Wednesday, September 17, 2014

The Myth of "Cross-Addiction" Debunked

For decades, the conventional wisdom and clinical lore in rehab facilities and recovery communities has warned against the risks of so-called "cross-addiction". "Be careful," they say, "you're at-risk of picking up a new addiction now that you've kicked one habit." Heroin addicts are warned against developing an addiction to alcohol, and cocaine addicts are warned against developing an addiction to opiates, Cross-addiction can even occur to things like exercise or sugar, according to pamphlets and even therapists who have worked in the field for years and years.

But is it even true? Is the notion of cross-addiction supported by empirical evidence - or does it fall on its face under scientific scrutiny?

According to a new report, published September 10 in JAMA Psychiatry, the answer is a resounding, "No."

The study, "Testing the Drug Substitution Switching-Addictions Hypothesis," analyzed data from the National Epidemiological Study on Alcohol and Related Conditions (NESARC) to investigate whether participants developed new-onset substance use disorders (SUD) after remission from a previous SUD. These data were then compared against people with a SUD who did not achieve remission but also developed a new-onset SUD.

The authors discovered that, "As compared with those who do not remit from an SUD, remitters have less than half the risk of developing a new SUD. Contrary to clinical lore, achieving remission does not typically lead to drug substitution but rather is associated with a lower risk of new SUD onsets."

This is probably the best evidence to-date that addresses the concept of cross-addiction. Will counselors and agencies begin to pull back from this concept - or will clients still be subjected to homework assignments and lectures warning against it?

Here's the abstract from JAMA Psychiatry (found here: http://archpsyc.jamanetwork.com/article.aspx?articleid=1901525):

Importance  Adults who remit from a substance use disorder (SUD) are often thought to be at increased risk for developing another SUD. A greater understanding of the prevalence and risk factors for drug substitution would inform clinical monitoring and management.
Objective  To determine whether remission from an SUD increases the risk of onset of a new SUD after a 3-year follow-up compared with lack of remission from an SUD and whether sociodemographic characteristics and psychiatric disorders, including personality disorders, independently predict a new-onset SUD.
Design, Setting, and Participants  A prospective cohort study where data were drawn from a nationally representative sample of 34 653 adults from the National Epidemiologic Survey on Alcohol and Related Conditions. Participants were interviewed twice, 3 years apart (wave 1, 2001–2002; wave 2, 2004–2005).
Main Outcomes and Measures  We compared new-onset SUDs among individuals with at least 1 current SUD at wave 1 who did not remit from any SUDs at wave 2 (n = 3275) and among individuals with at least 1 current SUD at wave 1 who remitted at wave 2 (n = 2741).
Results  Approximately one-fifth (n = 2741) of the total sample had developed a new-onset SUD at the wave 2 assessment. Individuals who remitted from 1 SUD during this period were significantly less likely than those who did not remit to develop a new SUD (13.1% vs 27.2%, P < .001). Results were robust to sample specification. An exception was that remission from a drug use disorder increased the odds of a new SUD (odds ratio [OR] = 1.46; 95% CI, 1.11-1.92). However, after adjusting for the number of SUDs at baseline, remission from drug use disorders decreased the odds of a new-onset SUD (OR = 0.66; 95% CI, 0.46-0.95) whereas the number of baseline SUDs increased those odds (OR=1.68; 95% CI, 1.43-1.98). Being male, younger in age, never married, having an earlier age at substance use onset, and psychiatric comorbidity significantly increased the odds of a new-onset SUD during the follow-up period.
Conclusions and Relevance  As compared with those who do not remit from an SUD, remitters have less than half the risk of developing a new SUD. Contrary to clinical lore, achieving remission does not typically lead to drug substitution but rather is associated with a lower risk of new SUD onsets.

Friday, June 13, 2014

Informed Consent in Addiction Treatment: An Ethical Obligation

Informed Consent in Opioid Addiction Treatment: An Ethical Obligation


This article was originally published in The Carlat Addiction Treatment Report, Volume 2, #3, May 2014
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Source: 
 CATR, May 2014, Vol 2, Issue 3, Opioid Addiction
Informed consent—whether it be for psychotherapy, prescribing a medication, or performing a surgical procedure—is an ethical principle firmly established in law and medicine.
While there has been no formal research on this subject, my experience suggests that many addiction treatment programs fail to obtain valid informed consent. The starkest example occurs in the treatment of opioid addiction, where the practices and beliefs of clinicians often differ markedly from the evidence regarding effective treatments.
What is Informed Consent?
Informed consent refers to the collaborative process that a provider and patient go through to develop a treatment plan for the patient’s problems. This moral requirement is based on the principle of respecting a person’s autonomy, that is, their right “to hold views, to make choices, and to take actions based on their values and beliefs” (Beauchamp TL & Childress JF.Principles of Bio-medical Ethics, 7th ed. New York: Oxford University Press, 2013:122–123).
Valid consent fulfills three criteria (Grimm DA, N M Law Rev 2007;37(1):39–83). First, the patient needs to have decision-making capacity. Capacity, in a medical context, refers to patients’ ability to understand information, appreciate their situation, use reason to make a decision, and communicate their choices (Applebaum PS, N Engl J Med 2007;357(18):1834–1840). This is referred to as the “capacity” criterion.
Second, the provider needs to present the full range of available treatment options based on current scientific knowledge. During this discussion, he or she needs to outline the risks and benefits of these various options and what could be reasonably expected if the patient declines treatment altogether. This is called the “disclosure” criterion.
Finally, valid consent requires that patients are free from coercion—that is, they are in a position to voluntarily choose any treatment option that they feel is best for them. This is described as the “voluntariness” criterion.
A provider has failed to obtain valid informed consent if any of these elements are missing.
Legal Standards
Legal requirements for consent have evolved over centuries. Until relatively recently, courts used a physician-oriented point of view: the physician was required to provide information he or she felt was in the patient’s best interests. This resulted in practices such as informing a spouse, but not the patient, of a terminal disease. In other cases, providers deliberately omitted certain treatment options from their discussions with patients because of their personal beliefs or biases against them.
Through a series of court decisions, a new standard, the “reasonable person” or “prudent person” standard, emerged. Providers are now expected to present patients with information that a reasonable or prudent person would want to know in order to make healthcare decisions (Berg JW et al.Informed Consent: Legal Theory and Clinical Practice, 2d ed. New York: Oxford University Press, 2001:48).
In clinical practice, a provider is not allowed to withhold information from a patient based on his or her judgment that one treatment is better than another. The provider is thus required to present the scientific evidence supporting available treatment options, the expected outcomes of these various treatments, and the clinician’s recommendation for the patient and the rationale for it. This recommendation also needs to take into account any patient-specific features that factored into the provider’s decision-making.
This means that clinicians are legally obligated to provide information that they may prefer to withhold. The purpose of informed consent, however, is not to “conveniently promote a treatment plan; it requires informing patients with the recognition that they may disagree with a recommended treatment plan and retain the authority to do so” (Berg et al, op.cit).
There is also an important distinction between the actual process of obtaining autonomous authorization for a treatment or procedure and institutional requirements that patients sign informed consent documents. Patients frequently sign such documents in the absence of true informed consent (Beauchamp & Childress, op.cit).
Evidence-Based Treatment
Providers are obligated to summarize the scientific data concerning the effectiveness of various treatment options. The only treatment with consistent, strong evidence of effectiveness for opioid addiction is indefinite opioid maintenance therapy with either buprenorphine or methadone (Mattick RP et al, Cochrane Database Syst Rev 2014;2:CD002207).
Currently, the World Health Organization, US Centers for Disease Control and Prevention, US Department of Health and Human Services, and many other agencies and organizations recommend methadone and buprenorphine maintenance as first-line treatments.
In contrast, there is no evidence commending drug-free (or so-called abstinence-based) treatments (Mayet S et al, Cochrane Database Syst Rev2005;1:CD004330). Moreover, there is good evidence that psychosocial or intensive behavioral approaches fail to improve outcomes compared to minimal drug counseling in patients receiving opioid maintenance therapy (Amato L et al, Cochrane Database Syst Rev 2011;10:CD004147; Fiellin DA et al, Am J Med 2013;126(1):74.e11–17).
Naltrexone is the only other medication that has been approved by the FDA for opioid addiction. Oral naltrexone (ReVia) is ineffective (Minozzi S et al,Cochrane Database Syst Rev 2011;4: CD001333) and the efficacy of extended-release, injectable naltrexone (Vivitrol) was established in just a single, industry-sponsored study conducted in Russia, where buprenorphine and methadone are not legally available (Krupitsky E et al, Lancet2011;377(9776):1506–1513).
Presently, evidence for Vivitrol’s effectiveness is limited and generalization of clinical trial data to other countries is questionable. (For more, see“Vivitrol: Another Option for Opioid Addiction?”)
Meeting the Capacity Criterion
In addiction treatment, patients who are experiencing severe withdrawal symptoms may not have capacity due to pain and emotional distress. Other confounders include co-occurring mental disorders and cognitive impairment associated with prescribed medications and substances of abuse. Although beyond the scope of this article, simple bedside instruments allow providers to evaluate and easily document a patient’s decision-making capacity (Tunzi M, Am Fam Physician 2001;64(2):299–306).
Meeting the Disclosure Criterion
Providers need to have a clear understanding of available treatment options and the scientific evidence supporting each one, so they can meet their obligation concerning disclosure.
This article’s brief summary may serve as a starting point. Standard textbooks are also a ready source of such information (eg, Strain EC & Stitzer ML eds. The Treatment of Opioid Dependence. Baltimore, MD: Johns Hopkins University Press, 2006). In addition, a number of plain language resources geared toward patients are available (eg,http://1.usa.gov/1ibCKou).
Providers need to present patients with more than their program’s philosophy or even the community standard of care. Remember, the standard for disclosure is what a reasonable or prudent patient would want to know, not a narrow presentation concerning usual care or the provider’s personal preferences. In the case of opioid addiction, this means summarizing the scientific data on the effectiveness of treatment options. This is a fiduciary duty that trumps the clinician’s personal preferences and their program’s philosophy of care.
Meeting the Voluntariness Criterion
Providers need to be very sensitive to overt, and more subtle covert, coercion when discussing treatment options with patients. Many people presenting for substance use treatment are subject to significant coercion from the legal system, employers, and families. Thus, we need to ensure that consent is truly voluntary and that we are not using coercion to impose our own views concerning treatment upon patients.
This ethical obligation may require advocating for a treatment option different than what a judge, probation officer, employer, or family prefers or recommends.
CATR’s Take: Addiction treatment has historically been very prescriptive and patients often had little choice about the care that they received. This article is a good reminder that providers have an affirmative duty to obtain informed consent and engage patients in shared decision-making.

Sunday, June 8, 2014

Alltyr Clinic Featured on NPR's Weekend Edition!

Alltyr Clinic is featured on NPR's Weekend Edition Sunday today, June 8, 2014. We are positioned as an alternative to traditional rehab, in this case Hazelden. One of our patients, Shane Linehan, was brave enough to share his experience with both Hazelden (where he went first) and Alltyr Clinic (where he is being treated now.) I want to thank him and applaud his courage for speaking out. (For the record, Alltyr Clinic gave him no incentive; we simply offered the opportunity to many of our patients.) We are honored to be compared to arguably the best known traditional rehab in the country (if not the world.)

Unfortunately, in the summary on the program's landing page, our approach is described as being almost totally oriented around prescribing anti-relapse medications. Although we use every proven anti-relapse medication, we also use every evidence-based behavioral/psychosocial approach. This includes individual and group therapy using motivational, cognitive-behavioral, coping skills, 12-Step Facilitation, EMDR, CRAFT, DBT, psychodynamic, community reinforcement, couples and family approaches. Which we use depends on the needs of the patient. Our team includes addiction psychiatrists, addiction medicine specialists, psychologists, social workers, counselors and recovery coaches.

Furthermore, we fully integrate treatment for any co-existing mental health disorder, such as anxiety, depression, PTSD, personality disorders, bipolar disorder, cognitive disorders, as well as medical problems such as insomnia and chronic pain. We really aim to be a "one-stop shop." If sober housing is needed we work with community partners to help our patients secure it. 
The bottom line is this: coming to Alltyr Clinic is like coming to a mental health clinic or any other health care service using a multi-disciplinary approach. Each patient receives a comprehensive individual evaluation upon which the treatment recommendations are based. Selecting from a large menu of services, a truly individualized treatment plan is arrived at by the patient, the treatment team, and if appropriate, the family. After treatment is started, the plan is modified as needed. The length and intensity of treatment is also completely individual and flexible. We do whatever we can and we stay with you as long as it takes. We aren't a program, we're a clinic.

At Alltyr Clinic, "We Don't Just Call Addiction a Disease, We Treat It Like One."TM

Tuesday, June 3, 2014

A Sad State of Affairs: Psychostimulant Addiction Treatment Leaves Much to be Desired

The authors of a new paper, published ahead of a special issue of Neuropharmacology, give the reader a good look at the current state of psychostimulant substance use disorder treatment - and the results are disappointing. Starting with behavioral treatments and ending with a review of medications, the clear fact remains that there is no single treatment that outperforms most others.

Meta-analyses of behavioral interventions for the treatment of cocaine use disorder have shown modest benefits; while one review found, "there is currently no evidence for a differential treatment effect of any psychosocial treatment in the management of" cocaine or amphetamine use disorders. CBT and Contingency Management (CM) remain the mainstay of psychostimulant treatment, and the authors cite data suggesting a combination of CM plus Community Reinforcement Approach might produce the best outcomes.

In terms of pharmacological treatments, researched medications include antagonist therapy, agonist therapy, medications to treat withdrawal symptoms and medications to treat co-occurring psychiatric symptoms or disorders; and the authors of the present paper devote the bulk of their attention to weighing the evidence of such options.

Naltrexone, they note, has shown some promise in laboratory studies, as it has been shown to weaken amphetamine- and cocaine-related effects in some subjects in both human and animal trials. Because it also seems to weaken the subjective euphoric effects of methylphenidate (Ritalin), one area of promise could be in the combination of naltrexone and methylphenidate to limit the abuse potential of an agonist-like treatment.

Disulfiram (aka Antabuse) has also shown some promise in the lab, but mainly in the treatment of cocaine-use disorders. It was shown to increase the brain ratio of dopamine to norepinephrine and to prevent stress-induced cocaine reinstatement. In pilot studies, disulfiram was shown to be effective in reducing cocaine use in patients with cocaine use disorders (CUD), and among buprenorphine-maintained polydrug users. However, in a more recent study, disulfiram showed less promise reducing cocaine use among methadone-maintained patients. The authors of the review point to evidence that disulfiram may only be effective among CUD patients with specific genotypes - and may be more effective among men than women.

Agonist-like treatments are also reviewed by the authors, and appear to offer some of the more exciting, and possibly effective, interventions for psychostimulant addiction. D-amphetamine has been shown to improve treatment retention and reduce illicit cocaine use in early trials; while a later study showed a reduction in withdrawal and craving, but a failure to reduce methamphetamine use. Not mentioned in the review, but a small study we wrote about in 2012 appeared to show promising results in the combination of mixed amphetamine salts (Adderall) and topiramate (Topamax)

For its part, sustained-release methamphetamine has been tested as a maintenance agent for CUD, and appeared to significantly reduce cocaine-positive urine samples and cocaine craving. The familiar medication, methylphenidate, has been shown to be non-superior to placebo in some studies for meth/amphetamine use and cocaine use, but appears to warrant further research at improved dosages. The other agonist-like medication discussed, modafanil, seems to be an interesting candidate for maintenance treatment. Known to be a cognitive enhancer, modafanil may be useful in addressing the impairments in a range of cognitive functions that can result from psychostimulant addiction; but studies have thus far produced more "equivocal" results in most trials as treatments for cocaine or for methamphetamine - even when combined with D-amphetamine. Post-hoc analysis of the available data does, however, suggest efficacy in the less severe cases of addiction.

Additionally, researchers in Latin America have argued in favor oral coca for the treatment of cocaine use disorder. Their "Handbook on Oral Cocaine as Agonist Therapy for Cocaine Dependence" is an intriguing read, and the authors of the review posit that political, cultural and commercial barriers - not scientific ones - are likely to blame for the "lack of follow-up on this line of research".

A host of other medications have been tried and tested for psychostimulant use disorders, with little success. Vaccines, on the other hand, are now gaining momentum in the field and are being used in multiple studies at various phases. A vaccine that that produces antibodies to prevent cocaine from crossing the blood-brain barrier has performed well in Phase I and Phase II trials. A methamphetamine vaccine is still in preclinical development, but initial results have shown good levels of antibodies in animal models and a Phase I  trial is scheduled to begin in 2015.

Considering the vast global toll which is the result of psychostimulant addiction, treatment for these disorders is as desperately needed as ever. If there is one thing that this review makes clear, it's the fact that we still have a long way to go before we can say that we have effective treatment options for the consumer. A question for readers of this blog: what are the techniques and interventions that you have found to be helpful stimulant use disorders? Is there a particular line of research that you feel would be important to investigate further? Do you see the utility of agonist-like medications? Your thoughts are always appreciated.

Tuesday, May 13, 2014

Many Patients with Alcohol Use Disorders Not Offered Medications

An exhaustive and brand new meta-analysis and systematic review, published today in the Journal of the American Medical Association, paints a disappointing picture of medication access for those with alcohol use disorders (AUD) in the US. The authors included 123 studies, involving nearly 23,000 participants, and determined that while acamprosate and naltrexone have been shown to be effective treatments, fewer than 10% of those who might benefit are ever prescribed an AUD medication.

Here's the Abstract, via JAMA:

IMPORTANCE Alcohol use disorders cause substantial morbidity and early mortality yet
remain greatly undertreated. Medications are considerably underused.

OBJECTIVE To conduct a systematic review and meta-analysis of the benefits and harms of
medications (US FDA-approved and others) for adults with alcohol use disorders.

DATA SOURCES PubMed, Cochrane Library, PsycINFO, CINAHL, EMBASE, FDA website, and
clinical trials registries (January 1, 1970, to March 1, 2014).

STUDY SELECTION Two reviewers selected randomized clinical trials (RCTs) with at least 12
weeks’ duration that reported eligible outcomes and head-to-head prospective cohort
studies reporting health outcomes or harms.

DATA EXTRACTION AND SYNTHESIS We conducted meta-analyses using random-effects
models and calculated numbers needed to treat for benefit (NNTs) or harm (NNHs).

MAIN OUTCOMES AND MEASURES Alcohol consumption, motor vehicle crashes, injuries,
quality of life, function, mortality, and harms.

RESULTS We included 122 RCTs and 1 cohort study (total 22 803 participants). Most assessed
acamprosate (27 studies, n = 7519), naltrexone (53 studies, n = 9140), or both. The NNT to
prevent return to any drinking for acamprosate was 12 (95% CI, 8 to 26; risk difference [RD],
−0.09; 95% CI, −0.14 to −0.04) and was 20 (95% CI, 11 to 500; RD, −0.05; 95% CI, −0.10 to
−0.002) for oral naltrexone (50 mg/d). The NNT to prevent return to heavy drinking was 12
(95% CI, 8 to 26; RD −0.09; 95% CI, −0.13 to −0.04) for oral naltrexone (50 mg/d).
Meta-analyses of trials comparing acamprosate to naltrexone found no statistically significant
difference between them for return to any drinking (RD, 0.02; 95% CI, −0.03 to 0.08) or
heavy drinking (RD, 0.01; 95% CI, −0.05 to 0.06). For injectable naltrexone, meta-analyses
found no association with return to any drinking (RD, −0.04; 95% CI, −0.10 to 0.03) or heavy
drinking (RD, −0.01; 95% CI, −0.14 to 0.13) but found an association with reduction in heavy
drinking days (weighted mean difference [WMD], −4.6%; 95% CI, −8.5% to −0.56%). Among
medications used off-label, moderate evidence supports an association with improvement in
some consumption outcomes for nalmefene (heavy drinking days per month: WMD, −2.0;
95% CI, −3.0 to −1.0; drinks per drinking day: WMD, −1.02; 95% CI, −1.77 to −0.28) and
topiramate (% heavy drinking days: WMD, −9.0%; 95% CI, −15.3% to −2.7%; drinks per
drinking day: WMD, −1.0; 95% CI, −1.6 to −0.48). For naltrexone and nalmefene, NNHs for
withdrawal from trials due to adverse events were 48 (95% CI, 30 to 112) and 12 (95% CI, 7 to
50), respectively; risk was not significantly increased for acamprosate or topiramate.

CONCLUSIONS AND RELEVANCE Both acamprosate and oral naltrexone were associated with
reduction in return to drinking. When directly compared with one another, no significant
differences were found between acamprosate and naltrexone for controlling alcohol
consumption. Factors such as dosing frequency, potential adverse events, and availability of
treatments may guide medication choice.

Would love to know what readers think about the results of this large study. What are the main drivers of this gap, and why aren't more patients requesting these medications? What needs to be done to improve access?

Wednesday, April 30, 2014

Who Benefits from Additional Drug Counseling among Prescription Opioid Dependent Patients on Suboxone?

In a secondary analysis of the Prescription Opioid Addiction Treatment Study (POATS), the original study's author, Roger Weiss, and colleagues parse the data to determine if there are common characteristics among those who benefited from additional opioid dependence counseling (ODC) - above and beyond the standard medical management (SMM) and buprenorphine-naloxone medication. It is a very good question, considering the host of recent studies which found no additional benefit to counseling in terms of measured outcomes, including the large and highly-regarded POATS.

In searching for an answer, the authors looked at two sources of variability - patient characteristics, and adherence to treatment. Specifically, the authors sought to answer three questions: 1) Did participants with more severe problems have better outcomes with SMM + ODC than with SMM alone (N=360)? 2) Among participants with adequate adherence to treatment, were those assigned to SMM + ODC more likely to have successful outcomes than those receiving SMM alone, regardless of severity (n = 266)? And 3), among participants with adequate adherence to treatment, were those with more severe problems more likely to succeed with additional counseling than with standard medical management only (n = 266)?

In response to question 1, the analysis found that "the association between severity and outcome did not vary by treatment condition for any of the three severity measures." Those without past use of heroin had more favorable outcomes across the entire study. Regarding question 2, "adequate adherence" was defined as attending at least 60% of scheduled scheduled sessions in both treatment conditions, and most participants (73.9%) attended at least 60% of sessions. Subjects in the SMM-only condition were more likely meet this criterion but, once again, outcomes did not differ by treatment condition. Finally, in answering question 3, the authors found that, "Among participants who had ever used heroin, those assigned to SMM + ODC were more likely to succeed than those in SMM only (66.7% vs. 35.0%, n = 70, χ2(1) = 6.88, p=.016)."

 Table 1
Likelihood of successful opioid use outcomes at Phase 2, weeks 9–12. a
OR
95% CI      p Value
(a) All participants ( n= 360)
Main effects
Heroin
2.0
1.3–3.3      .004

Chronic pain
1.3
0.8–2.0      .240

Drug severity
2.9
0.2–58.2    .484

Interaction with Phase 2 treatment
Heroin
1.6
0.6–4.2      .342

Chronic pain
0.6
0.2–1.4      .218

Drug severity
0.2
0.0–76.8    .585
.
(b) Participants with adequate adherence to treatment ( n= 266)
Main effect of Phase 2 treatment
0.7
0.4–1.1     .107

Interaction with Phase 2 treatment
Heroin
3.7
1.1–11.8     .03

Chronic pain
0.5
0.2–1.5      .213

Drug severity
1.5
0.001–4023.5   .915

a All models were adjusted for Phase 1 treatment condition.

Treatment outcomes did not appear to differ among those who had never used heroin, suggesting that prescription opioid-addicted patients with a history of heroin use may be the participants who are most likely to benefit from additional counseling in suboxone treatment. Importantly, those patients had to also attend enough sessions (and receive an adequate "dose" of counseling) in order to see their outcomes improve to rates similar to those without a history of heroin use.

So, do these results line up with the experience of the readers of this blog? Are there populations with whom you believe counseling is especially important? Or, do the results simply reinforce the lessons of past studies? Let us know

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:

Abstract

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:




















Source:
http://www.sciencedirect.com/science/article/pii/S0028390814001099