Thursday, April 17, 2014

Can THC Protect the Brain against Methamphetamine's Toxicity?

A fascinating new study in the journal Neuropharmacology, suggests the brain's endocannabinoid system can be aided in its neuroprotective efforts against the toxicity of methamphetamine by introducing external cannabinoids to increase the system's "endogenous tone". The cannabinoids in question, THC, URB and JZL, appear to inhibit the breakdown of the brain's own endocannabinoids, improving the ability of the brain to protect itself against the "external insult" of overdoses of methamphetamine.

Here is the abstract, via ScienceDirect:


Methamphetamine toxicity is associated with cell death and loss of dopamine neuron terminals in the striatum similar to what is found in some neurodegenerative diseases. Conversely, the endocannabinoid system (ECS) has been suggested to be neuroprotective in the brain, and new pharmacological tools have been developed to increase their endogenous tone. In this study, we evaluated whether ECS stimulation could reduce the neurotoxicity of high doses of methamphetamine on the dopamine system. We found that methamphetamine alters the levels of the major endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in the striatum, suggesting that the ECS participates in the brain responses to methamphetamine. Δ9-tetrahydrocannabinol (THC), a cannabis-derived agonist of both CB1 and CB2cannabinoid receptors, or inhibitors of the main enzymes responsible for the degradation of AEA and 2-AG (URB597 and JZL184, respectively), blunted the decrease in striatal protein levels of tyrosine hydroxylase induced by methamphetamine. In addition, antagonists of CB2, but not of CB1, blocked the preventive effects of URB597 and JZL184, suggesting that only the former receptor subtype is engaged in neuroprotection exerted by ECS stimulation. Finally, we found that methamphetamine increases striatal levels of the cytokine tumor necrosis factor alpha, an effect that was blocked by ECS stimulation. Altogether, our results indicate that stimulation of ECS prior to the administration of an overdose of methamphetamine considerably reduces the neurotoxicity of the drug through CB2 receptor activation and highlight a protective function for the ECS against the toxicity induced by drugs and other external insults to the brain.
And here is a table showing levels of two of the major endocannabinoids, AEA and 2-AG,  following doses of methamphetamine:

And finally striatal levels of the cytokine tumor necrosis factor alpha:


Friday, April 4, 2014

Baclofen Shows Promise for Treating Relapse in Cocaine Use Disorders

Via ScienceDaily:

Relapse is the most painful and expensive feature of drug addiction -- even after addicted individuals have been drug-free for months or years, the likelihood of sliding back into the habit remains high. The National Institute on Drug Abuse estimates that 40 to 60 percent of addicted individuals will relapse, and in some studies the rates are as high as 80 percent at six months after treatment. Though some relapse triggers can be consciously avoided, such as people, places and things related to drug use, other subconscious triggers related to the brain's reward system may be impossible to avoid -- they can gain entry to the unconscious brain, setting the stage for relapse.
Researchers at Penn Medicine's Center for Studies of Addiction have now found that the drug baclofen, commonly used to prevent spasms in patients with spinal cord injuries and neurological disorders, can help block the impact of the brain's response to "unconscious" drug triggers well before conscious craving occurs. They suggest that this mechanism has the potential to prevent cocaine relapse. The new findings are reported in the Journal of Neuroscience.
"The study was inspired by patients who had experienced moments of 'volcanic craving', being suddenly overcome by the extreme desire for cocaine, but without a trigger that they could put their finger on," says senior author Anna Rose Childress, PhD,research professor of Psychiatry, director of the Brain-Behavioral Vulnerabilities Division in the Perelman School of Medicine at the University of Pennsylvania. Dr. Childress and colleagues previously found that subliminal drug "reminder cues" (the sights, sounds, smells, and memories of the drug) could activate the brain's reward circuit. "Now, we wanted to understand whether a medication could inhibit these early brain responses," said Childress.
Kimberly Young, PhD, an NIH/NIDA Post-doctoral Fellow at Penn, and first author of the study explained that, "Drug reward and motivation is largely mediated by dopamine transmission in the brain's reward circuit -- even drug "reminder cues" can cause dopamine release. Since baclofen and similar medications reduce these effects in laboratory animals, we wanted to examine whether it could prevent drug-cue induced activation in the human brain."
The study tested baclofen, which was approved by the U.S. Food and Drug Administration in 1977 for spasm, on 23 cocaine-dependent men, ages 18 to 55. Each reported using cocaine on at least eight of 30 days before screening. Inclusion in the study required that they stay for up to 10 days in a supervised inpatient drug treatment facility, be drug-free for the duration, not be on any medication affecting dopamine or neurotransmitter response, and have no history of psychosis, seizures, or brain syndromes unrelated to cocaine use.
Upon admission, patients were randomized to receive baclofen or placebo. Over the first six days, patients in the baclofen group received the medication in increasing dosage to 60 mg. While on the full 60 mg dose of baclofen, patients were placed in an fMRI and shown a series of images, to measure their neural responses to "ultra-brief" pictures of cocaine or other comparison pictures. Each of the ultra-brief 33 msec "target" pictures was immediately followed by longer picture of non-drug objects or scenes. Under these conditions, the participants are aware of the longer pictures, but the ultra-brief target pictures remain completely outside conscious awareness -- they are "backward-masked."
"We wanted to present the key stimulus: images of drug use and preparation, sexual images, and other aversive images in a way such that the brain could not consciously process them, but so that we could measure their earliest, subconscious effect on the brain," said Childress.
What the team found was that the patients who were treated with baclofen showed a significantly lower response in the reward and motivational circuits to subliminal cocaine cues versus neutral cues, as compared to the placebo-treated control group. In addition, no difference was seen in the active versus the control group in their response to sexual and aversive cues, indicating that the effects of baclofen on cue-induced brain activation were specific to drug cues.
"These findings suggest that the brain response to drug cues presented outside of awareness can be pharmacologically inhibited, providing a mechanism for baclofen's potential therapeutic benefit in addiction," says Young. "Further studies will show whether the prevention of these early brain responses is associated with reduced rates of craving and relapse in cocaine-dependent patients," added Childress. 

This could be exciting news for one of the most difficult substance use disorders to treat. Does anyone have experience using baclofen with patients with cocaine use disorders?

Monday, March 31, 2014

Study: Are Drug Screens Sufficient for Adolescent Treatment?

Could it be that we are missing something when it comes to treating adolescents with a substance use disorder? According to a study in the most recent edition of the Journal of Studies on Alcohol Drugs, if you aren't using drug screens when treating this population, the answer is likely "Yes".
In the article, Schuler, et al. looked at data from SAMHSA's CSAT 2007 adolescent treatment database, which tracks outcomes for CSAT-sponsored providers. The total sample consisted of 5,186 adolescents who received either Motivational Enhancement Therapy/Cognitive Behavioral Therapy5 (MET/CBT5) - with or without biological drug screen (BDS) - or were part of the BDS-only or No-Treatment groups within another study. Below is a breakdown of the subjects:

All participants responded to the GAIN structured clinical interview, so scores on the Substance Use Frequency Scale and Substance Problem Scale were the primary outcomes measured. Propensity score methods were used to adjust for baseline differences among youth in the four groups, given the non-randomized nature of the data. The results are striking:

The BDS-only condition seemed to outperform all groups at baseline, 3-, 6- and 12-months on Substance Problem Scale scores and at 6- and 12-months on Substance Frequency Scale scores.
What could account for the significant differences? The authors point out that many adolescents who are involved in treatment and/or the criminal justice system may earn rewards for negative drug screens - or face significant consequences for positive screens. Therefore, the self-report nature of the data could skew the results. That would not necessarily explain the consistent differences across groups, however.

What do you think about these results? If you work with adolescents, does this surprise you? Could evidence like this impact the interventions you use?

Friday, March 21, 2014

What Aren't More Docs Prescribing Buprenorphine?

On the heels of recent coverage over the "dangers" of the medication buprenorphine, researchers are seeking to better understand what keeps doctors from using one of the two the most effective tools for opioid use disorders at their disposal. The most recent study, "Barriers to Primary Care Physicians Prescribing Buprenorphine", was published in the Annals of Family Medicine and is available in-full online - for free. The study came out of the Rural Opioid Addiction Management in Washington state, during which 120 physicians were trained in opioid addiction and buprenorphine prescribing. Disappointingly, of the 78 respondents who were analyzed for the study, 50 went on to obtain a DATA waiver, yet a mere 22 doctors ever went on to prescribe the medication to anyone. It begs the question: why aren't more docs prescribing buprenorphine?

Here's the breakdown from the piece of perceived barriers to prescribing:

Among the barriers cited by the doctors in the study, "Lack of psychosocial support" was cited as the number one barrier by both prescribers and non-prescribers, despite the lack of evidence that behavioral adjuncts or additional counseling improve outcomes. (Granted, the authors point out that in order to get reimbursed by a number of payers, additional counseling must be offered to patients.)

A quick scan across the literature leads us to another important and common driver of physician attitudes toward this medication: institutional support. It appears that study after study cite the impact of the hospital/clinic/practice culture on the subsequent interest. training and prescription of buprenorphine by its docs. In the present study, "resistance from practice partners" and "lack of institutional support" were commonly cited as barriers. A recent article from the March issue of the Journal of Substance Abuse Treatment described how important "A strong leader championing the new treatment" was to the implementation of buprenorphine prescribing across a large system. 

What do you think? How can we be more effective at impacting change at the prescriber level? If culture plays an important role, how do we improve the culture around this proven tool?

Monday, March 17, 2014

Is Addiction Always Permanent?

Recently, a colleague challenged what he perceived to be my "insistence that addiction is permanent." Here is my reply:

Dear John (not his real name):

As you know, I'm well aware of the studies regarding the life course of people who at some point in their lives meet dxic criteria for a SUD. And also, as you are aware, I've been talking about that, and therefore the need to have a wider continuum of care and to individualize approaches to SUDs for at least 10 years. In my presentation, Alcoholism Isn't What It Used to Be, which you frequently reference, I point out that 20 years after onset of DSM IV Alcohol Dependence, the most common outcome is low-risk drinking (40%), followed by abstinence (roughly 1/3), partial remission (about 20%) and then finally currently dependent (8%). So I'm not sure what the basis is for concluding that I have made blanket statements about ALL addicts in ALL circumstances.
What I do believe, and here I think the science and epidemiology are equally persuasive, is that in the case of severe addiction, there are brain neuroadaptations that are irreversible. For example, the likelihood of achieving non-abstinent recovery is inversely related to the severity of alcohol dependence. Conversely, abstinent outcomes become more likely as severity increases. This is as true in rodents as in humans. Since rehab and AA are populated almost exclusively by people at the very severe end of the spectrum, the likelihood of sustained non-abstinent recovery for current treatment seekers or AA members is relatively low. Thus, the AA stance is accurate for most AA members. Severity of dependence is the strongest predictor of AA affiliation, especially long-term affiliation, as opposed to a few weeks or months after a spell in rehab. Established heroin or other opioid addiction is another example; thus buprenorphine and methadone maintenance and the virtually complete failure of abstinence (or moderation) for treatment seekers. Those who could stop on the their own do so and therefore do not present for tx. That, of course, is a function of the awfulness, expense, stigmatization and disruption most current treatment includes.
At Alltyr Clinic, for example, I have seen many pts who come with a mild AUD who achieve non-abstinent recovery.
Just as abstinence is not a requirement for everyone who develops a SUD, neither is moderation possible for a sizeable proportion of them. The size varies by drug: Probably close to 100% of dependent smokers will require lifelong abstinence, whereas, most cannabis users will not, etc. Heroin, meth and cocaine addiction also probably have high to relatively high proportions where abstinence (which includes people taking opioid agonist therapy) is the only positive outcome option. In alcohol, I think it's probably somewhere in the middle, a large minority achieve non-abstinent recovery.
So the newer data simply seem to affirm the NESARC data, that conclusions have been based on clinical samples, and that if you look at community samples, the picture is very different. That's true for almost all common complex diseases, such as asthma or arthritis or even hypertension, the difference being that with SUDs there is a very high full remission rate, something that happens in very few other common complex diseases. Depression is very likely to be a pretty good analogue as well.
Finally, noting that many people have milder, self-limiting forms of SUDs doesn't mean they aren't brain disesases. How can you have a behavioral illness that doesn't include failures in brain regulation of behavior? It's just that in too many instances, people misinterpret "brain disease" to mean "permanent". Also, it hasn't helped that NIDA and SAMHSA keep stressing the chronicity of addiction, something I constantly fought against when i was at NIH. It's often not chronic. Neither is asthma, but I suspect you wouldn't have trouble thinking of mild, self-limited childhood asthma as a lung disease, or immune disease.

Thursday, March 13, 2014

Americans Spending $100 Billion on Illegal Drugs Annually

The U.S. White House Office of National Drug Control Policy (ONDCP) commissioned the RAND Corporation to investigate how much Americans were spending on the four most common illegal drugs from 2000-2010. The study, published recently on the website, uses a variety of sources to develop an estimate in yearly spending by consumers of cannabis, heroin, cocaine (including crack), and methamphetamine. Their conclusion: over $100 billion is spent on just these four drugs, every year. Interestingly, this number has stayed relatively constant throughout the past decade, despite the $25.2 billion that was spent "to reduce drug use and its consequences" in the US in fiscal year 2014 alone (!).

Since 2002, spending on cocaine and marijuana has flipped. Researchers note that cocaine consumption has dropped by about half, while marijuana consumption has increased by around 40%. Heroin consumption has remained stable throughout the decade, with a small increase detected in the later years. Methamphetamine consumption, the authors note, has been harder to track, as "national datasets do not do a good job of capturing its use." Across the board, heavy users are the main drivers of spending and consumption, and are defined as folks who use at least 21 days/month.

The authors culled data from a variety of sources, including the National Survey on Drug Use and Health, the Arrestee Drug Abuse Monitoring Program, various law enforcement and seizure databases, and more. Despite the apparent rigor involved in the creation of these estimates, the authors caution about the inherent uncertainty in this type of data analysis - especially considering that the bulk of the data came from self-report surveys.

Nevertheless, the fact remains that despite the increasing public investments in the so-called War on Drugs, demand-side consumption and expenditures are constant or rising throughout the country. Could this be one reason the Attorney General has agreed to endorse changes to Federal drug sentencing? What do readers think about the current state of availability and expense?

You can read the full report here:

Thursday, March 6, 2014

"First Controlled Study of LSD-Assisted Psychotherapy in More Than 40 Years"

Researchers from Switzerland and the Multidisciplinary Association for Psychedelic Studies have conducted what they are calling the first study of its kind in over 40 years: a randomized, double-blind, active placebo-controlled study of LSD-assisted psychotherapy. The participants, 12 patients with anxiety related to life-threatening illnesses like metastatic cancer, non-Hodgkin's lymphoma, Parkinson's disease, etc., participated in drug-free therapy sessions as well as 2 LSD-assisted psychotherapy sessions over the course of the study. Follow-up interviews were conducted at 2- and 12-months post-treatment and indicated lasting, statistically-significant improvements in anxiety. The study is posted in its entirety for free online via The Journal of Nervous and Mental Disease.

The main outcome measures were scores on the State-Trait Anxiety Inventory (STAI). Exclusion criteria included current drug or alcohol disorders, primary psychotic, dissociative or bipolar 1 disorders, neurocognitive impairment or pregnancy/nursing. Participants in the experimental arm participated in 2 full-day LSD-assisted psychotherapy sessions, 2 to 3 weeks apart, that were "embedded within an ongoing process of [six]drug-free psychotherapy sessions for preparatory and integrative purposes." Subjects received doses of 200 micrograms of pure LSD and the day-long sessions lasted 8 hours, or until the effects of the medication wore off. Participants in the active placebo group received the exact same set of psychotherapy sessions, but were given 20-microgram doses of LSD. After the 2-month follow-up interview, these participants were informed of their place in the control group and were offered the full, open-label intervention.

The results indicate statistically significant STAI scores for both state and trait anxiety at 2 and 12 months for the experimental groups. The active placebo did not produce statistically-significant improvements. The researchers calculate the effect size at 1.1 for trait anxiety, and 1.2 for state anxiety. They also, as you would imagine, call for more research with larger controlled studies. Importantly, neither the experimental drug nor the placebo produced any serious adverse effects, leading the authors to seem confident in the safety of this type of therapy.

Considering the research on LSD ground to a halt by the 1970s, do readers think it's time to revisit this(or other psychedelics, for that matter) as a therapeutic tool? If you have experience with this, it would be fascinating to hear your take, too.

Interested to hear readers opinions on the matter...