Looking Beyond the Smoke and Mirrors: Cannabis Use and the Development of Chronic Psychotic Disorders

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1 Looking Beyond the Smoke and Mirrors: Cannabis Use and the Development of Chronic Psychotic Disorders Pharmacotherapy Grand Rounds December 20, 2013 Rosana Oliveira, Pharm.D., BCPS PGY2 Psychiatric Pharmacy Resident Department of Pharmacy, South Texas Veterans Health Care System, San Antonio, TX Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy Pharmacotherapy Education and Research Center The University of Texas Health Science Center at San Antonio Learning Objectives: 1. Describe the effect of cannabis and medical cannabinoids on the endocannabinoid system 2. Explain the risks and adverse effects of cannabis and medical marijuana 3. Define the risk factors associated with the development of psychosis for cannabis users 4. Evaluate the literature associating the risk of chronic psychotic disorders with cannabis use

2 Cannabis I. History of Cannabis sativa (C. sativa) a. First used for medicinal purposes in 2737 B.C. in China 1-3 b. Included in the United States (U.S.) Pharmacopeia in 1851 but later removed in c. Classified as a Schedule I substance in 1970 by Congress 1-3 d. California became first state to legalize its medical use in e. As of September 2013, 20 states and the District of Columbia have enacted laws to legalize medical marijuana and two states have legislation for recreational use 5 II. Epidemiology of cannabis use a. Due to its low lethality, many believe cannabis causes little harm b. It is the world s most widely used illicit drug with between 119 and 224 million users 6 c. The prevalence of cannabis use among the general population continued to increase in 2010 to 14.1% compared to 13.7% in 2009 in the U.S. 6 d. There is a continued increase in illicit drug use, including cannabis, among teenagers 6,7 Figure 1: Annual prevalence of illicit drug use among the population aged 12 and over in the U.S., (percentage) 6 e. The use of cannabis currently exceeds that of tobacco smoking in adolescents in the U.S. Figure 2: Cannabis consumption in adolescents in Oliveira 2

3 f. There are over 6,000 first time cannabis users per day in the U.S., over 60% under the age of g. Data from the National Longitudinal Study for Adolescent Health found that 6.6% of teens report daily use 7 h. Research in the U.S. indicates that about 10% of those who ever use cannabis become daily users, and 20-30% become weekly users 8 III. Endocannabinoid (ecb) system a. Regulates numerous biological processes involved in development and neuroplasticity 7 b. Tightly regulated biosynthetic and degradative pathways ensure proper signaling throughout development 7 c. Endocannabinoids 4,7,9 i. Endogenous lipid- derived ligands, receptors, and enzymes that orchestrate intracellular communication and intracellular metabolism ii. Most characterized ecbs include the endogenous compounds 2- arachidonol glycerol and anandamide iii. Most common G protein- coupled receptor in the central nervous system is the cannabinoid receptor- 1 (CB1) iv. CB1 is involved in the neurotransmission of gamma- aminobutyric acid (GABA), glutamate, serotonin, dopamine, and acetylcholine v. CB1s are nearly absent in the brainstem; therefore, the drug spares the autonomic nervous system and no lethal overdose has been reported Table 1: Brain areas affected by CB1 receptors and physiologic outcome 4 Brain Area Physiologic Outcome Affected Cerebellum and basal ganglia - Motor tone and coordinated movement Hippocampus - Mood Hippocampus and prefrontal cortex - Cognition, concentration, short- term memory processing, attention, tracking behavior Mesolimbic system - Pleasurable activities vi. Cannabinoid receptor- 2 (CB2) receptor 9 1. Cellular and humoral responses related to neuroinflammation and pain 2. Digestion and host defense d. Phytocannabinoids 4 i. Hundreds of these compounds found in C. sativa ii. Two most medically relevant are 9 - tetrahydrocannabinol (THC) and cannabinidiol Table 2: Main phytocannabinoids in cannabis 4,7 Phytocannabinoids Physiologic Effect 9 - THC - Psychoactive compound found in the recreational drugs marijuana and hashish - Occurs via THC s interactions with the ecb system (CB1) Cannabidiol - Lacks psychoactivity, may mitigate anxiety and paranoia from THC - Shown some promise as an antipsychotic, anxiolytic, anticonvulsant Oliveira 3

4 e. Synthetic cannabinoids (Appendix I) i. Laboratory produced analogues of THC and cannabidiol 4 ii. Foundation of the pharmaceutical industry in cannabinoid- related products 4 iii. Drug interactions have been identified 10 IV. Medical marijuana a. Due to Schedule I classification, difficult for researchers to study b. In 1999, the Institute of Medicine released a report indicating cannabinoids may have a role in the treatment of pain and memory, but risk associated with use have been observed 11 i. Two meta- analyses have evaluated various forms of cannabis for pain ii. Showed significant improvement in various types of pain with medical cannabis c. Other therapeutic uses of cannabinoids Table 3: Therapeutic uses of cannabinoids by organ system Organ System Therapeutic Use Digestive - Obesity, anorexia, emesis Muscular - Huntington s disease Nervous - Multiple sclerosis, Parkinson s disease, Alzheimer s disease, Tourette s syndrome, epilepsy, glaucoma, bipolar disorder, schizophrenia, post- traumatic stress disorder, depression, insomnia Various - Cancer, cancer pain d. Patients can access medical marijuana through cannabis dispensaries and statewide programs 5 i. As of September 2013, 20 U.S. states and the District of Columbia have laws that allow the use and possession of cannabis for medicinal reasons (Appendix II) ii. Colorado and Washington have legislation for recreational use of marijuana e. Pediatric implications in the legalization of marijuana 1 i. National Poison Data Center reported 5,371 calls pertaining to marijuana exposure in 2011; 358 (7%) for children less than 12 years old ii. Total calls and calls pertaining to children aged 12 years or younger increased compared to previous years Number of Calls Year Figure 3: Marijuana calls to national poison centers < 12 years of age 1 Oliveira 4

5 iii. Retrospective cohort study from January 1, 2005 to December 21, Found statistically significant new appearance of unintentional marijuana ingestions by young children after modification of drug enforcement laws for marijuana possession in Colorado 2. Nine patients had lethargy, 1 had ataxia, 1 had respiratory insufficiency; 8 were admitted and 2 of those went to the intensive care unit 3. Eight out of 14 involved medical marijuana, 7 were food products V. Adverse effects a. Ingestion of exogenous THC produces supraphysiological effects of ecb- targeted receptors, causing marked disruption of neuronal signaling and circuit dynamics in the finely tuned endogenous system 7 b. No reliable information exists about the concentration of THC and other cannabinoids in commonly used cannabis products, however, it is thought that the THC content increased from 2% in 1980 to 8.5% in c. C. sativa strains are bred to amplify THC contents and diminish counteracting cannabidiol 6 d. Acute effects 8 i. High becomes more intense, anxiety levels increase, as do panic and psychosis particularly in naïve users and in unfamiliar stressful situations ii. Studies of the effects of cannabis upon on- road driving found more modest impairments than those caused by intoxicating doses of alcohol 17 e. Chronic effects 8 i. Challenging interpretation of studies since cannabis use is highly correlated with the use of tobacco, alcohol, or other illicit drugs ii. Over the past 20 years an increasing number of people have sought help in the U.S., Europe, and Australia to stop cannabis 1. Develop tolerance to the effects of THC 2. Withdrawal syndrome can include anxiety, insomnia, appetite disturbance, and depression Table 4: Chronic effects of cannabis 8,18 Organ system Effect Circulatory - Increased heart rate in dose dependent fashion Nervous - Deficits in verbal learning, memory, attention - Changes in brain function that can be detected by cerebral blood flow, positron emission tomography and electroencephalography Respiratory - Wheezing, sputum production, chronic cough (chronic bronchitis - Most studies have not shown an increase in lung cancer with chronic cannabis use after controlling for tobacco use f. Pregnancy 19 i. High doses of cannabis cause growth retardation and malformations in animals ii. Epidemiological studies are scarce for women who use cannabis during pregnancy 1. Reduced birth weight, but less so than that seen with tobacco smoking Oliveira 5

6 2. Causal interpretation of any effects is weakened by the poor study designs which did not control for other drug use during pregnancy, poor parenting, and genetic factors g. Systematic review of adverse effects of medical cannabinoids (Appendix III) 20 i. 23 randomized controlled trials and 8 observational studies ii. Included oromucosal spray and oral 9 - tetrahydrocannabinol- cannabidiol and oral THC i. 4,779 adverse events reported over 8-12 months ii. 4,615 (96.6%) were not serious 1. Most common was dizziness (15.5%) 2. Rate higher in patients in the medical cannabinoid group (Rate ratio 1.86, 95% confidence interval (CI) ) iii. 164 (3.43%) serious events 1. Most common was relapse of multiple sclerosis (12.8%) 2. Not higher in patients in the medical cannabinoid group (Rate ratio 1.04, 95% CI ) Psychiatric Consequences of Cannabis Use I. Psychosis a. Mental state characterized by delusions, hallucinations, or gross disorganization of speech or behavior b. Can occur without necessarily being part of a psychotic disorder c. Schizophrenia and schizophreniform disorder Table 5: DSM- IV Diagnosis of Schizophrenia and Schizophreniform Disorder Characteristic Schizophrenia Schizophreniform Disorder Symptoms Delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, negative symptoms Delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, negative symptoms Number of symptoms needed 2 or more 2 or more Time- frame Occupational dysfunction DSM- 5 changes Disturbance occurs during the significant part of a one- month period, continuous signs of disturbance for at least 6 months Yes At least 1 of the 2 symptoms must be delusions, hallucinations, or disorganized speech Total duration of illness is greater than 1 month but less than 6 months No At least 1 of the 2 symptoms must be delusions, hallucinations, or disorganized speech d. Schizophreniform disorder 22 i. One- third of individuals with an initial diagnosis of schizophreniform recover within the 6- month period Oliveira 6

7 ii. The majority of the remaining two- thirds of individuals will eventually receive a diagnosis of schizophrenia or schizoaffective disorder II. Cannabis use and risk factors for development of psychosis, a. Cannabis use as an adolescent 23,24 i. Puberty is a period of significant cerebral reorganization, particularly of the frontal lobes implicated in behavior ii. Brain is especially vulnerable to adverse effects from exogenous cannabinoids iii. Early exposure to cannabis could potentially have lasting consequences on cognition, may increase the risk for neuropsychiatric disorders, promote further illegal drug intake, and increase the likelihood of cannabis dependence b. Amount and duration of cannabis consumption 25 c. Individual predisposing genetic factors that increase vulnerability 25 i. Catechol- O- methyltransferase (COMT) gene is responsible for metabolism of dopamine at synapses, predominately expressed in the prefrontal cortex ii. COMT polymorphisms, specifically Val/Val genotype, are associated with increased COMT activity resulting in reduced dopamine in the prefrontal cortex and increased levels of mesolimbic signaling, thought to result in increased risk of experiencing delusions and hallucinations d. Environmental factors 25 e. Proposed mechanism of psychosis in recent cannabis use Figure 4: Pathway to psychosis in recent cannabis users 25 AO=age of onset, CU=cannabis use, DUP=duration of untreated psychosis Oliveira 7

8 Clinical Question and Literature Review I. Is cannabis independently associated with the development of chronic psychotic disorders? II. Literature review a. Swedish male conscripts by Zammit and colleagues b. Netherlands Mental Health Survey And Incidence Study by van Os and colleagues c. Dunedin Multidisciplinary Health and Development Study by Caspi and colleagues d. Systematic review and meta- analysis by Minozzi and colleagues e. Systematic review by McLaren and colleagues Swedish Male Conscripts by Zammit and Colleagues 26 Table 6: Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: Historical cohort study Objective - Further analysis of the Swedish conscript cohort to address concerns that association found in original study between cannabis use and schizophrenia was due to use of other drugs, premorbid personality traits, and use of cannabis secondary to the presence of schizophrenia Design - Historical cohort study Patients - Survey of Swedish men conscripted for compulsory military training in More than 98% were years of age - Included 50,087 subjects Exclusion - Severe mental or physical handicap (34 cases) Outcomes - Primary outcome measure: - Admissions to hospital for international classification of diseases, 8 th or 9 th revision (ICD- 8/9) schizophrenia and other psychoses, as determined by record linkage Methods - Initial enrollment: - Conscription procedure included intelligence tests and non- anonymous self- reported questionnaire on family, social background, behavior during adolescence, and substance use - Substance use questions asked first drug used, drug most commonly used, frequency of use, and direct questions regarding use of a list of specified drugs - All subjects underwent a structured interview conducted by a psychologist, and those reporting any psychiatric symptoms were interviewed by a psychiatrist and given a diagnosis according to ICD- 8/9 - Follow- up: - Swedish national hospital discharge register recorded about 70% of all psychiatric admissions in 1970, 83% in 1973, 97% in , virtually 100% since 1987 Statistical analyses - Logistic regression to calculate odds ratios (OR) and 95% CI - Confounders assessed: psychiatric diagnosis at conscription, IQ score, personality variables concerned with interpersonal relationships, place of upbringing, paternal age, cigarette smoking, disturbed behavior in childhood, history of alcohol misuse, family history of psychiatric illness, financial situation of the family, and fathers occupation Oliveira 8

9 Table 6: Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: Historical cohort study, continued Results - Out of the 50,053 subjects, 362 received a diagnosis of schizophrenia by 1996 (0.71%, 95% CI 0.65%- 0.80%) - 5,391 subjects (10.8%) ever used cannabis, and 73 of these (1.4%) developed schizophrenia - Data on drug use was missing on 16 (4.4%) subjects developing schizophrenia, and on 1,522 (3.1%) of non- cases (p<0.2) - Cannabis was associated with an increased risk of developing schizophrenia in a dose dependent fashion both for subjects who had ever used cannabis and for subjects who had used only cannabis and no other drugs Table 7: Adjusted OR for developing schizophrenia with cannabis use Patient population OR (95% CI) p value Ever used cannabis, linear trend for frequency of use 1.2 ( ) <0.001 Ever used cannabis, used > 50 times 3.1 ( ) Not reported Only ever used cannabis, linear trend for frequency of use 1.3 ( ) <0.015 Only ever used cannabis, used > 50 times 6.7 ( ) Not reported - - Association between schizophrenia and stimulant use in crude analysis, but became non- significant after adjustment for confounders Association observed between schizophrenia and frequency of cannabis use was unchanged after adjustment for stimulant use Authors conclusions Table 8: Adjusted OR for developing schizophrenia with stimulant use Patient population OR (95% CI) p value Stimulant use 1.5 ( ) Not significant Stimulant use adjusted for frequency of cannabis use 1.1 ( ) Not significant - Cannabis use is associated with an increased risk of developing schizophrenia, consistent with a causal relation - Risk of developing schizophrenia increased in a dose dependent manner, largest risk for those subjects reporting use of cannabis > 50 times - This association is not explained by use of other psychoactive drugs or personality traits Strengths - Control for confounders, including other drugs - Attempt to quantify cannabis use Limitations - Included only Swedish males - Difficult to accurately measure personality traits - Residual confounding is possible - Only have data regarding use of cannabis before conscription and no information for drug- use in follow- up period - Potential for under- reporting of drug use and not confirmed with toxicology screening - No information regarding if there are individuals with pre- existing vulnerability - Cases reported were restricted to persons requiring hospital admission Oliveira 9

10 Netherlands Mental Health Survey and Incidence Study by Van Os and Colleagues 27 Table 9: Cannabis use and psychosis: A longitudinal population- based study Objective - To determine if cannabis use increases the risk of psychosis independent of the use of other drugs, and if those with an established vulnerability to psychotic disorders are more susceptible to this risk- increasing effect Design - Part of the Netherlands Mental Health Survey and Incidence Study (NEMESIS), a prospective longitudinal population- based study Patients - 90 municipalities and addresses of private households were sampled randomly - Person who had the most recent birthday and was aged was asked to participate Exclusion - Persons living in institutions, including those residing in psychiatric hospitals Outcomes - Association between cannabis use and psychosis, and the interaction with vulnerability to psychosis Methods - Multistage, stratified, random sampling procedure - Contacted three times 1996 (baseline), 1997 (T1), and 1999 (T2) - Study sample was interviewed at home by telephone using the Composite International Diagnostic Interview (CIDI) which generates a DSM- III- R diagnosis - Only patients with a lifetime absence for all of the individual items in the CIDI psychosis section were included - Clinical re- interviews were conducted using questions from the Structured Clinical Interview for DSM- III- R (SCID) by an experienced clinician for all subjects who had evidence of significant psychosis at baseline and at T2 - Patients who met DSM- III- R diagnosis of psychosis at baseline but not needing treatment were referred to as patients with established vulnerability to psychosis - At T2: - Three Brief Psychiatric Rating Scale (BPRS) items (unusual thought content, hallucinations, and conceptual disorganization) were scored by the clinician - Scored ranged from 1 (absent) to 7 (very severe) - Ratings of 2-3 indicate nonpathologic intensities and 4-7 indicate pathologic intensities of symptoms - Unusual thought content and hallucinations were used in analysis - Any rating of more than 1 for either of these two items was classified as BPRS any psychosis - Any rating of 4 or more on either of these items was referred to as BPRS pathology- level psychosis - Assessment for need of treatment for psychosis was determined at T2 by a consensus reached by four clinicians using the Camberwell Assessment of Needs (CAN) - Substance Use: - Section in the CIDI assessed use of a variety of substances: Cannabis, psychostimulants, cocaine, phencyclidine, and psychedelics - Exposure was classified as any use, and frequency of use over three assessment periods was quantified using a 1-5 scale - Cumulative exposure was the overall longitudinal exposure defined as the sum of the five- level frequency ratings at baseline, T1, and T2 Statistical analyses - Adjusted OR was computed by using logistic regression - All analyses were a priori adjusted for age, sex, ethnic group, level of education, unemployment, and single marital status - Controlled for two previous risk factors: Urbanicity and experience with discrimination Oliveira 10

11 Table 9: Cannabis use and psychosis: A longitudinal population- based study Results - In the 4,045 subjects who, at baseline, had a rating of lifetime absence for all individual items, 7 subjects (0.17%) at T2 had a probable or definite need for care related to psychotic symptoms - The number of subjects at T2 with BPRS any psychosis was 38 (0.94%) - Subjects with psychosis outcome at T2 had higher levels of cannabis use at baseline - - Baseline cannabis use predicted the presence at follow- up of any level of psychotic symptoms Cannabis baseline and cumulative frequency were associated with a high risk of psychosis outcome at T2 Table 10: Patterns of cannabis use and psychosis outcome Cannabis exposure BPRS any psychosis n=38 T2 BPRS pathology- level psychosis n=10 Any use at baseline Any use at T1 Any use at T2 Linear trend Needs- based diagnosis of psychotic disorder n=7 Adj. OR 95% CI Adj. OR 95% CI Adj. OR 95% CI The effect of cannabis use was much stronger in those with a baseline diagnosis of psychotic disorder - Risk difference 54.7% vs. 2.2% for those without psychotic disorder, p for interaction = Authors conclusions - Cannabis use increases the risk of both the incidence of psychosis in psychosis- free persons and poor prognosis for those with an established vulnerability to psychotic disorders Strengths - Drug use was documented in the context of a structured diagnostic interview at baseline and over the follow- up period - Not restricted to cases of psychosis requiring hospitalization - Clarify the temporal relation between cannabis exposure and increased risk of psychosis Limitations - Vague psychotic disorder diagnosis - Potential for under- reporting of drug use as it was self- reported data and not confirmed with toxicology screening - Some cases of psychosis between baseline and T1 may have been missed - Definition of hereditability and need for treatment Oliveira 11

12 Dunedin Multidisciplinary Health and Development Study by Caspi and Colleagues 28 Table 11: Moderation of the effect of adolescent- onset cannabis use on adult psychosis by a functional polymorphism in the catechol- O- methyltransferase gene: Longitudinal evidence of a gene x environment interaction Objective - To determine why cannabis use is associated with the emergence of psychosis in a minority of users, but not in others Design - Longitudinal cohort study Patients - Members of the Dunedin Multidisciplinary Health and Development study - Birth cohort of 1,037 children (52% male children) was established at age 3 when investigators enrolled 91% of consecutive births between April 1972 and March 1973 in Dunedin, New Zealand Exclusion - Maori ethnicity Hypothesis - Carriers of the Val allele of COMT gene would be at greatest risk for the potential long- term effects of cannabis, testing a gene x environment hypothesis Methods - Follow- ups have been carried out at ages 3, 5, 7, 9, 13, 15, 18, 21, and most recently at age 26 when 96% of the living cohort was assessed - At age 26, DNA was obtained from 953 study members to determine COMT genotype - Psychosis outcomes were assessed at age 26 using a standardized psychiatric interview - Established whether study members met diagnostic criteria for schizophreniform disorder during the year before the age- 26 assessment according to criteria from the DSM- IV - Computed a continuous scale of psychotic symptoms by summing study members report about hallucinations and delusions - Collected informant reports about symptoms related to psychosis to document that findings from this study were not based solely on self- reports - Participants were asked at ages 13 and 15 if they had used cannabis in the past year, and at age 18, they were asked about the frequency with which they used cannabis in the past year - Participants were also asked about the use of amphetamines and hallucinogens within the past year at each time point Statistical analyses - Moderated regression framework to estimate the influence of adolescent cannabis use, the COMT genotype, and their interaction on adult psychosis outcomes Results individuals were analyzed - Individuals not assessed were deceased (2%), lacked prospective data on cannabis use (7%), lacked assessment of psychosis outcomes (4%), did not give DNA (3%), or were not genotyped (7%) - Genotyping results: - Homozygous for the low- COMT- activity allele (Met/Met, 25% of sample, 52% male) - Homozygous for the high- COMT- activity allele (Val/Val; 25% of sample, 49% male) - - Heterozygotes, intermediate activity (Val/Met; 50% of sample, 52% male) Of the total sample, 26% of study members were classified as adolescent- onset cannabis users if they had used cannabis before age 15 or if they were at least monthly cannabis users by age 18 - No gender difference in adolescent- onset cannabis use - Of study members with the Met/Met, Val/Met, and Val/Val genotype, 24%, 23%, and 27%, respectively, were adolescent- onset cannabis users - The three COMT genotypes did not differ on exposure to cannabis in adolescence nor on cannabis dependence Oliveira 12

13 Table 11: Moderation of the effect of adolescent- onset cannabis use on adult psychosis by a functional polymorphism in the catechol- O- methyltransferase gene: Longitudinal evidence of a gene x environment interaction, continued Results, continued - No gender difference in adolescent- onset cannabis use - Of study members with the Met/Met, Val/Met, and Val/Val genotype, 24%, 23%, and 27%, respectively, were adolescent- onset cannabis users - The three COMT genotypes did not differ on exposure to cannabis in adolescence nor on cannabis dependence - Carriers of the COMT valine allele were most likely to exhibit psychotic symptoms and to develop schizophreniform disorder if they used cannabis Table 12: Schizophreniform disorder in adulthood for adolescent cannabis use x genotype Genotype OR (95% CI) Val/Val 10.9 ( ) Val/Met 2.5 ( ) Met/Met 1.1 ( ) - Adult onset cannabis users were not at increased risk of psychosis, measured as schizophreniform (p=0.99), self- reported psychotic symptoms (p=0.32), hallucinatory experiences (p=0.93), delusional beliefs (p=0.3), or informant reports of psychotic symptoms (p=0.66) - No significant interactions between adult- onset cannabis use and COMT in predicting psychosis outcomes Authors conclusions - Findings provide evidence of a gene x environment interaction and suggests that a role of some susceptibility genes influences vulnerability to environmental pathogens - COMT Val and Met polymorphism moderates the link between psychosis and adolescent- onset cannabis use - Alternative explanations must not be ruled out and it is possible that pre- existing early behavior or cognitive problems lead psychosis- prone carriers of the Val allele to take up cannabis use as teenagers Strengths - Established evidence that a functional polymorphism in the COMT gene interacted with adolescent- onset cannabis use may predict emergence of adult psychosis - Suggests that adolescence could be a sensitive period of neurobiological vulnerability to cannabis for some young people - Provides information that may help better understand a population that could be at risk of developing psychosis related to cannabis use Limitations - Focus on the broader phenotype of schizophrenia- spectrum psychosis rather than on clinic- registered schizophrenia cases - Only Caucasians were genotyped - Variable indexing adolescent cannabis use was not ideal - Study members were interviewed about cannabis use at ages 13, 15 and 18 years, but frequency data were collected only at age 18 years - Statistical controls are imperfect Oliveira 13

14 Systematic Review and Meta- analysis by Minozzi and Colleagues 29 I. Minozzi and Colleagues: Systematic review and meta- analyses on cannabis and psychosis 29 Table 13: Quality of meta- analyses presented in Minozzi and Colleagues 26 Item Arseneault et al. Henquet et al. Semple et al. Moore et al Search methods described Search comprehensive Inclusion criteria reported Selection bias avoided Criteria used appropriate Methods to combine findings reported Findings appropriately combined Conclusions supported by the data Adjusted OR: 2.1 (95% CI ) Crude OR: 2.93 (95% CI ) Table 14: Results of meta- analyses presented in Minozzi and colleagues 29 Author Results # of Studies Included Arseneault et al Adjusted OR: 2.34 (95% CI ) - Longitudinal studies 5 studies, n = 101,497 - Ever use and dependence considered together - The same cohort from the Swedish conscript s study was included twice Henquet et al. 7 studies, n = 112, Cross- sectional and longitudinal studies - Ever use and dependence considered together Semple et al. 7 studies, n = 51, Cross- sectional and longitudinal studies - Ever use and dependence considered together Moore et al Adjusted OR: Ever use OR 1.41 (95% CI ), heavy users OR 2.09 (95% CI ) 7 studies, n = not reported - Longitudinal studies a. Demonstrate a consistent association between cannabis use and psychotic symptoms, though it is not possible to draw firm conclusions about a causal relationship b. Limited by methodological quality c. Authors concluded that there was insufficient knowledge to determine the level of risk associated with cannabis use in relation to psychotic symptoms Oliveira 14

15 Systematic Review by McLaren and Colleagues 34 Table 15: Systematic review by McLaren and colleagues Purpose Included studies Conclusions Limitations Review the methodological strengths and limitations of major cohort studies which have looked at the link between cannabis and psychosis - Prospective studies of general population cohorts - 10 key studies from 7 general populations were identified - 5 studies reviewed symptoms, 5 reviewed psychotic disorders - Support causal association between cannabis and psychosis - Cannot answer whether cannabis use can cause serious psychotic disorders that otherwise would not have occurred - Pre- existing vulnerability to psychosis emerged as an important factor that influences the link between cannabis use and psychosis - Measurement of psychosis differs between studies - Control of potential confounders may have been incomplete - No measurement of drug use during the follow- up period Table 16: Cohort studies on cannabis use and psychotic disorders 31 Sample Cannabis use measure Outcome measure Cases/cannabis Cases/no cannabis Controls Andreasson et al Zammit et al van Os et al Arseneault et al Caspi et al ,570 Swedish 50,053 Swedish male conscripts male conscripts aged 18 aged 18 More than 10 times by age 18 Hospital admission for schizophrenia 15 years later at age 33 (records) 49/4, /41,280 Psychiatric diagnosis at age 18, social and family background, school adjustment, tobacco, alcohol and solvent use More than 50 times by age 18 Hospital admission for schizophrenia 27 years later at age 45 (records) 73/5, /36,429 Psychiatric diagnosis at age 18, IQ, social integration, disturbed behavior, tobacco use, place of upbringing, other drug use 4104 Dutch males and females from population sample, aged Used cannabis at baseline Need for treatment (judged by clinicians) 4/312 3/3,652 Age, gender, ethnic group, marital status, education, urban dwelling, discrimination, other drug use. Those with psychotic symptoms at baseline excluded 759 New Zealander males and females from Dunedin birth cohort Used cannabis at age 15, continued at age 18 DSM- IV diagnosis of schizophreniform disorder at age 26 3/29 22/730 Age, gender, ethnic group, marital status, education, urban dwelling, discrimination, other drug use 803 New Zealander males and females from Dunedin birth cohort Used cannabis at age 15, or used regularly at age 18 DSM- IV diagnosis of schizophreniform disorder at age 26 14/193 15/610 Use of other drugs, childhood psychotic symptoms, IQ, conduct disorder Oliveira 15

16 Table 16: Cohort studies on cannabis use and psychotic disorders, continued 31 Adjusted OR (95% CI) Andreasson et al Zammit et al van Os et al Arseneault et al Caspi et al No significant 3.1 ( ) 10.5 ( ) No significant 10.9 ( ) effect after effect with genetic adjustment vulnerability, no association for those without such vulnerability Summary and Conclusions I. Effects of cannabis and medical cannabinoids on the endocannabinoid system a. Cannabinoid receptors are present throughout the brain b. Stimulation of these receptors by cannabis or medical cannabinoids can have numerous physiologic effects including effects on motor tone, mood, and cognition c. Cannabis is used recreationally for its THC content which produces the psychoactive properties users seek d. Medical marijuana has a number of therapeutic benefits that continue to be explored e. Legalization for medical use of marijuana continues to grow II. III. IV. Risks and adverse effects of cannabis a. Supraphysioligcal effects of endocannabinoids can cause disruption of neuronal signaling b. Cannabis may acutely cause anxiety, psychosis, and impairments in operating a vehicle c. Chronic effects may include dependence, chronic bronchitis, and cognitive deficits Risk factors for the development of psychosis a. Use of cannabis an adolescent while cerebral reorganization is occurring b. Amount and duration of cannabis consumption c. Genetic predisposition by COMT polymorphisms d. Environmental factors Literature- based conclusion a. Appears to be a correlation between cannabis use and the development of chronic psychotic disorders b. Cannot state that cannabis causes the development of chronic psychotic disorders c. Studies vary in methodological design and quality, making comparisons and conclusions difficult to draw d. For most cannabis users, the risk for the development of chronic psychotic disorders appears to be low e. Appears to a small at- risk population i. Early age of cannabis use (before 18 years of age) ii. Frequent use iii. Genetic vulnerability may be implicated, but replication of the results by Caspi and colleagues is necessary 36 Oliveira 16

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19 Appendices Appendix I: Synthetic Cannabinoids 10,37 Table 17: Synthetic cannabinoids approved in the U.S. Brand Name Generic Name Schedule Classification Dosage Form Active Ingredient Marinol Dronabinol III Capsule Synthetic 9 - THC Nabilone Cesamet II Capsule Synthetic 9 - THC Indications - Anorexia associated with weight loss in patients with AIDS - Prophylaxis of chemotherapy induced nausea and vomiting - Refractory chemotherapy- induced nausea and vomiting Table 18: Drug- drug interactions with dronabinol and nabilone 10 Concomitant Drug Clinical Effect Amphetamine, cocaine, sympathomimetic agent Additive hypertension, tachycardia, cardiotoxicity Atropine, scopolamine, antihistamines, other Additive or super- additive tachycardia, drowsiness anticholinergic agent Amitriptyline, amoxapine, desipramine, other Additive tachycardia, hypertension, drowsiness tricyclic antidepressants Barbiturates, benzodiazepines, ethanol, lithium Additive drowsiness and CNS depression opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants Disulfiram Reversible hypomanic episode in a 28 year old man; confirmed by dechallenge and rechallenge Fluoxetine 21 year old female with depression and bulimia receiving 20 mg/day x 4 weeks became hypomanic after smoking marijuana; resolved after 4 days Antipyrine, barbiturates Decreased clearance of these agents, presumable via competitive inhibition of metabolism Theophylline Increased theophylline metabolism reports with smoking of marijuana Appendix II: Medical marijuana states Table 19: States with enacted laws to allow marijuana use for medical purposes 5 State Year Passed Possession Limit Alaska oz usable; 6 plants (3 mature, 3 immature) Arizona oz usable; 0 12 plants California oz usable; 6 mature or 12 immature plants Colorado oz usable; 6 plants (3 mature, 3 immature) Connecticut mo supply (exact amount to be determined) Delaware oz usable District of Columbia oz dried; limits on other forms to be determined Hawaii oz usable; 7 plants (3 mature, 4 immature) Oliveira 19

20 Table 19: States with enacted laws to allow marijuana use for medical purposes, continued 5 State Year Passed Possession Limit Illinois oz of usable cannabis during a period of 14 days Maine oz usable; 6 plants Massachusetts day supply for personal medical use Michigan oz usable; 12 plants Montana oz usable; 4 plants (mature), 12 seedlings Nevada oz usable; 7 plants (3 mature, 4 immature) New Hampshire oz of usable cannabis during a 10- day period New Jersey oz usable New Mexico oz usable; 16 plants (4 mature, 12 immature) Oregon oz usable; 24 plants (6 mature, 18 immature) Rhode Island oz usable; 12 plants Vermont oz usable; 9 plants (2 mature, 7 immature) Washington oz usable; 15 plants Appendix III: Systematic review of medical cannabinoids Table 20: Serious adverse effects of medical cannabinoids 20 Adverse Effects Cannabinoid exposure, # (%) Control, # (%) Respiratory, thoracic, and mediastinal disorders Dyspnea Pneumonia Pleural effusion Lower respiratory tract infection Pulmonary embolism 27 (16.5%) (3 deaths) (11.7%) 3 3 (1 death) Gastrointestinal disorders Vomiting Diarrhea Gastroenteritis Abdominal pain Constipation Duodenal ulcer Nervous system disorder Relapse of multiple sclerosis Convulsion Dizziness Multiple sclerosis 27 (16.5%) (15.2%) 21 2 (1 death) (6.7%) (30.0%) Urinary tract infections 15 (9.1%) 8 (13.3%) Psychiatric disorders 11 (6.7%) 1 (1.7%) Neoplasm, benign and malignant 14 (8.5%) 2 (3.3%) Death 10 (6.1%) 1 (1.7%) Oliveira 20