Juan M. Ruiz M.D. - Memorial Physicians

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Transcript Juan M. Ruiz M.D. - Memorial Physicians

Marijuana and Chronic Pain
Juan M. Ruiz M.D.
Water’s Edge, Memorial’s Institute for Pain Relief
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
› Cannabis is the third most widely used drug globally, after
alcohol and tobacco.
› Worldwide prohibition of cannabis in the middle of the 20th
› In 1964 Israeli scientists Mechoulam and Gaoni identify delta9-tetrahydrocannabinol as the primary psychoactive
ingredient of cannabis.
› 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: Gprotein 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
› 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,
› 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
Pain Medicine Perspective
› Chronic pain is the most common reason for patients to report
the medical use of cannabis (estimates of use range from 1215%).
› 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
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 proinflammatory 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).
In studies of Pain, what is a clinically
significant result????
Clinical importance of changes in chronic pain intensity
measured on an 11-point numerical pain rating scale
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.
On average, a reduction of approximately two points or a
reduction of approximately 30% in the PI-NRS represented a
clinically important difference.
Recent Meta-analysis
Cannabiniods for Medical Use, A Systematic Review and MetaAnalysis
Penny 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.
Cannabiniods for Medical Use, A Systematic Review and MetaAnalysis
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, 0.992.00]; 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 MetaAnalysis
Penny F. Whiting, et al. JAMA 2015;313(24):2456-2473
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)
Medical Marijuana for Treatment of Chronic Pain
and Other Medical and Psychiatric Problems
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 highquality 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
- 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
- Withdrawal: anxiety, irritability, craving, dysphoria and
Benefits of an add-on treatment with the synthetic cannabinomimetic
nabilone on patients with chronic pain--a randomized controlled trial
Pinsger, M. et al
› 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.
› 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).
Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine
for chronic neuropathic pain: randomised, crossover, double blind study
B Frank, MG Serpell, J Hughes, BMJ 2008;336:199
› 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
› 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 0100 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.
Reality: yes there are studies, but even in well known
journals you must scrutinize the evidence. As always.
Medical Cannabis Laws and Opioid Analgesic Overdose
Mortality in the United States, 1999-2010
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
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).
Current Patient Safety Issues
› 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 Public Health Implications
› 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
› 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).
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 criminal
penalties in the CSA
From the National Drug Control
Strategy 2014
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
Barriers to Access
› 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
› Supply Quality
– Multiple strains and multiple
– potencies
› No standardized dosing
› Over 600 different strains
What does the Practicining Clinician Need to
› 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
› 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
› 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 substanceabuse specialists (13).
What does the Practicining Clinician Need to
› Step 1: Re-evaluate your own perspectives around cannabis
› 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
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
› 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
Future of Cannabis Research
› 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.
More Education
› University of Washington CME
“Medical Cannabis and Chronic Pain Project”
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.
4. Ware MA. Adams H. Guy GW. The medicinal use of cannabis
in the UK: Results of a Nationwide Survey. Int J Clin Pract
References (cont.)
› 5. Lee MC, Ploner M, Wiech K. Amygdala activity contributes to the
dissociative effect of cannabis on pain perception. Pain
› 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–
› 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
› 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.
Thank you!!