Cannabis is considered by the Food and Drug Administration, along with heroin and peyote, as a schedule I drug. It has no accepted medical purpose and has a high potential for abuse. Commonly prescribed drugs like opiates and stimulants are schedule II drugs, meaning they have a high risk of abuse but are medically useful. Benzodiazepines are schedule IV substances, meaning they have a low potential for abuse and dependence. Despite federal regulations in the latter half of the 20th century, marijuana is still the most commonly abused drug in the United States. The most common users are teenagers and adolescents, and usage tends to decline as these groups age into adulthood due to careers, marriage, cohabitation, and parenthood.
Nevertheless, cannabis use has increased with the state-directed legislature turning the tide against federal regulation. State legalization of marijuana has increased cultivation demand, selective breeding for more potent strains, and competition in the marijuana dispensary industry. Expanding use and legislation for the legalization of marijuana are propagated by potential health benefits and absence of health concerns that are not well substantiated.
Cannabis abuse is a term describing the continued use of cannabis despite impairment in psychological, physical, or social functioning. It is an outdated medical definition formerly used in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) which divided substance use from substance dependence. The Diagnostic and Statistical Manual of Mental Disorders (DSM–5) has revised the terms of cannabis use disorder defined by nine pathological patterns classified under impaired control, social impairment, risky behavior or physiological adaptation. This activity will focus on cannabis abuse and related components – states of intoxication and withdrawal, and cannabis use disorder.
Cannabis use varies based on demographics. Research shows college students, and young adults most commonly use cannabis to socially conform (42%), experiment (29%), and for enjoyment (24%). Twelve percent primarily use the agent to manage stress or relax  consistent with other studies associating its use for depression, anxiety, social anxiety, and post-traumatic stress disorder. 
During pregnancy, mothers who reported using marijuana say they did so primarily to manage depression, anxiety, and stress (63%); pain (60%); nausea or vomiting (48%), and for recreational purposes (39%).
Biologically speaking, impaired inhibition can predispose individuals to substance use disorders. However, healthcare professionals are unsure if this is true for marijuana.
Nearly four percent of the global population was using cannabis in 2015. Amongst teenagers, eight percent in the US and 16% in Europe report use. Nine percent of all users experience addiction of which nearly a fifth began to use in adolescence. There is limited evidence for cannabis use among the elderly. However, its consumption may be considered to be increasing as legal permission for its medical use may justify its use among former non-users. In the medical profession, first-year psychiatry residents are more likely to have Cannabis Use Disorder and seek out experiences to be disinhibited; these individuals also have a history of sedative use and anxiety. 
During pregnancy, four percent of mothers admit to using drugs, most commonly with cannabis. A retrospective cohort study of more than 12 million pregnant women revealed nearly a tripling of cannabis abuse or dependence from 1999 through 2003, and a significant association for perinatal complications. Thirty-five percent of mothers who have used marijuana have done so during pregnancy, and 18% used it while breastfeeding.
As consumption increases among adults, so does the unintended consequence of exposure to children. Between 2005 and 2009, 985 unintentional exposures to children (median age of 1.7 years) were reported. States legalizing marijuana have had a 20-fold increase in calls to poison centers and admissions to critical care units for its exposure.
Overall, the trend for using cannabis is increasing over time for most, if not all demographics.
Researchers know that prolonged and heavy cannabis use can alter brain circuitry. However, the specific pathophysiological mechanisms are yet unclear. In terms of addiction, tetrahydrocannabinol (THC) is the primary molecule responsible for the reinforcing properties of marijuana.Interestingly, despite the striatal dopamine system typically being involved with substances of abuse such as alcohol and opioids, meta-analysis reveals insufficient evidence at this time to support such a conclusion for cannabis. And also that dopamine receptors may not be involved.
At a symptomatic level, heavy use modifies conscious experience through alteration of the brain’s network for self-awareness. By reducing anxiety and impairing memory, it also affects motivation and personal experience. At a molecular level, the story is more complex.
The botanical provides over 500 different active chemical compounds, which interact with numerous molecular targets, thereby modulating transmission of endocannabinoids, gamma-aminobutyric acid, glutamate, and serotonin. Psychoactive effects are primarily derived from tetrahydrocannabinol (THC) which binds cannabinoid receptors (CB)1 and CB2. CB1 receptors are located throughout the central nervous system (CNS), lungs, liver, and kidneys. CB2 receptors predominate within the immune hematopoietic cells. Binding these receptors modulates G-protein-coupled inhibition of cyclic adenosine monophosphate, thereby influencing pain, mood, appetite, nausea, and sexual activity. CNS effects also appear to be mediated by glial cells, particularly microglia and astrocytes. In vitro studies show microglial to produce greater endocannabinoids than neurons, and astrocytes may play a role in signaling by regulating endocannabinoid turnover.Thus an influence of the neuropil, not just the neurons, may better describe the CNS changes mediated by cannabis.
Unlike synthetic substances and alcohol, cannabis is a more complex drug. Consumption or inhalation of the botanical exposes the user to hundreds of compounds including cannabinoids (e.g., THC and cannabidiol) and non-cannabinoids (e.g., terpenes and flavonoids), many of which are bioactive compounds . The sheer complexity of the plant compared to isolated pharmaceutical derivatives (e.g., dronabinol and cannabidiol) makes a comparison between the two difficult. It is important to establish that what is currently known about marijuana is actually derived from studies of a single active constituent, tetrahydrocannabinol, and less so from the plant itself. This problem is primarily due to its Federal status as a schedule I substance and thus prohibition from federal research funds for its study.
Absorption, distribution, metabolism:
THC, the principal psychoactive and addictive component, is most commonly smoked. It is rapidly absorbed by the lungs and distributed systemically via perfusion. The rapid influence on the brain contributes to its pleasure and abuse potential . Ingestion typically follows a more gradual course and delay to its peak blood concentration. It is extensively bound to lipoproteins with only 3% in the free state. Metabolism through the liver can produce over 80 metabolites of delta-9-THC with the most common pathway involving allylic hydroxylation at the 11-position followed by oxidation to a carboxy derivative . Conjugation occurs with some metabolites, but it is not a major step . Bioavailability varies greatly amongst and between individuals pending on their smoking topography such as number, duration, and spacing of puffs; hold time; and inhalation volume . It remains in the body for extended periods due to its lipophilic properties, allowing it to accumulate and slowly release from adipose tissue, along with its further processing via the enterohepatic circulation, which produces active metabolites as well . Chronic daily smokers can produce detectable levels of THC and its metabolites one month after its last intake . It is suggested that its lipophilic metabolites can form conjugates, allowing for greater stability, thereby prolonging its metabolism, and thus half-life, so that release from adipose tissue is the rate-limiting step of THC. This high lipophilicity explains why withdrawal is a slow onset.
It is worth noting that the pharmacokinetics of THC is further complicated with multiple factors such as its physical/chemical form, route of administration, genetics, and concurrent consumption of alcohol .
Upon evaluation, the patient history should investigate substance use, mental health, family history for substance use and mental health disorder, medical history, medications, use of substances amongst social circle (particularly in adolescents), and environmental stressors.
The mental status of the individual is a critical part of the exam and can point at the phase of cannabis use. Intoxication can include euphoria, anxiety, uncontrollable laughter, increased appetite, inattentiveness, forgetfulness, restlessness, tachycardia, conjunctival injection, and dry mouth. And less commonly may include delusions, hallucinations, and derealization. Prolonged continuous use or withdrawal typically causes depressed mood characterized by apathy, lack of motivation, irritability, loss of interest in typical activities, difficulty concentrating, and isolation. (Side note: Cognition can quickly be assessed by testing three-word recall, asking multi-step math problems, or recalling details from a brief fictional story as demonstrated on the St. Louis University Mental Status Exam.) This depressed mood can also include on the differential persistent depressive disorder and major depressive disorder. Substance use and a mood or anxiety disorder are not necessarily mutually exclusive and frequently co-occur. Even suicidality and homicidal tendency can be a result of dysregulated mood, a recent stressor, or substance use. Differentiation requires an understanding of the symptoms intensity and temporality; persistent symptoms during periods of sobriety can indicate a comorbid primary psychiatric disorder.
Classifying cannabis use in the US is dictated by the DSM-5. Generally, it can be understood as the acute and chronic effects. The acute phase includes intoxication and withdrawal states, along with secondary complications - delirium, psychosis, anxiety, and insomnia. Chronic regular use can be characterized by disordered behavior.
Pending on the setting (i.e., Emergency Department, office visit, or rehabilitation program), different effects of cannabis may be of focus. The diagnostic criteria of the varying effects of cannabis are listed below, as defined by the DSM-5.
It should be noted that evidence suggests that withdrawal only occurs in a subset of patients. Symptoms usually begin within the first 24 hours, peak by day 3, and can last for up to 2 weeks. Increased use and more recent use can predict the severity of withdrawal .
Cannabis intoxication delirium
This diagnosis relies on the definition of delirium and is appropriate when the following two symptoms predominate in someone who has taken cannabis:
Cannabis-induced psychotic disorder
Cannabis-induced anxiety disorder
Cannabis-induced sleep disorder
The chronic effects: Cannabis Use Disorder
Cannabis abuse and dependence were combined in the DSM-5 into a single entity capturing the behavioral disorder that can occur with chronic cannabis use and named Cannabis Use Disorder, it is defined as:
It has the following specifiers:
In early remission - After full criteria for cannabis use disorder were previously met, none of the criteria for cannabis use disorder has been met for at least three months but less than 12 months (with an exception provided for craving).
In sustained remission - After full criteria for cannabis use disorder were previously met, none of the criteria for cannabis use disorder has been met at any time during 12 months or longer (with an exception provided for craving).
Severity is graded as either Mild, Moderate, or Severe pending if 2-3, 4-5, or 6+ of the above criteria are present.
Laboratory testing of urine, blood, saliva, or hair can be useful to detect cannabis use, but results should be considered along with clinical rationale. Assays typically rely on detection of the most common active metabolite- delta 9 -tetrahydrocannibinolic acid. It has been studied thoroughly, and this abundant acid metabolite has become an established urinary marker of cannabis consumption in forensic, clinical, and environmental analyses . A positive result can indicate usage but not necessarily a substance use disorder or intoxication, and a negative result does not rule it out. It is possible to quantify tolerance by comparing the reported intake of cannabis to blood levels. Heavy or chronic cannabis smokers will take longer to clear THC compared to sporadic or one-time users.
Also, other tests to rule out additional conditions may be of benefit. These include head imaging, or laboratory testing of heavy metals, infection and immunological markers, electrolyte disturbances, or hormones.
The aim should be to improve the individual's overall function which is multiphasic and multifactorial. Supportive treatment may be provided during detoxification; enabling access to psychiatric services allows addressing underlying disorders; psychological counseling can modify behavior, develop healthier coping skills in the face of stressors, and enlighten them as to their temperament.
As cannabis strains become more potent and accessible, the risk will increase for frequency and severity of serious adverse reactions. For individuals with marked intoxication or withdrawal, or cannabis use disorder, the goal should be a cessation of the drug altogether. A gradual decrease as opposed to abrupt cessation is likely to decrease the discomfort of the withdrawal, and prevent relapse. Cannabis intoxication most often does not require medical management and will self-resolve. Supportive management such as a calm, non-stimulating environment helps patients. Symptomatic treatment can be considered for specific symptoms such as alpha-2-adrenergic agonists or beta-blockers for tachycardia, benzodiazepines for panic attacks, off-label use of first-generation antihistamines for anxiety and restlessness, and neuroleptics for psychosis. It is important to monitor psychological symptoms which may be features of the withdrawal or part of the patient’s primary psychiatric illness - which may not have been previously identified.
Pharmacologic detoxification is still under investigation. A systematic review indicates most studies are preliminary and cannot statistically support clinical rationale as they are small sizes, inconsistent, and have a risk of attrition bias .
There is no medication that is FDA approved to treat cannabis use disorder. Tetrahydrocannabinol does show some potential in treatment, but more information is needed to demonstrate the validity and inform on dose, duration, formulation, and adjunct therapies . Gabapentin and N-acetylcysteine are also used but have unclear benefits . Another component of cannabis, cannabidiol, holds promise by modulating the serotonergic, glutamatergic, and endocannabinoid systems .
Cannabis Intoxication, Cannabis Withdrawal, and Cannabis Use Disorder: the differential for these may include intoxication syndromes from other substances. These may include amphetamine or cocaine intoxication, withdrawal from benzodiazepines or hypnotics, atrial tachycardia, an anxiety disorder, and panic attacks. A thorough medical history, psychiatric history, substance use history, family psychiatric and medical history, medication review, toxicology screen, and blood alcohol level are needed. Endogenous psychiatric disorders such as Generalized Anxiety Disorder or Panic Disorder or a primary psychotic disorder such as the Schizophrenia Spectrum Disorder will typically demonstrate symptomology before and long after cessation of cannabis. Collateral sources, typically from family members, long-standing friends, or other providers, can be of help.
Side effects for short-term use of cannabis include impaired short-term memory, which can affect learning, impaired motor coordination as required for driving, and increased high-risk sexual behaviors . Also, judgment is impaired on tasks measuring the quality of decision-making and executive planning .
Children aged less than twelve are a separate concern. Their exposure is typically via unintentional consumption of edibles meaning the dosage of THC taken in is not considered. This has lead to increased presentations to the ED, often for central nervous system depression such as lethargy and somnolence, and rarely for respiratory insufficiency.
The likelihood of continuing cannabis abuse can vary from person to person. Impulsive individuals are more likely to experiment with substances, including cannabis . Using cannabis for experimentation is associated with less use and fewer problems . Factors such as enjoyment, habit, activity enhancement, and altered perception or perspectives are associated with heavier use and more problems . Those more avoidant of punishment, boredom, or unpleasant events are less likely to discontinue use and are at risk for abuse . Also, those experiencing withdrawal or who are avoidant of stressful situations can perpetuate usage .
Heavy or chronic users are more likely to report a decreased sense of life satisfaction and achievement in comparison to the general population . Additionally, effects can impair neuropsychiatric, physical, and social domains. These include addiction, altered brain development, cognitive impairment, poor educational outcome, increased likelihood of dropping out of school, and lower IQ among those who were frequent users during adolescence . In addition to acute users, also chronic users demonstrate cognitive and psychomotor driving impairments . Females may be more likely to demonstrate deficits in attentional inhibition (i.e., ignoring irrelevant features in a situation). Those with the tendency for chronic psychotic disorders are at increased risk of "unmasking the illness" with prolonged use. THC levels measured in hair amongst chronic heavy marijuana-only users were found to be predictive of delusions, hallucinations, and organic brain dysfunction . Discontinuation of cannabis did not lead to a resolution of these symptoms even after three months, indicating organic neurological dysfunction .
Also at risk is the respiratory system as the byproducts of combustion and heated smoke can result in chronic bronchitis with inhaled use . Chronic use may also affect fertility in both sexes may .
The risk is not only restricted to the user. Extensive evidence of perinatal cannabis exposure reveals the future child to be at risk for a broad array of cognitive impairments including intelligence, attention, activity, restraint, visual-motor coordination, processing speed, visual memory, and interhemispheric transfer of information as late as adolescence . There is evidence, albeit inconclusive, for a potential risk for preterm delivery , low-birth-weight , and stillbirth; wherever the truth may lie, it should not be considered a harmless substance.
Consultation for cannabis use disorder includes involving Behavioral Health for substance use disorder and psychopathology management. Neurology or Pain Management for chronic pain interventions and sleep professionals for insomnia if needed. All specialties including emergency providers should also include the primary care provider as they are best suited for long term monitoring and most accessible for early interventions.
It is important for providers to educate patients, especially those under the age of 21 who are a higher risk for long term, potentially irreversible, cognitive impairments. With the increased access to misinformation about cannabis being safe with no risks, it is important to bring evidence to the discussion. Pregnant patients should be counseled, if they admit to usage or not, on the potential impact of cannabis on the fetus. Adults should be informed that if they desire to use, cannabis and its paraphernalia should be kept in a locked and hidden location to prevent pediatric intoxication. Despite the legalization of medical marijuana in many states, employers can still enforce their company policies and terminate workers who present to work intoxicated or test positive for cannabis.
It is important for providers across all specialties to familiarize themselves with the effects of cannabis use. It is increasingly becoming ubiquitous in our society. The evidence for supporting the use of marijuana for specific conditions is limited and most often derived from pharmaceutical preparations of isolated THC. Researchers struggle to gain funding for these studies given that it is a schedule I controlled substance with the Food and Drug Administration. Providers should be aware that providing permission to access medical marijuana for a given symptom does not restrict that patient to its limited usage. The dispensary’s employees can influence the strain, dosing, formulation, and its indications used on the basis of an opinion. Also, it should be stressed that continuous and/or heavy use of cannabis can increase the risk of intoxication or withdrawal requiring medical attention, and long term complications which may be irreversible. Despite its paler comparison to an opiate, benzodiazepine, and alcohol use, it is still a substance with potential for ill health effects and marked impairment on social and occupational functioning. With the expansion of evidence-based uses, it is important to separate the abuse of marijuana from use with a thorough history taking. Differences in state regulations governing medical indications for cannabis should be considered. And providers should not forget that Medical Marijuana is a not product of the tightly regulated and scientifically back pharmaceutical industry - it is a product produced by growing operations without similar oversight and indicated for conditions mostly not based on rigorous medical or scientific evidence required for products they prescribe, as opposed to a permitted use.
Deterring patients from substance use is often best supported by a team effort with the goal to relieve the underlying cause. A non-judgemental approach to understanding the reasons for use are best. Amongst children, cannabis use can indicate coping with home or school stressors. Counseling, particularly cognitive behavioral therapy and Multidimensional Family Therapy should be provided at school, home or an outpatient clinic to improve behavioral issues in both environments - Level 1b evidence. Assessment by psychiatry for mental health disorders is important. Among adults, a similar strategy may be utilized with counseling and psychiatry. There is a longitudinal relationship between reductions in cannabis use and improvements in anxiety, depression, sleep quality, but not the quality of life  - Level 3 evidence. Peer Network Counseling-txt (PNC-txt), a 4-week, automated text-delivered cannabis treatment that focuses on close peer relations was able to decrease usage and relationship problems -Level 1b evidence. Also, intensive outpatient programs for substance use disorders can be beneficial. For chronic pain, pain management or neurology can be involved. For insomnia, sleep studies are useful. Providers should know that a patient with a history of substance use disorder is more likely to misuse controlled substances, and tools for monitoring of controlled prescriptions should be utilized if available.
|||Bostwick JM, Blurred boundaries: the therapeutics and politics of medical marijuana. Mayo Clinic proceedings. 2012 Feb [PubMed PMID: 22305029]|
|||Chen K,Kandel DB, Predictors of cessation of marijuana use: an event history analysis. Drug and alcohol dependence. 1998 Apr 1 [PubMed PMID: 9649962]|
|||Duncan GJ,Wilkerson B,England P, Cleaning up their act: the effects of marriage and cohabitation on licit and illicit drug use. Demography. 2006 Nov [PubMed PMID: 17236542]|
|||Volkow ND,Baler RD,Compton WM,Weiss SR, Adverse health effects of marijuana use. The New England journal of medicine. 2014 Jun 5 [PubMed PMID: 24897085]|
|||Lee CM,Neighbors C,Woods BA, Marijuana motives: young adults' reasons for using marijuana. Addictive behaviors. 2007 Jul [PubMed PMID: 17097817]|
|||Moitra E,Christopher PP,Anderson BJ,Stein MD, Coping-motivated marijuana use correlates with DSM-5 cannabis use disorder and psychological distress among emerging adults. Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors. 2015 Sep [PubMed PMID: 25915689]|
|||Bonn-Miller MO,Vujanovic AA,Zvolensky MJ, Emotional dysregulation: association with coping-oriented marijuana use motives among current marijuana users. Substance use [PubMed PMID: 18752166]|
|||Buckner JD,Bonn-Miller MO,Zvolensky MJ,Schmidt NB, Marijuana use motives and social anxiety among marijuana-using young adults. Addictive behaviors. 2007 Oct [PubMed PMID: 17478056]|
|||Bonn-Miller MO,Vujanovic AA,Feldner MT,Bernstein A,Zvolensky MJ, Posttraumatic stress symptom severity predicts marijuana use coping motives among traumatic event-exposed marijuana users. Journal of traumatic stress. 2007 Aug [PubMed PMID: 17721963]|
|||Lipari RN,Hedden SL,Hughes A, Substance Use and Mental Health Estimates from the 2013 National Survey on Drug Use and Health: Overview of Findings null. 2013 [PubMed PMID: 27656739]|
|||Wang GS, Pediatric Concerns Due to Expanded Cannabis Use: Unintended Consequences of Legalization. Journal of medical toxicology : official journal of the American College of Medical Toxicology. 2017 Mar [PubMed PMID: 27139708]|
|||Peacock A,Leung J,Larney S,Colledge S,Hickman M,Rehm J,Giovino GA,West R,Hall W,Griffiths P,Ali R,Gowing L,Marsden J,Ferrari AJ,Grebely J,Farrell M,Degenhardt L, Global statistics on alcohol, tobacco and illicit drug use: 2017 status report. Addiction (Abingdon, England). 2018 Oct [PubMed PMID: 29749059]|
|||Fond G,Bourbon A,Micoulaud-Franchi JA,Auquier P,Boyer L,Lançon C, Psychiatry: A discipline at specific risk of mental health issues and addictive behavior? Results from the national BOURBON study. Journal of affective disorders. 2018 Oct 1 [PubMed PMID: 29936392]|
|||Petrangelo A,Czuzoj-Shulman N,Balayla J,Abenhaim HA, Cannabis Abuse or Dependence During Pregnancy: A Population-Based Cohort Study on 12 Million Births. Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC. 2018 Nov 14 [PubMed PMID: 30448107]|
|||Wang GS,Roosevelt G,Le Lait MC,Martinez EM,Bucher-Bartelson B,Bronstein AC,Heard K, Association of unintentional pediatric exposures with decriminalization of marijuana in the United States. Annals of emergency medicine. 2014 Jun [PubMed PMID: 24507243]|
|||Adams IB,Martin BR, Cannabis: pharmacology and toxicology in animals and humans. Addiction (Abingdon, England). 1996 Nov [PubMed PMID: 8972919]|
|||De Luca MA,Di Chiara G,Cadoni C,Lecca D,Orsolini L,Papanti D,Corkery J,Schifano F, Cannabis; Epidemiological, Neurobiological and Psychopathological Issues: An Update. CNS [PubMed PMID: 28412916]|
|||Russo EB,Marcu J, Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads. Advances in pharmacology (San Diego, Calif.). 2017 [PubMed PMID: 28826544]|
|||Kamp F,Proebstl L,Penzel N,Adorjan K,Ilankovic A,Pogarell O,Koller G,Soyka M,Falkai P,Koutsouleris N,Kambeitz J, Effects of sedative drug use on the dopamine system: a systematic review and meta-analysis of in vivo neuroimaging studies. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2018 Aug 27 [PubMed PMID: 30188512]|
|||Pujol J,Blanco-Hinojo L,Batalla A,López-Solà M,Harrison BJ,Soriano-Mas C,Crippa JA,Fagundo AB,Deus J,de la Torre R,Nogué S,Farré M,Torrens M,Martín-Santos R, Functional connectivity alterations in brain networks relevant to self-awareness in chronic cannabis users. Journal of psychiatric research. 2014 Apr [PubMed PMID: 24411594]|
|||Papaseit E,Pérez-Mañá C,Pérez-Acevedo AP,Hladun O,Torres-Moreno MC,Muga R,Torrens M,Farré M, Cannabinoids: from pot to lab. International journal of medical sciences. 2018 [PubMed PMID: 30275754]|
|||Walter L,Franklin A,Witting A,Wade C,Xie Y,Kunos G,Mackie K,Stella N, Nonpsychotropic cannabinoid receptors regulate microglial cell migration. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2003 Feb 15 [PubMed PMID: 12598628]|
|||Melis M,Frau R,Kalivas PW,Spencer S,Chioma V,Zamberletti E,Rubino T,Parolaro D, New vistas on cannabis use disorder. Neuropharmacology. 2017 Sep 15 [PubMed PMID: 28373077]|
|||Huestis MA,Henningfield JE,Cone EJ, Blood cannabinoids. I. Absorption of THC and formation of 11-OH-THC and THCCOOH during and after smoking marijuana. Journal of analytical toxicology. 1992 Sep-Oct [PubMed PMID: 1338215]|
|||Ohlsson A,Lindgren JE,Wahlen A,Agurell S,Hollister LE,Gillespie HK, Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clinical pharmacology and therapeutics. 1980 Sep [PubMed PMID: 6250760]|
|||Kelly P,Jones RT, Metabolism of tetrahydrocannabinol in frequent and infrequent marijuana users. Journal of analytical toxicology. 1992 Jul-Aug [PubMed PMID: 1323733]|
|||Dinis-Oliveira RJ, Metabolomics of Δ9-tetrahydrocannabinol: implications in toxicity. Drug metabolism reviews. 2016 [PubMed PMID: 26828228]|
|||Perez-Reyes M, Marijuana smoking: factors that influence the bioavailability of tetrahydrocannabinol. NIDA research monograph. 1990 [PubMed PMID: 2176276]|
|||Bergamaschi MM,Karschner EL,Goodwin RS,Scheidweiler KB,Hirvonen J,Queiroz RH,Huestis MA, Impact of prolonged cannabinoid excretion in chronic daily cannabis smokers' blood on per se drugged driving laws. Clinical chemistry. 2013 Mar [PubMed PMID: 23449702]|
|||Grotenhermen F, Pharmacokinetics and pharmacodynamics of cannabinoids. Clinical pharmacokinetics. 2003 [PubMed PMID: 12648025]|
|||Johansson E,Halldin MM, Urinary excretion half-life of delta 1-tetrahydrocannabinol-7-oic acid in heavy marijuana users after smoking. Journal of analytical toxicology. 1989 Jul-Aug [PubMed PMID: 2550702]|
|||Johansson E,Norén K,Sjövall J,Halldin MM, Determination of delta 1-tetrahydrocannabinol in human fat biopsies from marihuana users by gas chromatography-mass spectrometry. Biomedical chromatography : BMC. 1989 Jan [PubMed PMID: 2539872]|
|||Bonnet U,Preuss UW, The cannabis withdrawal syndrome: current insights. Substance abuse and rehabilitation. 2017 [PubMed PMID: 28490916]|
|||Preuss UW,Watzke AB,Zimmermann J,Wong JW,Schmidt CO, Cannabis withdrawal severity and short-term course among cannabis-dependent adolescent and young adult inpatients. Drug and alcohol dependence. 2010 Jan 15 [PubMed PMID: 19783382]|
|||Budney AJ,Hughes JR,Moore BA,Vandrey R, Review of the validity and significance of cannabis withdrawal syndrome. The American journal of psychiatry. 2004 Nov [PubMed PMID: 15514394]|
|||Marshall K,Gowing L,Ali R,Le Foll B, Pharmacotherapies for cannabis dependence. The Cochrane database of systematic reviews. 2014 [PubMed PMID: 25515775]|
|||Mandolini GM,Lazzaretti M,Pigoni A,Oldani L,Delvecchio G,Brambilla P, Pharmacological properties of cannabidiol in the treatment of psychiatric disorders: a critical overview. Epidemiology and psychiatric sciences. 2018 Aug [PubMed PMID: 29789034]|
|||Grant JE,Chamberlain SR,Schreiber L,Odlaug BL, Neuropsychological deficits associated with cannabis use in young adults. Drug and alcohol dependence. 2012 Feb 1 [PubMed PMID: 21920674]|
|||Wang GS,Roosevelt G,Heard K, Pediatric marijuana exposures in a medical marijuana state. JAMA pediatrics. 2013 Jul [PubMed PMID: 23712626]|
|||Prince van Leeuwen A,Creemers HE,Verhulst FC,Ormel J,Huizink AC, Are adolescents gambling with cannabis use? A longitudinal study of impulsivity measures and adolescent substance use: the TRAILS study. Journal of studies on alcohol and drugs. 2011 Jan [PubMed PMID: 21138713]|
|||Bondallaz P,Favrat B,Chtioui H,Fornari E,Maeder P,Giroud C, Cannabis and its effects on driving skills. Forensic science international. 2016 Nov [PubMed PMID: 27701009]|
|||Bosker WM,Kuypers KP,Theunissen EL,Surinx A,Blankespoor RJ,Skopp G,Jeffery WK,Walls HC,van Leeuwen CJ,Ramaekers JG, Medicinal Δ(9) -tetrahydrocannabinol (dronabinol) impairs on-the-road driving performance of occasional and heavy cannabis users but is not detected in Standard Field Sobriety Tests. Addiction (Abingdon, England). 2012 Oct [PubMed PMID: 22553980]|
|||Bosker WM,Theunissen EL,Conen S,Kuypers KP,Jeffery WK,Walls HC,Kauert GF,Toennes SW,Moeller MR,Ramaekers JG, A placebo-controlled study to assess Standardized Field Sobriety Tests performance during alcohol and cannabis intoxication in heavy cannabis users and accuracy of point of collection testing devices for detecting THC in oral fluid. Psychopharmacology. 2012 Oct [PubMed PMID: 22581391]|
|||Broyd SJ,van Hell HH,Beale C,Yücel M,Solowij N, Acute and Chronic Effects of Cannabinoids on Human Cognition-A Systematic Review. Biological psychiatry. 2016 Apr 1 [PubMed PMID: 26858214]|
|||Albertella L,Le Pelley ME,Copeland J, Frequent cannabis use is associated with reduced negative priming among females. Experimental and clinical psychopharmacology. 2016 Oct [PubMed PMID: 27337025]|
|||Nestoros JN,Vakonaki E,Tzatzarakis MN,Alegakis A,Skondras MD,Tsatsakis AM, Long lasting effects of chronic heavy cannabis abuse. The American journal on addictions. 2017 Jun [PubMed PMID: 28314070]|
|||Bari M,Battista N,Pirazzi V,Maccarrone M, The manifold actions of endocannabinoids on female and male reproductive events. Frontiers in bioscience (Landmark edition). 2011 Jan 1 [PubMed PMID: 21196184]|
|||Day NL,Richardson GA,Goldschmidt L,Robles N,Taylor PM,Stoffer DS,Cornelius MD,Geva D, Effect of prenatal marijuana exposure on the cognitive development of offspring at age three. Neurotoxicology and teratology. 1994 Mar-Apr [PubMed PMID: 8052191]|
|||Goldschmidt L,Day NL,Richardson GA, Effects of prenatal marijuana exposure on child behavior problems at age 10. Neurotoxicology and teratology. 2000 May-Jun [PubMed PMID: 10840176]|
|||Willford JA,Chandler LS,Goldschmidt L,Day NL, Effects of prenatal tobacco, alcohol and marijuana exposure on processing speed, visual-motor coordination, and interhemispheric transfer. Neurotoxicology and teratology. 2010 Nov-Dec [PubMed PMID: 20600845]|
|||Fried PA,Watkinson B,Gray R, Differential effects on cognitive functioning in 13- to 16-year-olds prenatally exposed to cigarettes and marihuana. Neurotoxicology and teratology. 2003 Jul-Aug [PubMed PMID: 12798960]|
|||Hayatbakhsh MR,Flenady VJ,Gibbons KS,Kingsbury AM,Hurrion E,Mamun AA,Najman JM, Birth outcomes associated with cannabis use before and during pregnancy. Pediatric research. 2012 Feb [PubMed PMID: 22258135]|
|||Saurel-Cubizolles MJ,Prunet C,Blondel B, Cannabis use during pregnancy in France in 2010. BJOG : an international journal of obstetrics and gynaecology. 2014 Jul [PubMed PMID: 24621183]|
|||Prunet C,Delnord M,Saurel-Cubizolles MJ,Goffinet F,Blondel B, Risk factors of preterm birth in France in 2010 and changes since 1995: Results from the French National Perinatal Surveys. Journal of gynecology obstetrics and human reproduction. 2017 Jan [PubMed PMID: 28403953]|
|||van Gelder MM,Reefhuis J,Caton AR,Werler MM,Druschel CM,Roeleveld N, Characteristics of pregnant illicit drug users and associations between cannabis use and perinatal outcome in a population-based study. Drug and alcohol dependence. 2010 Jun 1 [PubMed PMID: 20171023]|
|||Crume TL,Juhl AL,Brooks-Russell A,Hall KE,Wymore E,Borgelt LM, Cannabis Use During the Perinatal Period in a State With Legalized Recreational and Medical Marijuana: The Association Between Maternal Characteristics, Breastfeeding Patterns, and Neonatal Outcomes. The Journal of pediatrics. 2018 Jun [PubMed PMID: 29605394]|
|||Varner MW,Silver RM,Rowland Hogue CJ,Willinger M,Parker CB,Thorsten VR,Goldenberg RL,Saade GR,Dudley DJ,Coustan D,Stoll B,Bukowski R,Koch MA,Conway D,Pinar H,Reddy UM, Association between stillbirth and illicit drug use and smoking during pregnancy. Obstetrics and gynecology. 2014 Jan [PubMed PMID: 24463671]|
|||van der Pol TM,Hendriks V,Rigter H,Cohn MD,Doreleijers TAH,van Domburgh L,Vermeiren RRJM, Multidimensional family therapy in adolescents with a cannabis use disorder: long-term effects on delinquency in a randomized controlled trial. Child and adolescent psychiatry and mental health. 2018 [PubMed PMID: 30140308]|
|||Hser YI,Mooney LJ,Huang D,Zhu Y,Tomko RL,McClure E,Chou CP,Gray KM, Reductions in cannabis use are associated with improvements in anxiety, depression, and sleep quality, but not quality of life. Journal of substance abuse treatment. 2017 Oct [PubMed PMID: 28847455]|
|||Mason MJ,Zaharakis NM,Moore M,Brown A,Garcia C,Seibers A,Stephens C, Who responds best to text-delivered cannabis use disorder treatment? A randomized clinical trial with young adults. Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors. 2018 Nov [PubMed PMID: 30265057]|