Long-term effects of cannabis

Cannabis flower with visible trichomes

The long-term effects of cannabis have been the subject of ongoing debate. Because cannabis is illegal in most countries, research presents a challenge; as such, there remains much to be concluded.^[1]

Memory and intelligence

There is evidence that cannabis use during adolescence, at a time when the brain is still developing, may have deleterious effects on neural development and later cognitive functioning.^[2] Rat models using synthetic cannabinoids have been criticized, as they are not necessarily translatable to human exposures.^[3] Acute cannabis intoxication has been shown to affect alterations in attention, psychomotor task ability, and short-term memory; however, a dose-response relationship has not been formally established through blind, randomized placebo controlled trials. While structural changes have been shown, studies have not demonstrated causation between cannabinoids and functionally significant long-term central nervous system effects of the drug or negative changes to brain composition.^[4]

Misrepresentation of data as demonstrating significance particularly regarding cannabinoids is a rampant issue in the scientific community and many of the studies that demonstrate structural changes in the brain have deluded confounding variables and selection bias that renders much of their data useless in drawing meaningful conclusions. Acute intoxication effects are often misrepresented as long term cognitive effects. Data has demonstrated, though, that chronic cannabis exposure needs longer to "wash out" of users and thus the acute intoxication effects appear to persist.^[5] Adequate time for wearing off produces data that demonstrates no difference in the performance of cognitive tasks.

Dependency

Cannabis is the most widely used illicit drug in the Western world,^[6] and in the US 10 to 20% of consumers who use cannabis daily become dependent.^[7] Cannabis use disorder is defined in the fifth revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) as a condition requiring treatment.^[6] A 2012 review of cannabis use and dependency in the US by Danovitch et al said that in the US, "42% of persons over age 12 have used cannabis at least once in their lifetime, 11.5% have used within the past year, and 1.8% have met diagnostic criteria for cannabis abuse or dependence within the past year. Among individuals who have ever used cannabis, conditional dependence (the proportion who go on to develop dependence) is 9%." Although no medication is known to be effective in combating dependency, combinations of psychotherapy such as cognitive behavioural therapy and motivational enhancement therapy have achieved some success.^[8]

Cannabis dependence develops in 9% users, significantly less than that of heroin, cocaine, alcohol, and prescribed anxiolytics, ^[9] but slightly higher than that for psilocybin, mescaline, or LSD. Dependence on cannabis tends to be less severe than that observed with cocaine, opiates, and alcohol.^[10]

Mental health

Historically, the possible connection between psychosis and cannabis has been long-debated.^[11] Recent medical evidence strongly suggests that the long-term use of cannabis in people who started using it when young heightens the risk of mental health problems and other physical and development disorders, although the causal link is not yet definitively established.^[12] These risks appear to be most acute in adolescent users.^[12]

Cannabis alone is not believed to cause psychosis, it may be a contributory factor, particularly when combined with an existing susceptibility.^[11]

Acute psychosis

Although there has been an association noted between cases of acute psychosis and long-term cannabis use, the precise nature of the relationship is controversial; evidence suggests that cannabis use may worsen psychotic symptoms and increase the risk of relapse.^[13]

Anxiety

A 2014 meta-analysis found an association between cannabis use and anxiety.^[14]

Depersonalization/derealization symptoms

Cannabis use may precipitate new-onset panic attacks and depersonalization/derealization symptoms simultaneously.^[15]

Chronic psychosis

According to one review, long term cannabis use "increases the risk of psychosis in people with certain genetic or environmental vulnerabilities", but does not cause psychosis. Important predisposing factors include genetic liability, childhood trauma and urban upbringing.^[11] A second review concluded that cannabis use may cause permanent psychological disorders in some users such as cognitive impairment, anxiety, paranoia, and increased risks of psychosis. Key predisposing variables include age of first exposure, frequency of use, the potency of the cannabis used, and individual susceptibility.^[16]

Schizophrenia

Among people with schizophrenia there is insufficient evidence to determine whether cannabis use leads to improvement or deterioration of the condition,^[17] but patients who use cannabis have been found to display increased cognitive performance compared to non-users.^[18]

Use of cannabis in adolescence or earlier is correlated with developing schizoaffective disorders in adult life, although the proportion of these cases is small. Susceptibility is most often found in users with at least one copy of the polymorphic COMT gene.^[19]

Cannabis with a high THC to CBD ratio produces a higher incidence of psychological effects. CBD may show antipsychotic and neuroprotective properties, acting as an antagonist to some of the effects of THC. Studies examining this effect have used high ratios of CBD to THC, and it is unclear to what extent these laboratory studies translate to the types of cannabis used by real life users.^[16][20] Research has shown that CBD can safely prevent psychosis in general.^[21]

Depressive disorder

Less attention has been given to the association between cannabis use and depression, though according to the Australian National Drug & Alcohol Research Center, it is possible this is because cannabis users who have depression are less likely to access treatment than those with psychosis.^[22]

Teenage cannabis users show no difference from the general population in incidence of major depressive disorder (MDD), but an association exists between early exposure coupled with continued use into adult life and increased incidence of MDD in adulthood.^[19] Among cannabis users of all ages, there may be an increased risk of developing depression, with heavy users seemingly having a higher risk.^[23]

Mania symptoms

Among those who have been previously diagnosed with bipolar disorder, cannabis may worsen the occurrence of manic symptoms.^[24]

Suicidal behaviour

Adolescent cannabis users show no difference from their peers in suicidal ideation or rate of suicide attempts, but those who continue to use cannabis into adult life exhibit an increased incidence of both, although multiple other contributory factors are also implicated.^[19]

In the general population a weak (indirect) association appears to exist between suicidal behaviour and cannabis consumption in both psychotic and non-psychotic users,^[25] although it remains unclear whether regular cannabis use increases the risk of suicide.^[26] Cannabis use is a risk factor in suicidality, but suicide attempts are characterized by many additional risk factors including mood disorders, stress, personal problems and poor support.^[25]

Gateway drug hypothesis

The gateway drug hypothesis asserts that the use of cannabis may ultimately lead to the use of harder drugs.

Some research suggests that marijuana use is likely to come before use of other drugs. Marijuana use is also linked to addiction to other substances, including nicotine. In addition, animal studies show that the THC in marijuana makes other drugs more pleasurable to the brain.

Physical health

A 2013 literature review said that exposure to marijuana was "associated with diseases of the liver (particularly with co-existing hepatitis C), lungs, heart, and vasculature". The authors cautioned that "evidence is needed, and further research should be considered, to prove causal associations of marijuana with many physical health conditions".^[6]

Brain

Imaging studies suggest that long-term exposure does not lead to decreases in white matter or grey matter volume, but may lead to reductions in hippocampal volume. Variations in the methodologies used lend some uncertainty to this conclusion.^[27]

Cancer

A 2012 review examining the relation of cancer and cannabis found little direct evidence that cannabinoids found in cannabis, including THC, are carcinogenic. Cannabinoids are not mutagenic according to the Ames test. Cannabis smoke has been found to be carcinogenic in rodents and mutagenic in the Ames test. Correlating cannabis use with the development of human cancers has been problematic due to difficulties in quantifying cannabis use, unmeasured confounders, and cannabinoids may have anti-cancer effects.^[28]

According to a 2013 literature review, marijuana could be carcinogenic, but there are methodological limitations in studies making it difficult to establish a link between marijuana use and cancer risk.^[6] The authors say that bladder cancer does seem to be linked to habitual marijuana use, and that there may be a risk for cancers of the head and neck among long-term (more than 20 years) users.^[6] Gordon and colleagues said, "there does appear to be an increased risk of cancer (particularly head and neck, lung, and bladder cancer) for those who use marijuana over a period of time, although what length of time that this risk increases is uncertain."^[6]

Testicular

In 2012 WebMD said that a number of studies had suggested a link between cannabis use and an increased risk of testicular cancer, but that the overall risk remained small and that more research is needed to confirm the findings.^[29] According to Gordon and colleagues, "several recent studies suggest an association between marijuana use and testicular germ cell tumors".^[6]

Lung

There have been a limited number of studies that have looked at the effects of smoking cannabis on the respiratory system.^[30] Chronic heavy marijuana smoking is associated with coughing, production of sputum, wheezing, and other symptoms of chronic bronchitis.^[31] Regular cannabis use has not been shown to cause significant abnormalities in lung function.^[32]

Regular cannabis smokers show pathological changes in lung cells similar to those that precede the development of lung cancer in tobacco smokers.^[33] Gordon and colleagues in a 2013 literature review said: "Unfortunately, methodological limitations in many of the reviewed studies, including selection bias, small sample size, limited generalizability, and lack of adjustment for tobacco smoking, may limit the ability to attribute cancer risk solely to marijuana use."^[6] Reviewing studies adjusted for age and tobacco use, they said there was a risk of lung cancer even after adjusting for tobacco use, but that the period of time over which the risk increases is uncertain.^[6]

A 2013 review which specifically examined the effects of cannabis on the lung concluded "Findings from a limited number of well-designed epidemiological studies do not suggest an increased risk for the development of either lung or upper airway cancer from light or moderate use, although evidence is mixed concerning possible carcinogenic risks of heavy, long-term use."^[32]

In 2013 the International Lung Cancer Consortium found no significant additional lung cancer risk in tobacco users who also smoked cannabis. Nor did they find an increased risk in cannabis smokers who did not use tobacco. They concluded that "Our pooled results showed no significant association between the intensity, duration, or cumulative consumption of cannabis smoke and the risk of lung cancer overall or in never smokers." They cautioned that "Our results cannot preclude the possibility that cannabis may exhibit an association with lung cancer risk at extremely high dosage."^[34]

Cannabis smoke contains thousands of organic and inorganic chemicals, including many of the same carcinogens as tobacco smoke.^[35] A 2012 special report by the British Lung Foundation concluded that cannabis smoking was linked to many adverse effects, including bronchitis and lung cancer.^[36] They identified cannabis smoke as a carcinogen and also said awareness of the danger was low compared with the high awareness of the dangers of smoking tobacco particularly among younger users. They said there was an increased risk from each cannabis cigarette due to drawing in large puffs of smoke and holding them.^[36] Marijuana smoke has been listed on the California Proposition 65 warning list as a carcinogen since 2009, but leaves and pure THC are not.^[37]

Head and neck

A 2011 review of studies in the US found that although some supported the hypothesis that cannabis use increased the risk of getting head and neck cancer, when other factors are accounted for the majority did not.^[28] Gordon and colleagues (2013) said there was a risk of these cancers associated with marijuana use over a long period of time.^[6] A 2015 review found no association with lifetime cannabis use and the development of head and neck cancer.^[38]

Respiratory effects

Cannabis sativa from Vienna Dioscurides, 512 AD

A 2013 literature review by Gordon and colleagues concluded that inhaled marijuana is associated with lung disease,^[6] although Tashkin's 2013 review has found "no clear link to chronic obstructive pulmonary disease".^[32]

Of the various methods of cannabis consumption, smoking is considered the most harmful; the inhalation of smoke from organic materials can cause various health problems (e.g., coughing and sputum). Isoprenes help to modulate and slow down reaction rates, contributing to the significantly differing qualities of partial combustion products from various sources.^[39][40]

Smoking cannabis has been linked to adverse respiratory effects including: chronic coughing, wheezing, sputum production, and acute bronchitis.^[36] It has been suggested that the common practice of inhaling cannabis smoke deeply and holding breath could lead to pneumothorax. In a few case reports involving immunocompromised patients, pulmonary infections such as aspergillosis have been attributed to smoking cannabis contaminated with fungi. The transmission of tuberculosis has been linked to cannabis inhalation techniques, such as sharing water pipes and 'Hotboxing'.^[41]

Reproductive and endocrine effects

Cannabis consumption in pregnancy is associated with restrictions in growth of the fetus, miscarriage, and cognitive deficits in offspring.^[42] Although the majority of research has concentrated on the adverse effects of alcohol, there is now evidence that prenatal exposure to cannabis has serious effects on the developing brain and is associated with "deficits in language, attention, areas of cognitive performance, and delinquent behavior in adolescence".^[43] A report prepared for the Australian National Council on Drugs concluded cannabis and other cannabinoids are contraindicated in pregnancy as it may interact with the endocannabinoid system.^[22]

Mortality

No fatal overdoses associated with cannabis use have been reported.^[26] Due to the small number of studies that have been conducted, the evidence is insufficient to show a long-term elevated risk of mortality from any cause. Motor vehicle accidents, suicide, and possible respiratory and brain cancers are all of interest to many researchers, but no studies have been able to show a consistent increase in mortality from these causes.^[26]

See also

• Medical cannabis
• Effects of cannabis
• Cannabinoid hyperemesis syndrome

References

1. "Medical Marijuana Policy in the United States". Stanford.edu. 2012-05-15. Retrieved 2013-01-15.
2. McLaren, J, Mattick, R P., Cannabis in Australia Use, supply, harms, and responses Monograph series No. 57 Report prepared for: Drug Strategy Branch Australian Government Department of Health and Ageing. National Drug and Alcohol Research Centre University of New South Wales, Australia.
3. Chronic cannabinoid exposure during adolescence leads to long-term structural and functional changes in the prefrontal cortex. Renard J1, Vitalis T2, Rame M1, Krebs MO3, Lenkei Z2, Le Pen G1, Jay TM4.
4. Harefuah. 2013 Dec;152(12):737-41, 751. [Short-and long-term effects of cannabinoids on memory, cognition and mental illness]. [Article in Hebrew] Sagie S1, Eliasi Y2, Livneh I3, Bart Y2, Monovich E2.
5. Hartman, RL; Huestis, MA (Mar 2013). "Cannabis effects on driving skills". Clin Chem. 59 (3): 478–92. doi:10.1373/clinchem.2012.194381.
6. Gordon AJ, Conley JW, Gordon JM (December 2013). "Medical consequences of marijuana use: a review of current literature". Curr Psychiatry Rep (Review). 15 (12): 419. doi:10.1007/s11920-013-0419-7. PMID 24234874.
7. Borgelt LM, Franson KL, Nussbaum AM, Wang GS (February 2013). "The pharmacologic and clinical effects of medical cannabis". Pharmacotherapy (Review). 33 (2): 195–209. doi:10.1002/phar.1187. PMID 23386598.
8. Danovitch I, Gorelick DA (June 2012). "State of the art treatments for cannabis dependence". Psychiatr. Clin. North Am. (Review). 35 (2): 309–26. doi:10.1016/j.psc.2012.03.003. PMC 3371269. PMID 22640758.
9. Wilkie G, Sakr B, Rizack T (March 2016). "Medical Marijuana Use in Oncology: A Review". JAMA Oncology. doi:10.1001/jamaoncol.2016.0155. PMID 26986677.
10. Budney AJ, Roffman R, Stephens RS, Walker D (December 2007). "Marijuana dependence and its treatment". Addict Sci Clin Pract (Review). 4 (1): 4–16. doi:10.1151/ascp07414. PMC 2797098. PMID 18292704.
11. Parakh P, Basu D (2013). "Cannabis and psychosis: have we found the missing links?". Asian J Psychiatr (Review). 6 (4): 281–7. doi:10.1016/j.ajp.2013.03.012. PMID 23810133.
12. Hoch E, Bonnetn U, Thomasius R, Ganzer F, Havemann-Reinecke U, Preuss UW (2015). "Risks associated with the non-medicinal use of cannabis". Dtsch Arztebl Int (Review). 112 (16): 271–8. doi:10.3238/arztebl.2015.0271. PMC 4442549. PMID 25939318.
13. Barceloux, Donald G (20 March 2012). "Chapter 60: Marijuana (Cannabis sativa L.) and synthetic cannabinoids". Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants. John Wiley & Sons. p. 901. ISBN 978-0-471-72760-6.
14. Kedzior, Karina; Laeber, Lisa (2014). "A positive association between anxiety disorders and cannabis use or cannabis use disorders in the general population- a meta-analysis of 31 studies". BMC Psychiatry. 14 (1): 136. doi:10.1186/1471-244X-14-136. PMC 4032500. PMID 24884989.
15. Diagnostic and statistical manual of mental disorders : DSM-5. (Fifth edition. ed.). American Psychiatric Association. 2013. p. 304.
16. Niesink, RJ; van Laar, MW (2013). "Does Cannabidiol Protect Against Adverse Psychological Effects of THC?". Frontiers in Psychiatry (Review). 4: 130. doi:10.3389/fpsyt.2013.00130. PMC 3797438. PMID 24137134.
17. Rathbone, John; Variend, Hannele; Mehta, Hetal (2008). Rathbone, John, ed. "Cannabis and schizophrenia". Cochrane Database of Systematic Reviews (Review) (3): CD004837. doi:10.1002/14651858.CD004837.pub2. PMID 18646115. (subscription required (help)).
18. Rabin RA, Zakzanis KK, George TP (May 2011). "The effects of cannabis use on neurocognition in schizophrenia: a meta-analysis". Schizophrenia Research (Meta-analysis). 128 (1-3): 111–6. doi:10.1016/j.schres.2011.02.017. PMID 21420282.
19. Chadwick, Benjamin; Miller, Michael L; Hurd, Yasmin L (2013). "Cannabis Use during Adolescent Development: Susceptibility to Psychiatric Illness". Frontiers in Psychiatry (Review). 4: 129. doi:10.3389/fpsyt.2013.00129. PMC 3796318. PMID 24133461.
20. Scuderi, C; Filippis, DD; Iuvone, T; Blasio, A; Steardo, A; Esposito, G (May 2009). "Cannabidiol in medicine: a review of its therapeutic potential in CNS disorders". Phytotherapy Research : PTR (Review). 23 (5): 597–602. doi:10.1002/ptr.2625. PMID 18844286.
21. Zuardi, AW; Crippa, JA; Hallak, JE; Bhattacharyya, S; Atakan, Z; Martin-Santos, R; McGuire, PK; Guimarães, FS (2012). "A critical review of the antipsychotic effects of cannabidiol: 30 years of a translational investigation.". Current pharmaceutical design. 18 (32): 5131–40. doi:10.2174/138161212802884681. PMID 22716160.
22. Copeland J, Gerber S, Swift W (2006). "Evidence-based answers to cannabis questions: a review of the literature" (PDF). Canberra: Australian National Council on Drugs. Archived from the original on August 21, 2006.
23. Lev-Ran S, Roerecke M, Le Foll B, et al. (June 2013). "The association between cannabis use and depression: a systematic review and meta-analysis of longitudinal studies". Psychological Medicine (Review). 44 (24): 1–14. doi:10.1017/S0033291713001438. PMID 23795762.
24. Gibbs, Melanie; Winsper, Catherine; Marwaha, Steven; Gilbert, Eleanor; Broome, Matthew; Singh, Swaran P. (January 2015). "Cannabis use and mania symptoms: A systematic review and meta-analysis". Journal of Affective Disorders. 171: 39–47. doi:10.1016/j.jad.2014.09.016.
25. Serafini G, Pompili M, Innamorati M, et al. (2012). "Can cannabis increase the suicide risk in psychosis? A critical review". Current Pharmaceutical Design (Review). 18 (32): 5165–87. doi:10.2174/138161212802884663. PMID 22716157.
26. Calabria B, Degenhardt L, Hall W, Lynskey M (May 2010). "Does cannabis use increase the risk of death? Systematic review of epidemiological evidence on adverse effects of cannabis use". Drug Alcohol Rev (Review). 29 (3): 318–30. doi:10.1111/j.1465-3362.2009.00149.x. PMID 20565525.
27. Rocchetti, M; Crescini, A; Borgwardt, S; Caverzasi, E; Politi, P; Atakan, Z; Fusar-Poli, P (2013). "Is cannabis neurotoxic for the healthy brain? A meta-analytical review of structural brain alterations in non-psychotic users". Psychiatry and Clinical Neurosciences. 67 (7): 483–92. doi:10.1111/pcn.12085. PMID 24118193.
28. Bowles DW, O'Bryant, CL; Camidge, DR; Jimeno, A (July 2012). "The intersection between cannabis and cancer in the United States.". Critical reviews in oncology/hematology (Review). 83 (1): 1–10. doi:10.1016/j.critrevonc.2011.09.008. PMID 22019199.
29. "Smoking Marijuana Tied to Testicular Cancer". WebMD. 9 September 2012. Retrieved November 2013. Check date values in: |access-date= (help)
30. Stephen Maisto; Mark Galizio; Gerard Connors (2014). Drug Use and Abuse. Cengage Learning. p. 278. ISBN 978-1-305-17759-8.
31. W. Hall; N. Solowij (1998-11-14). "Adverse effects of cannabis". Lancet. 352 (9140): 1611–16. doi:10.1016/S0140-6736(98)05021-1. PMID 9843121.
32. Tashkin, DP (June 2013). "Effects of marijuana smoking on the lung.". Annals of the American Thoracic Society. 10 (3): 239–47. doi:10.1513/annalsats.201212-127fr. PMID 23802821.
33. Hall W, Degenhardt L (2009). "Adverse health effects of non-medical cannabis use". Lancet. 374 (9698): 1383–91. doi:10.1016/S0140-6736(09)61037-0. PMID 19837255.
34. Zhang R, Zuo-Feng Z, Morgenstern H, et al. (15 February 2015). "Cannabis smoking and lung cancer risk: Pooled analysis in the International Lung Cancer Consortium". International Journal of Cancer. 136 (4): 894–903. doi:10.1002/ijc.29036.
35. Hashibe M, Ford DE, Zhang ZF (November 2002). "Marijuana smoking and head and neck cancer". J Clin Pharmacol (Review). 42 (11 Suppl): 103S–107S. doi:10.1002/j.1552-4604.2002.tb06010.x. PMID 12412843.
36. "The impact of cannabis on your lungs". British Lung Association. June 2012. Retrieved 2013-01-09.
37. http://www.oehha.ca.gov/prop65/prop65_list/files/P65single060614.pdf
38. de Carvalho, MF; Dourado, MR; Fernandes, IB; Araújo, CT; Mesquita, AT; Ramos-Jorge, ML (15 September 2015). "Head and neck cancer among marijuana users: A meta-analysis of matched case-control studies.". Archives of oral biology. 60 (12): 1750–1755. doi:10.1016/j.archoralbio.2015.09.009. PMID 26433192.
39. Grotenhermen, F. (2001). "Harm Reduction Associated with Inhalation and Oral Administration of Cannabis and THC". Journal of Cannabis Therapeutics. 1 (3–4): 133–152. doi:10.1300/J175v01n03_09.
40. Tashkin DP (June 2005). "Smoked marijuana as a cause of lung injury". Monaldi Arch Chest Dis (Review). 63 (2): 93–100. PMID 16128224.
41. Lutchmansingh, D; Pawar, L; Savici, D (2014). "Legalizing Cannabis: A physician's primer on the pulmonary effects of marijuana.". Current respiratory care reports. 3 (4): 200–205. doi:10.1007/s13665-014-0093-1. PMID 25401045.
42. Fonseca BM, Correia-da-Silva G, Almada M, Costa MA, Teixeira NA (2013). "The Endocannabinoid System in the Postimplantation Period: A Role during Decidualization and Placentation". Int J Endocrinol (Review). 2013: 510540. doi:10.1155/2013/510540. PMC 3818851. PMID 24228028. In fact, maternal marijuana use has been associated with foetal growth restrictions, spontaneous miscarriage, and cognitive deficits in infancy and adolescence.
43. Irner TB (2012). "Substance exposure in utero and developmental consequences in adolescence: a systematic review". Child Neuropsychol (Review). 18 (6): 521–49. doi:10.1080/09297049.2011.628309. PMID 22114955.