Juan M. Ruiz M.D. Water’s Edge, Memorial’s Institute for Pain Relief

Marijuana and Chronic Pain

› NONE

Disclosures

› History

› Clinical Effects

› Pain Medicine Perspective

› Recent Studies

› Current Patient Safety Issues

› Current Public Health Implications

› Barriers to Access

› What does the Practicing Physician need to know?

› Future and More Education

Contents

› Cannabis is the third most widely used drug globally, after alcohol and tobacco.

› Worldwide prohibition of cannabis in the middle of the 20th century.

› In 1964 Israeli scientists Mechoulam and Gaoni identify delta-9-tetrahydrocannabinol as the primary psychoactive ingredient of cannabis.

History

› This discovery led to the isolation of a series of compounds unique to cannabis called cannabinoids. Cannabis may contain over 100 such compounds.

› In 1971 Harvard psychiatrist Lester Grinspoon published a book of case series of patients with intractable conditions whose use of cannabis allegedly led to powerful and positive results. This marked the re-introduction of cannabis for medical use

› In the 1980’s drugs based on the THC molecule were developed for the treatment of anxiety, anorexia and pain.

Dronabinol and nabilone (both synthetic THC analogues)

› Early 1990’s the target for these drugs was identified: G-protein coupled cannabinoid receptors type 1 and 2 (CB1 and CB2). Thus the “Endocannabinoid system” was discovered.

› In the 1990’s there was a surge and the so called “Medical Cannabis Movement” started. Mostly patient led effort, that gave rise to compassionate access in Holland, Canada and Israel.

› At the time of writing, In the United States, 22 states have passed voter initiatives and referenda to allow the medical use of cannabis, despite federal resistance and a refusal to reschedule cannabis from Schedule 1.

› Acute psychoactive effects:– Euphoria, relaxation, heightened sensations, increased appetite, distorted

sense of time, slowed reaction time, illusions and hallucinations, paranoia, anxiety

› Acute somatic effects:– Conjunctival injection, xerostomia, increased heart rate and blood pressure,

muscle relaxation, reduced intraocular pressure

› Overdose effects:– No known risk of dangerous overdose

› Withdrawal effects:– Generally mild but include irritability,

cravings, diminished appetite, insomnia

CLINICAL EFFECTS

› Chronic pain is the most common reason for patients to report the medical use of cannabis (estimates of use range from 12-15%).

› Population based studies of patients with fibromyalgia, arthritis, spinal cord injury and multiple sclerosis have all described cannabis use for the relief of pain (4).

› At the fundamental level the ECS has been identified as a valid and promising target for therapeutic analgesic drug development. The CB1 receptor is strategically in the PNS and CNS.

Pain Medicine Perspective

› Preclinical studies have reported analgesic properties of CB1 agonists in a wide array of animal pain models, and imaging studies have demonstrated the dissociative effects of cannabis on the pain neuromatrix (5).

› The CB2 receptor has also been linked to the liberation of pro-inflammatory mediators participating in antinociceptive effects (6).

› Now, there is a hunt for novel pharmaceutical agents to selectively target peripheral CB1 and CB2 receptors.

Pain Medicine Perspective

› At the clinical level, the evidence base is accumulating.

› The early cannabinoid antiemetic drugs dronabinol and nabilone have been re-discovered as having analgesic potential and the herbal cannabis extract nabiximols have been approved in Canada as analgesic in neuropathic pain associated with MS and advanced cancer pain.

› Inhaled cannabis (smoked and vaporized) has been shown to have analgesic properties in neuropathic pain associated with HIV/AIDS, trauma and MS.

Pain Medicine Perspective

› These trials have been generally small and of short duration, and long term efficacy is currently limited to two studies of oral cannabis extracts (7)(8).

Pain Medicine Perspective

In studies of Pain, what is a clinically significant result????

Ferrar, J, Young J. Pain. Volume 94, Issue 2, November 2001, Pages 149–158

Pain intensity is frequently measured on an 11-point pain intensity numerical rating scale (PI-NRS), where 0=no pain and 10=worst possible pain. However, it is difficult to interpret the clinical importance of changes from baseline on this scale (such as a 1- or 2-point change). To date, there are no data driven estimates for clinically important differences in pain intensity scales used for chronic pain studies. We have estimated a clinically important difference on this scale by relating it to global

assessments of change in multiple studies of chronic pain. Data on 2724 subjects from 10 recently completed placebo-controlled clinical trials of pregabalin in diabetic neuropathy, postherpetic neuralgia, chronic low back pain, fibromyalgia, and osteoarthritis were used. The studies had similar designs and measurement instruments, including the PI-NRS, collected in a daily diary, and the standard seven-point patient global impression of change (PGIC), collected at the endpoint. The changes in the PI-NRS from baseline to the endpoint were compared to the PGIC for each subject. Categories of ‘much improved’ and ‘very much improved’ were used as determinants of a clinically important difference and the relationship to the PI-NRS was explored using graphs, box plots, and sensitivity/specificity analyses. A consistent relationship between the change in PI-NRS and the PGIC was demonstrated regardless of study, disease type, age, sex, study result, or treatment group. The relationship between percent change and the PGIC was also consistent regardless of baseline pain, while higher baseline scores required larger raw changes to represent a clinically important difference. The application of these results to future studies may provide a standard definition of clinically important improvement in clinical trials of chronic pain therapies. Use of a standard outcome across chronic pain studies would greatly enhance the comparability, validity, and clinical applicability of these studies.

Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale

On average, a reduction of approximately two points or a reduction of approximately 30% in the PI-NRS represented a clinically important difference.

Cannabiniods for Medical Use, A Systematic Review and Meta-AnalysisPenny F. Whiting, et al. JAMA 2015;313(24):2456-2473

Design: Randomized clinical trials of cannabinoids for the following indications: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma or Tourette Syndrome.

Data extraction: Study quality was assessed using Cochrane risk of bias tool. All review stages were conducted independently by 2 reviewers.

Recent Meta-analysis

Cannabiniods for Medical Use, A Systematic Review and Meta-Analysis

Focus on Chronic Pain

› 28 studies

› 13 nabiximols, 4 smoked THC, 5 for nabilone, 3 for THC oromucosal, 2 dronabinol, 1 vaporized cannabis, 1 for oral THC, 1 for ajuvenic acid. One trial compared nabilone with amitriptyline all other studies were placebo controlled.

› Conditions treated: neuropathic pain (central, peripheral or not specified; 12 studies). 3 for cancer pain, 3 for diabetic neuropathy, 2 for fibromyalgia, 2 for HIV associated sensory neuropathy and 1 study for each of the following: refractory MS pain, rheumatoid arthritis, central pain (not specified), msk problems and chemotherapy induced pain.

› 2 studies were at low risk of bias, 9 at unclear risk and 17 at high risk of bias.

› Results: A total of 79 trials (6462 participants). 4 were judged at low risk bias. Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs. 20%;odds ratio 3.82[95% CI, 1.55-9.42] trials. Reduction in pain (37% vs 31%; OR, 1.41 [95% CI, 0.99-2.00]; 8 trials), a greater average reduction in numerical rating scale pain assessment (on a 0-10-point scale; weighted mean difference [WMD], −0.46 [95% CI, −0.80 to −0.11]; 6 trials), and average reduction in the Ashworth spasticity scale (WMD, −0.12 [95% CI, −0.24 to 0.01]; 5 trials). There was an increased risk of short-term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination.

Figure Legend: Improvement in PainOdds indicate 30% or greater improvement in pain with cannabinoid compared with placebo, stratified according to cannabinoid. The square data markers indicate odds ratios (ORs) from primary studies, with sizes reflecting the statistical weight of the study using random-effects meta-analysis. The horizontal lines indicate 95% CIs. The blue diamond data markers represent the subtotal and overall OR and 95% CI. The vertical dashed line shows the summary effect estimate, the dotted shows the line of no effect (OR = 1).

› One trial assessed smoked THC and reported the greatest beneficial effect (OR, 3.43 [95% CI, 1.03-11.48]), and 7 trials assessed nabiximols

› Pain conditions evaluated in these trials were neuropathic pain (OR, 1.38 [95% CI, 0.93-2.03]; 6 trials) and cancer pain (OR, 1.41 [95% CI, 0.99-2.00]; 2 trials), with no clear differences between pain conditions.

› Nabiximols was also associated with a greater average reduction in the Numerical Rating Scale (NRS; 0-10 scale) assessment of pain (weighted mean difference [WMD], −0.46 [95% CI, −0.80 to −0.11]; 6 trials), brief pain inventory-short form, severity composite index (WMD, −0.17 [95% CI, −0.50 to 0.16]; 3 trials), neuropathic pain scale (WMD, −3.89 [95% CI, −7.32 to −0.47]; 5 trials), and the proportion of patients reporting improvement on a global impression of change score (OR, 2.08 [95% CI, 1.21 to 3.59]; 6 trials) compared with placebo.

› There was no difference in average quality-of-life scores as measured by the EQ-5D health status index (WMD, −0.01 [95% CI, −0.05 to 0.02]; 3 trials) between nabiximols and placebo.

Cannabiniods for Medical Use, A Systematic Review and Meta-AnalysisPenny F. Whiting, et al. JAMA 2015;313(24):2456-2473

Conclusions:

There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short-term AES

› Overall, yes they faired better than placebo statistically, yet is the improvement clinically significant?

› Measures to evaluate outcome were not consistent

› Few trials

› Bias?

› Dosing??

› Pain conditions (neuropathic, nociceptive, cancer, etc)

Issues

Kevin P. Hill, MD, MHS. JAMA. 2015;313(24):2474-2483.

Study Design: The medical literature on medical marijuana was reviewed from 1948 to March 2015 via MEDLINE with an emphasis on 28 randomized clinical trials of cannabinoids as pharmacotherapy for indications other than those for which there are 2 US Food and Drug Administration–approved cannabinoids (dronabinol and nabilone),

Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems

Kevin P. Hill, MD, MHS. JAMA. 2015;313(24):2474-2483.

› Findings: Use of marijuana for chronic pain, neuropathic pain, and spasticity due to multiple sclerosis is supported by high-quality evidence. Six trials that included 325 patients examined chronic pain, 6 trials that included 396 patients investigated neuropathic pain, and 12 trials that included 1600 patients focused on multiple sclerosis. Several of these trials had positive results, suggesting that marijuana or cannabinoids may be efficacious for these indications

Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems

Kevin P. Hill, MD, MHS. JAMA. 2015;313(24):2474-2483.

Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems

Kevin P. Hill, MD, MHS. JAMA. 2015;313(24):2474-2483

- Acute adverse effects: impaired short term memory, motor coordination and judgement, paranoid ideation, psychotic symptoms.

- Long-term use: addictive, anxiety, depression, psychotic illness, poor school performance, lower income, increased likelihood of requiring socioeconomic assistance, unemployment, criminal behavior, decreased satisfaction with life.

- Withdrawal: anxiety, irritability, craving, dysphoria and insomnia

Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems

› METHODS: The placebo-controlled double-blinded pilot study was divided into a 14 week cross-over period (two 4 week medication phases plus wash-out phases) followed by a 16 week medication switch period with free choice of the study drugs (drug A and drug B) by the study participants. The principal inclusion criterion was chronic therapy-resistant pain in causal relationship with a pathologic status of the skeletal and locomotor system. The study participants chose the dosage of the study drug themselves (between 1 und 4 capsules/day, in the case of nabilone this corresponds to (1/4)-1 mg/day). Pain intensity was assessed by a visual analogue scale (VAS), quality of life by the Mezzich and Cohen QOL-score.

Benefits of an add-on treatment with the synthetic cannabinomimetic nabilone on patients with chronic pain--a randomized controlled trialPinsger, M. et al

› RESULTS: Altogether, 30 patients were included and analyzed. From the results, it is obvious that throughout the cross-over periods the nabilone treatment was superior (medians [25%-; 75%-percentiles]: nabilone/placebo): decrease of the average spinal pain intensity within the last 4 weeks (DeltaVAS) 0.9 [0.0; 2.0] / 0.5 [0.0; 1.7], decrease of the current spinal pain intensity (DeltaVAS) 0.6 [0.0; 2.5] / 0.0 [-1.0, 1.0] (p =.006), decrease of the average headache intensity within the last 4 weeks (DeltaVAS) 1.0 [-1.0; 2.4] / 0.2 [-0.9; 1.0], increase of the number of days without headache within the last 4 weeks 2.0 [0.0; 6.5] / 0.0 [-5.0; 4.0], increase of the quality of life (DeltaQOL-Score) 5.0 [0.8; 10.8] / 2.0 [-2.3; 8.0]. In the medication switch period, the number of study participants who favoured nabilone (nabilone intake > or =85% of all medication days) was more than 4 times higher than those who favoured placebo. The number of days with nabilone intake was clearly higher than the number with placebo intake (medians: 89% vs. 11% of all medication days, p =.003).

› Main outcome measures The primary outcome was difference between nabilone and dihydrocodeine in pain, as measured by the mean visual analogue score computed over the last 2 weeks of each treatment period. Secondary outcomes were changes in mood, quality of life, sleep, and psychometric function. Side effects were measured by a questionnaire.

› Intervention Patients received a maximum daily dose of 240 mg dihydrocodeine or 2 mg nabilone at the end of each escalating treatment period of 6 weeks. Treatment periods were separated by a 2 week washout period.

› Results: Mean baseline visual analogue score was 69.6 mm (range 29.4-95.2) on a 0-100 mm scale. 73 patients were included in the available case analysis and 64 patients in the per protocol analysis. The mean score was 6.0 mm longer for nabilone than for dihydrocodeine (95% confidence interval 1.4 to 10.5) in the available case analysis and 5.6 mm (10.3 to 0.8) in the per protocol analysis. Side effects were more frequent with nabilone.

› Conclusion :Dihydrocodeine provided better pain relief than the synthetic cannabinoid nabilone and had slightly fewer side effects, although no major adverse events occurred for either drug.

Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind studyB Frank, MG Serpell, J Hughes, BMJ 2008;336:199

Reality: yes there are studies, but even in well known journals you must scrutinize the evidence. As always.

JAMA Intern Med. 2014;174(10):1668-1673.

- A time-series analysis was conducted of medical cannabis laws and state-level death certificate data in the United States from 1999 to 2010; all 50 states were included.

- Conclusion: Three states (California, Oregon, and Washington) had medical cannabis laws effective prior to 1999. Ten states (Alaska, Colorado, Hawaii, Maine, Michigan, Montana, Nevada, New Mexico, Rhode Island, and Vermont) enacted medical cannabis laws between 1999 and 2010. States with medical cannabis laws had a 24.8% lower mean annual opioid overdose mortality rate (95% CI, −37.5% to −9.5%; P = .003) compared with states without medical cannabis laws. Examination of the association between medical cannabis laws and opioid analgesic overdose mortality in each year after implementation of the law showed that such laws were associated with a lower rate of overdose mortality that generally strengthened over time: year

Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in the United States, 1999-2010

Current Patient Safety Issues

› Population based studies of recreational cannabis use suggest that the toxicity of cannabis is extremely low (owing in part to the lack of CB receptors in critical brainstem regions controlling respiratory drive).

› Associations are reported between recreational cannabis use and early onset psychosis, myocardial infarction, stroke, impairments in driving, increased risk of accidents; risks of chronic bronchitis (associated with smoking of herbal cannabis) and cyclical vomiting (9).

› In clinical trials , the adverse events associated with cannabinoids are similar in quality and quantity to those of many other conventional centrally acting analgesics and serious adverse drug reactions to cannabinoids are rare (10).

Current Patient Safety Issues

› Legal limit is 5 nanograms/mL in blood of 9-deltaTHC

› 60 percent of drivers in fatal accidents from 2010 to 2014 were tested for drugs, with 20 percent of those testing positive for marijuana. (Washington Traffic Safety Commission).

› In 2014, 85 percent of drivers who tested positive for marijuana were high when they crashed, up from less than half of drivers tested in 2010, with men ages 21 to 25 making the largest increase. (WTSC)

Current Public Health Implications

› Studies have shown that among youth who earn mostly D’s and F’s in school, 66% had used marijuana, a higher percentage than other risk behaviors studied (CDC) (14).

› Heavy cannabis use during the teen years has been found to result in a average 8 point drop in IQ between childhood and adulthood; by comparison those who did not use marijuana showed no drop in IQ (16).

Current Public Health Implications

Barriers to Access› Federal Law– Marijuana is illegal, even for medical use

› Exceptions: Compassionate Investigational New Drug Program– Federally approved research

– Schedule 1 controlled substance› Physicians may not prescribe... only discuss and recommend› Pharmacies may

not dispense– DEA enforces

marijuana criminalpenalties in the CSA

From the National Drug Control Strategy 2014

https://www.whitehouse.gov/sites/default/files/ondcp/policy-and-research/ndcs_2014.pdf

Excerpt from page 3

Barriers to Access› Risk of Arrest and Prosecution

– Federal law trumps state law– Constant fear of participating in illegal activity– Stress of arrest/prosecution worsens preexisting health problems

› Risk of Loss of Employment– No exemption from job termination if fail employee drug screen

› Risk of Violence and Robbery– Risk personal safety to obtain marijuana– Illicit status attracts crime– Physical violence, intimidation, robbery– Home cultivators worry about robbery

› Risk of Diversion– High illicit demand creates potential for diversion to illegal users– Law enforcement have serious concerns

› More marijuana makes tracking harder and diversion easier

› Cost of Supply– Patients can be on limited income– No health insurance coverage– Illicit dealers have high prices and frequent price fluctuations

› Physical Limitations– Consider time, effort, space, and location to maintain plants– Takes time to grow product

Barriers to Access

› Supply Quality– Safety and consistency dependent on quality of supply– Unsafe growing and handling techniques compromises product

› Contamination with molds, bacteria, pesticides, herbicides, heavy metals› Patients may be immunocompromised

– Illicit dealers lace with other drugs

Barriers to Access

Barriers to Access› Supply Quality– Multiple strains and multiple – potencies

› No standardized dosing› Over 600 different strains

› There is a escalating scientific knowledge base.

› The response that there is “not enough information” is disingenuous at best and at worst an abnegation of clinical responsibility.

› A refusal to discuss medical cannabis candidly with patients does two things:– 1. it undermines the doctor-patient relationship – 2. it drives the patient to sources where information may be less

robust and to “pot docs”

What does the Practicining Clinician Need to Know?

› Cannabinoids have been listed as third or fourth line agents for chronic neuropathic pain (from Canadian Pain Society Guidelines) (11).

› They have risen to second-line therapy in the case of central neuropathic pain caused by MS (In Europe) (12).

› Cannabis dependency is increasingly well recognized. Patients whose cannabis use does not meet therapeutic standards and whose use is not controlled may warrant referral to substance-abuse specialists (13).

What does the Practicining Clinician Need to Know?

› Step 1: Re-evaluate your own perspectives around cannabis use.

› Step 2: Appreciate the important risk factors in cannabis use.

Contraindications currently accepted: personal or family history of psychosis or schizophrenia and unstable ischemic heart disease.

Other concerns: pregnancy or breastfeeding, sever liver or kidney disease, use in elderly and use in pts. <25 years old.

As with opioids, a careful screening for substance abuse risk factors.

What does the Practicining Clinician Need to Know?

› Step 3: Explore all reasonable standard therapeutic approaches and DOCUMENT, before suggesting cannabis use.

Caution: the patient demanding cannabis and refusing to consider options may have motivations other than amelioration of pain and improvement in quality of life.

REMEMBER: Any decision to incorporate cannabis in therapy will depend on the severity of the underlying pain condition and the success or extent of other approaches that have been tried or considered.

› Create a plan: mutually agreed upon treatment goals, realistic expectations, documenting functional outcomes and if there is failure to demonstrate positive outcomes in a reasonable time frame should prompt reconsideration and cessation of therapy.

› Although purified analogs and extracts of cannabis are available as prescription medicines, the clinical study of inhaled or vaporized cannabinoids is limited by restricted access to supplies of clinical grade material, lack of intellectual property incentives and concerns that studying the medical benefits of cannabis runs contrary to global antidrug and antismoking strategies.

› Until such issues are addressed it is unlikely that we will ever see the sort of large scale phase III trials need to definitely establish the efficacy of herbal cannabis.

Future of Cannabis Research

› University of Washington CME

“Medical Cannabis and Chronic Pain Project”

http://adai.uw.edu/mcacp/

More Education

1. Ware, Mark A., Desroches, Julie. Medical Cannabis and Pain. IASP Clinical Updates. October 2014

2. Whiting, et al. Cannabinoids for Medical Use, A Systematic Review and Meta-analysis. JAMA. 2015;313(24):2456-2473

3. Hill, Kevin P. Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems, A Clinical Review.

JAMA.2015;313(24)2474-2483

4. Ware MA. Adams H. Guy GW. The medicinal use of cannabis in the UK: Results of a Nationwide Survey. Int J Clin Pract 2005;59:291-5

References

› 5. Lee MC, Ploner M, Wiech K. Amygdala activity contributes to the dissociative effect of cannabis on pain perception. Pain 2013;154:124-34

› 6. Rom S., Persidisky Y. Cannabinoid receptor 2:potential role in immunomodulation and neuroinflammation. J Neuroimmune Pharmacol 2013;8:608-20

› 7. Zajicek JP, Sanders HP, Wright DE, Vickery PJ, Ingram WM, Reilly SM, Nunn AJ, Teare LJ, Fox PJ, Thompson AJ. Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatry 2005;76:1664–9.

› 8. Wade DT, Makela PM, House H, Bateman C, Robson P. Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Mult Scler 2006;12:639–4

References (cont.)

› 9. Hall W, Degenhardt L. Adverse health effects of non-medical cannabis use. Lancet 2009;374:1383–91.

› 10. Wang T, Collet JP, Shapiro S, Ware MA. Adverse effects of medical cannabinoids: a systematic review. CMAJ 2008;178:1669–78

› 11. Moulin DE, Clark AJ, Gilron I, Ware MA, Watson CP, Sessle BJ, Coderre T, Morley-Forster PK, Stinson J, Boulanger A, Peng P, Finley GA, Taenzer P, Squire P, Dion D, Cholkan A, Gilani A, Gordon A, Henry J, Jovey R, Lynch M, Mailis-Gagnon A, Panju A, Rollman GB, Velly A. Pharmacological management of chronic neuropathic pain: consensus statement and guidelines from the Canadian Pain Society. Pain Res Manag 2007;12:13–21.

References (cont.)

› 12. Attal N, Cruccu G, Haanpaa M, Hansson P, Jensen TS, Nurmikko T, Sampaio C, Sindrup S, Wiffen P. EFNS guidelines on pharmacological treatment of neuropathic pain. Eur J Neurol 2006;13:1153–6

› 13. Van der Pol P. Liebregets, et al. Mental Health differences between frequent cannabis users with and without dependence and the general population. Addiction. 2013;108:1459-69.

› 14. Centers for Disease Control and Prevention. (2009). Health risk behaviors and academic achievement. Retrieved from http://www.cdc.gov/healthyyouth/health_and_academics/pdf/health_risk_behaviors.pdf

› 15. Meier, M.H., Caspi, A., Ambler, A., Harrington, H., Houts, R., Keefe, R.S., McDonald, K., Ward, A., Poulton, R., & Moffitt, T.E. (2012). Persistent cannabis users show neuropsychological decline from childhood to midlife. Proceedings of the National Academy of the Sciences of the United States, 109(40), E2657-64.

References (cont.)

Thank you!!