (i.e. an action potential is generated) in a specific part of the brain. Using this technique, the scientists measured dopamine neurons in an important region of the brain called the VTA and how often these neurons fire in THC vs control rats. Check out this video for more details on in vivo electrophysiology.

Finally, brains from animals were dissected and a number of protein molecules were studied using a common technique in molecular biology called a Western blot (or known as an immunoblot). A Western blot takes advantage of antibodies that are able to recognize and stick to one specific type of protein. Therefore, this assay can tell you two main things 1) if your protein of interest is present in your sample and 2) approximately how much of your protein there is compared to other samples. In this paper, tissue from a specific brain region is used and the protein is analyzed by Western blots in order to comparing quantities of proteins between the different experimental groups. Of course, the limitation of a Western blot is if you have a good antibody for your protein of interest. Luckily there are many biotech companies such as Cell Signaling that specialize in making and testing reliable antibodies. The scientists used the Western blots to study many proteins in a region of the brain called the prefrontal cortex (PFC), which is believed to be important in self-control and other high-function brain processes. Check out this video for more details on Western Blots.

What did they find?

THC-adolescent rats exhibited deficits in numerous behavioral experiments compared to controls while THC-adult rats did not appear to have any behavioral changes.

*Recall that these experiments were conducted 30 days after the last THC dose so the author’s show that these are long-term effects of THC on the brain of adolescent rats.

In the social activity test, rats showed little interest in interacting with a stranger rat (normal rats are usually curious about the novel stranger). THC-adolescents also did not walk around or explore a new cage as much. In the two different anxiety tests, THC-rats appeared to have be more anxious (demonstrated more anxiety-like behavior).

In the electrophysiology experiment, VTA DA neurons fired more frequently for some reason in THC-adolescents compared to the other groups.

Finally, numerous protein changes in the PFC were observed in a number of important signaling pathways such as Wnt and mTOR pathways. Interestingly, THC-adolescents vs THC-adults seemed to have opposite effects on this proteins.

Limitations to the study?

  1.  The behavioral changes observed were statistically significant (meaning, most likely a real effect and not some kind of fluke of random chance) but were modest changes in some of the tests performed. Would the changes last beyond the 30 days post injection in this study?
  2. There are impressive arrays of behavioral tests that rats can perform to measure numerous aspects of cognition (for example, memory and learning) but none of these experiments were performed. A far greater range of behavioral experiments would have made this study more compelling.
  3. While the electrophysiology and Western blot data are intriguing, the author’s performed no experiments to determine if these changes are responsible for the difference in behavior (association vs causation). These changes could merely be an incidental change and have nothing to do with the behaviors studies.
  4. The doses that the mice were injected with, while based on a previous study, are somewhat arbitrary. Would the changes be more pronounced or less pronounced with higher/lower doses or a shorter/longer dosing regimen?
  5. Only male rats were studied. Would the same behavioral and molecular changes occur in female rats?

What does it mean?

Based on the behavioral and molecular data presented, this data paper suggests that adolescent rats (but not adults) exposed to THC have long-lasting changes in the brain. The author’s argue that these effects recapitulate schizophrenia-like symptoms but I am not entirely convinced. Also, THC given to rats is not the same thing as marijuana smoked by human teenagers. So it’s important to keep in mind that this is one study. In science, we never draw grand conclusions about anything based on one study. Nevertheless, several other reports have corroborated these findings (see this review paper for a summary of many of them [11]). Indeed, it does seem that marijuana use can cause long-term deficiencies in human and rodent brains. The results of this paper are certainly intriguing and, if true, a whole host of stricter regulations on marijuana use in states that have legalized it may need to put in place to help curb increasing marijuana abuse amongst youths.

References

  1. Cascini F, et al. Increasing delta-9-tetrahydrocannabinol (Delta-9-THC) content in herbal cannabis over time: systematic review and meta-analysis. Current drug abuse reviews. 2012;5(1):32-40.
  1. Mehmedic Z, et al. Potency trends of Delta9-THC and other cannabinoids in confiscated cannabis preparations from 1993 to 2008. Journal of forensic sciences. 2010;55(5):1209-17.
  1. Keshavan MS, et al. Changes in the adolescent brain and the pathophysiology of psychotic disorders. The lancet Psychiatry. 2014;1(7):549-58.
  1. Spear LP. The adolescent brain and age-related behavioral manifestations. Neuroscience and biobehavioral reviews. 2000;24(4):417-63.
  1. Arseneault L, et al. Causal association between cannabis and psychosis: examination of the evidence. The British journal of psychiatry : the journal of mental science. 2004;184:110-7.
  1. Di Forti M, et al. Daily use, especially of high-potency cannabis, drives the earlier onset of psychosis in cannabis users. Schizophrenia bulletin. 2014;40(6):1509-17.
  1. Moore TH, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007;370(9584):319-28.
  1. Gage SH, et al. Association Between Cannabis and Psychosis: Epidemiologic Evidence. Biological psychiatry. 2015.
  1. Rubino T, Parolaro D. Long lasting consequences of cannabis exposure in adolescence. Molecular and cellular endocrinology. 2008;286(1-2 Suppl 1):S108-13.
  1. Stefanis NC, et al. Early adolescent cannabis exposure and positive and negative dimensions of psychosis. Addiction. 2004;99(10):1333-41.
  1. Renard J, et al. Long-term consequences of adolescent cannabinoid exposure in adult psychopathology. Frontiers in neuroscience. 2014;8:361.
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Presidential Candidates Support an End to Addiction Stigma

(© Alan Cleaver flickr https://www.flickr.com/photos/alancleaver/4104954991)
(© Alan Cleaver flickr https://www.flickr.com/photos/alancleaver/4104954991)

Something remarkable is occurring in the way politicians are speaking about addiction (I’ve written about this previously). The discussion has shifted to focus on addiction as a disease and addicts as human beings requiring treatment, opposed to addicts as criminals requiring punishment or incarceration. Importantly, this shift away from the “war on drugs” rhetoric reaches across the political spectrum.

During the Democratic presidential debate held in December, Bernie Sanders called addiction “a disease and not a criminal activity” while Hilary Clinton and Martin O’Malley expressed similar sentiments.

New Hampshire, a state that has been particularly hard hit by the opioid epidemic sweeping the nation, recently held an Addiction Policy Forum at Southern New Hampshire University. Several GOP candidates attended the forum, including Jeb Bush, Chris Christie, Carly Fiorina, and John Kasich. The candidates spoke personally about addiction, humanized addicts, and referred to addiction as a disease. Particularly moving was Carly Fiorina’s tragic story regarding her step-daughter’s struggle with addiction.

Despite these encouraging remarks, no candidate at the forum issued a call to increase accessibility to medication-assisted treatment of addiction.

NPR’s report on the forum offers an important analysis that I had not previously considered. One reason why the attitude in addiction is changing may be that the current opioid epidemic effects affects nearly every strata of society, including every race, whereas other drug epidemics in the past (such as the crack cocaine epidemic of the 80s and 90s) primarily affected only minority communities. NPR reports that some people refer to this as “the gentrification of the drug crisis.”

Even GOP candidate John Kasich of Ohio said, “This disease knows no bounds, knows no income, knows no neighborhood, it’s everywhere. And sometimes I wonder how African-Americans must have felt when drugs were awash in their community and nobody watched. Now it’s in our communities, and now all of a sudden we’ve got forums, and God bless us, but think about the struggles that other people had.”

A more political spin on the recent trend posted on the Hill blog discusses the rise of the “recovery voter”, an increasingly vocal group of people that place addiction as their number one issue. Clearly the presidential candidates are responding to the call for increasing governmental action on addiction.

I am cautiously optimistic about these positive trends but will reserve judgment until either Democratic or Republican candidates outline specific policy details.

Response to HuffPost Marc Lewis Interview on Addiction

So the Huffington Post runs a sub-blog on Addiction and Recovery and sometimes they present excellent reporting (for example, the piece on opioid addiction by Jason Cherkis who actually interviewed my boss, Dr. Mary Jeanne Kreek, for the article). But more often than not, they present quite variable reporting on addiction.  A recent interview with psychologist Marc Lewis, PhD is one such example.

Based on my own neuroscience of addiction background, I unfortunately find a number of Dr. Lewis’s claims not supported by scientific evidence and I believe the spread of such false statements can have the exact opposite of his intended effect—hurting more addicts rather than helping them. I do not claim to be the consensus voice of the addiction field but present my own arguments based on my own research and work done in the field. I also admit have not read any of Dr. Lewis’s books and am merely responding to the statements made in his interview. I include references at the end of the post.

The original interview between Carolyn Gregoire, Senior Health and Science Writer for Huffington Post and psychologist Marc Lewis, PhD

The questions (Q) by Carolyn Gregoire in the original interview are in bold, Dr. Lewis’s response (L) is italicized, and my response (S) is the un-italicized larger-size text.

Q: What’s wrong with the disease model of addiction? 

L: I know what scientists are looking at when they say addiction is a disease. I don’t dispute the findings, but I dispute the interpretation of them. They see addiction as a chronic brain disease — that’s how they define it in very explicit terms. 

My training is in emotional and personality development. I see addiction as a developmental process. So the brain changes that people talk about and have shown reliably in research can be seen as changes that are due to learning, to recurrent and deep learning experiences. But it’s not an abnormal experience and there’s nothing static or chronic about it, because people continue to change when they recover and come out of addiction. So the chronic label doesn’t make much sense.

S: The brain is a physical organ that operates under defined molecular biological principles. Drugs are physical chemical substances that perturb the molecular function of the brain. It is true that addiction is a process that can take months or even years to develop but the end result is a physical neurobiological change in how the brain functions [1, 2]. And when neuroscientists say chronic brain disease—or what my lab says A disease of the brain with behavioral manifestations—what we mean is that repeated drug use has caused a change is brain function which in turn results in a change in behavior. That doesn’t mean that this change is irreversible but, like other diseases, the first step to treatment is recognizing the underlying biological cause. Defining addiction as a chronic brain disease is not a judgment or interpretation of the development of addiction (which definitely does involve a learning and memory component [3, 4]) but is a statement asserting that drug addiction and drug cravings, compulsive drug use, and relapse are ultimately based on physical changes in the brain. It is important that we recognize this because otherwise we would not be able to treat it with effective and safe medications, in combination with other behavioral and psychological therapies.

Q: What’s problematic about the way we treat addiction, based on the disease model? 

L: Well, lots. The rehab industry is a terrible mess — you either wait on a long list for state-sponsored rehabs that are poorly run or almost entirely 12-Step, or else you pay vast amounts of money for residential rehabs that usually last for 30-90 days and people often go about five to six times. It’s very difficult to maintain your sobriety when you go home and you’re back in your lonely little apartment. 

What I emphasize is that the disease label makes it worse. You have experts saying, “You have a chronic brain disease and you need to get it treated. Why don’t you come here and spend $100,000 and we’ll help you treat it?” There’s a very strong motivation from the family, if not the individual, to go through this process, and then the treatments offered in these places are very seldom evidence-based, and the success rates are low. 

S: I strongly agree with this assessment. The rehab industry and many 12-step programs are ineffective, expensive, and rarely based on scientific evidence. The primary reason is that for decades addiction was thought of a problem of “spiritual weakness” or “lack of will power”. In reality addiction is a medical disorder based on physical neurobiological processes that make it seem like an addict has no “will power”, when in reality that addict’s brain has been hijacked to crave the drug compulsively and practically uncontrollably. However, again, I disagree that calling addiction a disease is what funnels people into rehab clinics. I believe it is the stigmatization of addiction that precludes treatment by doctors (unlike for every other disease), which in turn fuels admission into the rehab industry. Sadly, effective medications exist (such as methadone and buprenorphine for opioid addicts) that can flick a switch off in an addicts brain, satisfying their craving and allow them to live a normal live [5, 6]. Or medications such as naltrexone may be effective at reducing drinking in alcohol addicts but is not widely used [7, 8]. It is only recently that public acknowledgement of the biological basis of addiction and appropriate shifts in public policy are beginning to take place. Importantly, addiction medicine is beginning to become incorporated into medical school education and the first accredited residency programs in addiction medicine have been announced.

Q: There are lots of ways to trigger a humanistic response besides calling something a disease. So you would say that telling people who are in recovery for addiction that they have a “chronic disease” is actually doing them a disservice? 

L: Well, the chronic part is really a yoke that people carry around their necks. [Proponents of the disease model] say that this is important because this is how to prevent the stigmatization of addicts, which has been a standard part of our culture since Victorian times. 

But I think that’s just bullshit. I don’t think it feels good when someone tells you that you have a chronic disease that makes you do bad things. There are ways to reduce stigmatization by recognizing the humanity involved in addiction, the fact that it happens to many people and the fact that people really do try to get better — and most of them do. There are lots of ways to trigger a humanistic response besides calling something a disease.  

S: I agree that stigma is a huge problem with the treatment of drug addiction and mental health. Admitting you are an addict or depressed or know someone who suffers from these disorders is accompanied with unnecessary shame and fear of admission of the problem. I disagree that acknowledgement of medical/neurobiological basis of these disorders (ie calling them diseases) increases stigma but in fact do humanize patients. It helps alleviates shaming–both public and self–and can help an addict to seek evidence-based, medical treatment. Acknowledging the chronic nature of the disorder is not intended to make people feel bad but is merely truthfully stating the nature of the problem in hopes that it can be properly treated; denial can be lead to false and ineffective treatments.

Q: It can be difficult to comprehend the idea that something as severe as a heroin addiction is a developmental process. Can you explain that? 

L: First of all, let’s include the whole bouquet of addictions. So there’s substances — drugs and alcohol — and there’s gambling, sex, porn and some eating disorders. The main brain changes that we see in addiction are common to all of them, so they’re not specific to taking a drug like heroin, which creates a physical dependence. We see similar brain changes in a region called the striatum, which is an area that’s very central to addiction, which is involved in attraction and motivational drive. You see that with gambling as much as you do with cocaine or heroin. So that’s the first step of the argument — it’s not drugs, per se. 

From there, it’s important to recognize that certain drugs, like opiates, create physical dependency. There’s a double whammy there. They’re hard to get off because they’re addictive, like sex or porn is, but they also make you uncomfortable when you stop taking them. People try to go off of them and get extremely uncomfortable and then they’re drawn back to it — now for physical as well as psychological reasons. 

S: It is true that all addictions involve the striatum and there are similarities between the different addictions but to say that ALL addictions affect the brain in the exact same way is an absurd simplification. Different drugs absolutely DO affect the brain differently and have differences in addiction potential and relapse potential. To say addiction to heroin is identical to addiction to alcohol is identical to gambling addiction and therefore has nothing to do with the specific drug or behavior is just plain wrong. A wealth of evidence is gathering that addictions to different drugs progress differently and effect different brain systems, despite certain changes common to all [9]. For example, even opioids such as morphine and oxycodone, whose pharmacology are probably the best understood of any drug of abuse (they interact with mu opioid receptors [10]), have different behavioral and neurobiological effects that may affect addictions to the individual drugs (see my blog post). In a paper published by the lab I work for, the Kreek lab, cocaine administration in drug naïve mice (mice that have never had cocaine in their system) results in a rapid release of dopamine [11]. In contrast, some studies show that self-administration of an opioid drug only increases dopamine in rats that have already been exposed to the drug and not naïve animals [10]. The differences in the dopamine profiles between cocaine and opioids obviously means that how these two drugs affect the brain is different and is drug-specific! These are just a few small examples demonstrating the scientific inaccuracy of lumping all addictions into one general category or making the false claim that addiction has “nothing to do with the drug” (just as reducing cancer to a single disease is entirely inaccurate and harmful for its treatment).

Q: In the case of any type of addiction, what’s going on in the brain? 

L: The main region of interest is the striatum, and the nucleus accumbens, which is a part of the striatum. That region is responsible for goal pursuit, and it’s been around since before mammals. When we are attracted to goals, that region becomes activated by cues that tell you that the goal is available, in response to a stimulus. So you feel attraction, excitement and anticipation in response to this stimulus, and then you keep going after it. The more you go after that stimulus, the more you activate the system and the more you build and then refine synaptic pathways within the system. 

The other part of the brain here that’s very important is the prefrontal cortex, which is involved in conscious, deliberate control — reflection, judgment and decision-making. Usually there’s a balance between the prefrontal cortex and the striatum, so that you don’t get carried away by your impulses. With all kinds of addictions — drugs, behavior, people — the prefrontal system becomes less involved in the behavior because the behavior is repeated so many times. It becomes automatic, like riding a bike. 

S: Dr. Lewis’s assessment is basically correct. The core of the reward circuit involves dopamine-releasing neurons of the ventral tegmental area (VTA) projecting to the nucleus accumbens (NAc; a part of the ventral striatum), which primarily drives motivated behavior and is involved in reinforcement of drug taking behavior. Conversely, the prefrontal cortex acts as a “stop” against this system and one model of addiction is the motivated-drive to seek the drug overpowers the “stop” signal from the prefrontal cortex. However, addiction is far more complex beyond just this basic system. Numerous other circuits and systems (hippocampus, amygdala, hypothalamus, just to name a few) are also involved and each individual drug or rewarding stimuli can affect these circuits in disparate ways [12].

Q: What would a scientifically informed approach to addiction look like? 

L: That’s a really hard question because the fact that we know what’s happening in the brain doesn’t mean that we know what to do about it. 

A lot of recent voices have emphasized that addiction tends to be a social problem. Often addicts are isolated; they very often have difficult backgrounds in terms of childhood trauma, stress, abuse or neglect — so they’re struggling with some degree of depression or anxiety — and then they are socially isolated, they don’t know how to make friends and they don’t know how to feel good without their addiction. 

S: As I’ve stated above, a scientifically informed approach to addiction treatment already exists but is not widely used. However, one day an addict will hopefully be able to consult with a medical doctor to receive appropriate medications specific to their addiction, which will be combined with individual counseling by a psychiatrist or psychologist and a specific cognitive behavioral therapy or other psychological/behavioral therapy. The combination of medications and psychological therapy administered by trained medical professionals will be the future of evidence-based addiction medicine. Development of additional medications and/or psychological therapies for future treatment absolutely requires solid scientific evidence supporting their efficacy, which includes use of randomized control trials,  prior to widespread implementation.

But to call addiction primarily a social problem once again ignores all the basic neuroscience research that shows the powerful effects drugs have on the brain. It also ignores the prominent effect of genetics and how, due to a random role of the dice, an individual’s risk of becoming an addict can drastically increase [2, 13]. Plus the opioid epidemic that is currently sweeping the nation effects nearly every strata of society regardless of socioeconomic status, age, gender or race, and therefore cannot be explained simply by the hypothesis that addicts are people that are socially isolated. Why someone starts using drugs in the first place and how exactly they progress from a casual drug user to an addict are incredibly complex questions that scientists all over the world are attempting to answer through rigorous research. Being socially isolated or experiencing childhood trauma may certainly be factors that eschew some people towards the development of addiction but are definitely not the only ones.

Q: So what can we do about that?

L: Other than certain drugs that can reduce withdrawal symptoms, there’s nothing much medicine can offer, so we have to turn to psychology, and psychology actually offers a fair bit. There’s cognitive behavioral therapy, motivational interviewing, dialectic behavioral therapy, and now there are mindfulness-based approaches, which I think are really exciting. 

There’s been good research from Sarah Bowen in Seattle [on Mindfulness-Based Relapse Prevention] showing that mindfulness practices can have a significant impact on people, even on people who are deeply addicted to opiates. 

S: This is a completely false statement: medications for treatment of addictions exist [14]! Once again, comprehensive systematic reviews of methadone and buprenorphine, two medications used for treatment of opioid cravings, have indisputably shown that these medications are effective at keeping addicts off of heroin compared to no medication [5, 6]. Furthermore, a number of other drugs are currently being explored for treatments to alcohol and cocaine addiction [15, 16]. Some people may consider methadone or buprenorphine replacing “one drug with another” but this is naïve view of how powerfully addictive opioid drugs can be and how use of these FDA-approved medications in combination with individual psychological counseling, can lead to gradual dose reduction and amelioration of cravings. Medication-assisted addiction treatment is designed to help addicts fight their craving so that they can live a normal life. With time, dose can be reduced and cravings can become less intense.

The study Dr. Lewis cites regarding mindfulness is well designed and intriguing. However, the study did not compare mindfulness-based approaches to medication-based approaches and is therefore incomplete [17]. Nevertheless, it is an interesting approach that may be able to be combined with medication-based treatment but definitely requires more research before its efficacy can be confirmed.

References

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