Marijuana: severe adverse effects increasingly common

 

A recent article appeared in the New York Times about the potential harms of the high potency marijuana currently widespread and well-distributed, refuting that this is nonaddictive and safe (see https://www.nytimes.com/2024/10/04/us/cannabis-marijuana-risks-addiction.html?smid=nytcore-ios-share&referringSource=articleShare&sgrp=c-cb or https://www.nytimes.com/2024/10/04/us/cannabis-marijuana-risks-addiction.html  ).

 

A few general comments:

-- there are many reports of patients being treated for extremely large amounts of marijuana intake daily, with the following problems associated with that:

 

“cannabinoid hyperemesis syndrome”, or CHS: severe vomiting, with patients “writhing around in pain” at times, and associated with severe dehydration, seizures, kidney failure, cardiac arrest, and at least eight attributable deaths

    -- it is hard to get accurate data on CHS since it is not consistently recorded in the medical records

            -- one concern about the medical information is that the appropriate coding for some of the marijuana-related diagnoses is deficient, so the numbers of patients seen in medical settings with marijuana-related adverse events is likely highly under-reported

        -- CHS has the unusual and unexplained feature that heat seems to relieve the nausea and vomiting, with many patients spending hours in hot tubs and showers, and some being scalded by the heat

        -- a survey in 2018 at Bellevue Hospital New York found that of those 18 to 49 years old who consumed cannabis at least 20 times a month, one third had met criteria for CHS; general estimates are that 6 million near-daily marijuana users in the US could have these symptoms

       -- as an example, a fatality associated with CHS in the NY Times: a 37yo who did not go to the hospital when he had severe CHS because he “didn’t want to be far from hot baths”. After his death, his mother wanted to make sure that CHS was listed as the primary cause of death but "the medical examiner never heard of it”

 

--psychoses/schizophrenia associated with cannabis use:

        -- there are acute, transient effects that can occur, including dread, paranoia and hallucinations/delusions

        -- and there are several studies finding potentially chronic psychotic disorders (see commentary below for some of these studies)

        -- the NY Times article quoted Dr. Carrie Bearden, a clinical psychologist and neuroscientist at UCLA who supervises a clinic for 12- to 25-year-olds in whom schizophrenia is starting to surface. She estimates that when the clinic opened 20 years ago, about 10 % of the patients used marijuana regularly. Now, she estimates, nearly 70% do

 

-- marijuana addiction, which includes requiring escalating doses for people to get the same effects, and quitting marijuana leading to anxiety, depression, and other signs of withdrawal as well as problems with decreased eating and sleep disturbances

    -- 18 million people (a third of all users aged 18 or more) have reported symptoms of cannabis use disorder (CUD, see below), finding that they continue the drug despite significant negative effects on their lives.

    -- approximately 3 million people are considered to be addicted, based on a 2022 US national drug use survey, which reported "any cannabis consumption" within the previous year, especially among those 18 to 25 years old

 

-- state/federal laws:

    -- 24 states and the District of Columbia now allow recreational use of marijuana, with 3 more states have upcoming ballot measures (though marijuana is illegal per federal law)

    -- 2 states limit the levels of THC (Delta-9-tetrahydrocannabinol) in the marijuana

    -- 10 states require that marijuana products come with warnings that cannabis can be habit-forming

    -- none of the states are equipped to assess the scope of health outcomes

    -- Congress legalized hemp in 2018; per the NY Times they “inadvertently legalized highly intoxicating hemp derived compounds like Delta-8 THC”

        -- The National Academies of the Sciences, Engineering, and Medicine (https://www.nationalacademies.org/news/2024/09/to-protect-public-health-federal-government-should-provide-guidance-to-states-that-have-legalized-marijuana-close-hemp-regulatory-loopholes-create-public-health-campaign ) produced a report last month critiquing the disjointed cannabis policies and calling for urgent action on the federal and state level

 

-- it does appear that a major concern with current marijuana is related to drug company shenanigans (a.k.a. greed):

    -- the initial legalization of marijuana was for medical use, with testimonials from AIDS and cancer patients indicating that it helped relieve their suffering. There is also the feeling that there was unnecessary and racist incarceration policies for marijuana users

    -- BUT the commercial marijuana industry actually pursued the process of developing a quicker and more intense high to appeal to recreational users, not to improving its ability to help patients with these and other medical conditions

    -- in the 1990s marijuana typically contained about 5% THC; current vape pens, fast-acting edibles, pre-rolled joints, have concentrations as much is 99% THC!!!

    -- marijuana legalization has led to a $33 billion industry, tens of millions of Americans use the marijuana for medical or recreational purposes

 

Cannabis Use Disorder diagnostic criteria in DSM and ICD-1:

Commentary: 

--Cannabis use disorder CUD) among people 18-25yo has now surpassed alcohol use disorder (16.6% vs 15.1%), as well in those 12-17yo (5% vs 3%). For federal data on increasing marijuana use in teens, see https://gmodestmedblogs.blogspot.com/2018/11/teen-drug-use-in-us-2016-survey.html

 

--a review of some of the relevant medical literature on cannabis:

 --A Danish register-based cohort study of all individuals (6,907,859) aged 16-49 during the years of 1972-2021 assessed the relationship between incident schizophrenia (45,327 individuals) and CUD, with follow-up of 129,521,260 person-years (see marijuana schiz more in young men vs women PsychMed2023 in dropbox, or doi.org/10.1017/S0033291723000880):

    -- adjusted hazards ratio for CUD and schizophrenia overall was slightly higher among males (aHR 2.42 (2.33-2.52)) versus females (aHR 2.02 (1.89-2.17))

    -- for those 16-20-years old: the adjusted incidence risk ratios (aIRR) for males was 3.84 (3.43-4.29) versus 1.81 (1.53-2.15) for females

    -- during 1972-2021, the overall population attributable risk fraction (PARF) for CUD and schizophrenia incidence was 4.8 among males (4.3-5.3), p<0.0001; and 3.2 (2.5-3.8), p<0.0001 for females

    -- in  2021 the PARF was 15% among males and 4% among females

    --which all suggests that at a population level, assuming causality that CUD leads to schizophrenia, 1 in 5 cases of schizophrenia among males might be prevented by averting CUD and that a key target for early detection and treatment of CUD would involve policies regarding cannabis use and access, particularly for those 16-25 years old

  

-- Another study assessed age-dependent associations of cannabis use with the risk of psychotic disorders (see marijuana psychotic disorder PsychMed2024 in dropbox, or doi.org/10.1017/S0033291724000990):

    -- 11,363 individuals aged 12 to 24 at baseline with no known prior psychotic disorder, along with a population-based survey from 2009-2012 with records with all services covered under their universal healthcare in Ontario Canada, compared outcomes during adolescence (12 to 19 years) and young adulthood (20 to 33 years), with the primary outcome of days to first hospitalization, ED visit, and outpatient visits related to psychotic disorder found:

       -- compared to no cannabis use, cannabis was associated with psychotic disorders during adolescence (aHR 11.2 (4.6-27.3)), though not during young adulthood (aHR 1.3 (0.6-2.6))

       -- restricting the outcome measured to hospitalizations and ED visits only in order to increase the specificity (i.e. excluding outpatient visits) did strengthen the association markedly: during adolescence aHR was 26.7 (7.7-92.8), though the results did not change meaningfully during young adulthood (aHR of 1.8 (0.6-5.4))

           -- so this study found that cannabis use was associated with 11 times greater risk of psychotic disorder during adolescence (actually 27-fold, if one assessed the more extreme cases of patient psychoses presenting to the hospital)

        -- this study therefore confirmed prior hypotheses that adolescence is a very sensitive risk period for psychotic disorder development; the data also do suggest that cannabis use is much more strongly associated with more severe psychotic outcomes, since outpatient diagnoses were not included in the later analysis

    -- The study was when cannabis had a much higher potency (the initial database was from 2009-2012 with health records until 2018, a more homogeneous assessment than in earlier studies)

 

-- And another study (see marijuana high potency and psychosis LancetPsych2019 in dropbox, or doi.org/10.1016/ S2215-0366(19)30048-3) assessed the incidence of psychotic disorders across 11 sites in Europe (901 patients with first episode of psychosis and 1237 population controls on the same sites, with mean age of 34), finding:

   -- daily cannabis use was associated with increased odds of psychotic disorder compared to never users, adjusted odds ratio 3.2 (2.2-4.1), which increased to nearly 5 times increased odds for daily use of high potency types of cannabis (OR 4.8 (2.5-6.3)). The population attributable fractions (PAFs) suggested that if high potency cannabis were no longer available, 12.2% (3.0-16.1) of the cases of first episode psychosis could be prevented across the 11 sites, rising to 30.3% (15.2- 40.0) in London and 50.3% (27.4- 66.0) in Amsterdam

    -- unlike most of the other studies, this one did have more granular data and their analysis was able to control for several important potential confounders: tobacco use, stimulants/hallucinogens/ketamine/novel psychoactive substances, alcohol, and all sociodemographic and drug-use variables (though many of these were binary and did not incorporate quantity/potency/regularity of use of these substances)

-- overall the differences in frequency of daily cannabis use and the use of high potency cannabis contributed to the striking variation in the incidence of psychotic disorder across the 11 studied sites (ie, the strongest independent predictors of whether an individual would have a psychotic disorder were daily use of cannabis and the use of high potency cannabis, at a rate of 3.2 times higher than for nonusers for daily cannabis users and 1.6 times higher for those users of high potency cannabis

-- starting cannabis by 15 years of age also increased the psychotic disorder odds, but this was not independent of the frequency of use or the potency of the cannabis

-- the remarkably high rates of psychotic disorders in London and Amsterdam were likely attributable to the fact that cannabis in those areas had a much higher THC content (e.g. 94% of the street market in London had average THC content of 14%, whereas in Italy, France, and Spain cannabis commonly used had THC contents less than 10%)

    -- if one assumes that cannabis causally led to psychotic disorders, 20% of new cases of psychosis would have been prevented if daily use of cannabis had been abolished, and the adjusted incidence rates for all psychotic disorder in Amsterdam  would drop from 37.9 to 18.8 cases per 100,000 person-years, and in London from 45.7 to 31.9 cases per 100,000 person-years

-- Prior relevant blogs on marijuana's adverse effects:

-- A study in adolescent rats found that brain changes from cannabinoid receptor stimulation were similar to those found in schizophrenia https://gmodestmedblogs.blogspot.com/2014/03/marijuana-psych-effects.html

-- A study in 88 adolescents and young adults who were regular cannabis users in 2015 found that even within one week of cannabis abstention, there was significant memory improvement,:

-- A 2007 study of individuals who’d ever used cannabis had an increased risk of psychotic outcomes independent of confounding and transient intoxication affects, with a dose-response curve (the more the worse): see marijuana psychotic effects lancet 2007 in dropbox, or Lancet 2007; 370: 319–28

-- A systematic review found that neonates exposed to marijuana in-utero had several adverse outcomes compared to non-marijuana users, including low birth weight, small-for-gestational age, preterm delivery, necessity for neonatal ICU care: https://gmodestmedblogs.blogspot.com/2022/03/marijuana-adverse-neonatal-outcomes.html

-- a systematic review/meta-analysis found that 23,317 individuals <18yo who had used marijuana had a subsequent increased risk of depression, anxiety and suicidality when later assessed between 18-32yo: https://gmodestmedblogs.blogspot.com/2019/02/cannabis-use-in-teens-increases-risk-of.html

-- an overall review of marijuana’s adverse effects found short-term effects including impaired short-term memory, impaired motor coordination, altered judgment, and paranoia and psychosis (especially with higher doses); and long-term effects included risk of addiction, brain development (brain is actively developing until around age 21 or so) finding decreased neural connections in specific areas of the brain, including the precuneus (a node involved in higher integration functions, such as alertness and self-conscious awareness), the fimbria (part of hippocampus important for learning and memory), prefrontal networks (for executive function), and subcortical networks (which process habits and routines): https://gmodestmedblogs.blogspot.com/2014/06/marijuana-adverse-effects-review.html

-- A pretty striking basic science article found that the epigenetic effects of marijuana in rats can actually be inherited in the next generation: https://gmodestmedblogs.blogspot.com/2015/07/marijuana-passing-through-generations.html

 

Limitations:

--there are many limitations and concerns about the accuracy of the association between marijuana and the psych effects, in particular;  and the psych adverse effects (anxiety, depression, Tourette syndrome, ADHD, PTSD, etc) were not found to be so clear in a 2019 review: https://gmodestmedblogs.blogspot.com/2019/11/cannabis-not-help-psych-symptoms.html:

    -- perhaps the biggest limitation in the association between CUD and psychosis is that these marijuana studies are all observational, and from different databases (it would be a tad difficult to do a randomized controlled trial, where young people were randomized to using marijuana in one group and not using it in the other group, and then assessing outcomes many years later).  this limitation brings up itself several issues:

        -- as with all observational studies, one can only assess associations and not causality (there are likely confounders that were not accounted for)

        -- even the best studies with long-term follow-up including data from individuals before beginning to use marijuana and tracking their outcomes, then comparing them to those not using marijuana at all are subject to bias:

            -- Is there commonality of the genetics involved in those who develop CUD and those who develop schizophrenia? and is it sufficient to explain an association? there are studies suggesting that there are in fact shared genes between these two conditions that could account for at least some of the association between these two entities

            -- we don’t have adequate information about the genetic backgrounds of the people involved in these studies. we do know that schizophrenia has a strong genetic component, and there are strong suggestions that cannabis use also has a genetic component based on twin studies (https://www.nature.com/articles/s41398-022-02215-2 )

       -- another issue is that the relationship between cannabis and schizophrenia could be bidirectional (i.e. those with CUD may be at higher risk of schizophrenia; and those with schizophrenia may be at higher risk for using cannabis). One of the complicating factors is that schizophrenia is most commonly identified in young people (mostly upper teens and up until low 30s). and the diagnosis of schizophrenia can be delayed in young people and may be misdiagnosed as emotional or behavioral problems by families. so, did some/many of the young people have early and perhaps undiagnosed schizophrenia for years and perhaps the marijuana was either incidental or more likely an augmenting risk factor for the schizophrenia that was likely to develop anyway???

    -- these studies are also missing lots of important data in terms of underlying medical conditions, underlying psychological conditions, medications and other drugs being used, alcohol consumption, family histories (given that both entities seem to run in families). 

    -- there are particular concerns about register-based data as in the Danish study above, since the registries mostly have just the diagnoses of CUD and schizophrenia, without a lot of details)

    -- we do not have a lot of granular data about the intensity of cannabis use or the THC content of the cannabis being used in most studies. The Danish study included people in the early 1970s and the few decades thereafter, where cannabis was significantly more potent than in the later years of the study: mixing apples with oranges a bit

    -- data on cannabis use were not validated biologically with assessments of urine, blood or hair samples; they did not include cannabidiol (CBD); some of the studies used a conservative cut off of 10% defining low versus high potency cannabis, an arbitrary and conservative cut point that obscures the vast differences in cannabis THC content within the high potency range

    -- and, i have learned my lesson about assuming that observational studies produce reliable results: there were huge numbers of studies of estrogen used in post-menopausal women found cardiac benefit, from basic science studies confirming biological plausibility, to several massive studies in women on hormones vs not (and with very  consistent results), to studies showing that women who had later menopause onset had less cardiovascular disease, with each additional year of menstruation mathematically being equivalent to using hormones for those numbers of years....  And, i was wrong!!! as found in actual randomized controlled trials (and, i had a lot of company in being wrong)

 

So, a pretty potent presentation in the NY Times of the potentially serious adverse effects of marijuana:

-- many of these effects have been known for several decades, as per several of the medical articles cited above (it was a bit shocking in the article that they reported how many people had been misdiagnosed but having these well-known issues, such as cannabis hyperemesis syndrome….)

-- it is very concerning that these adverse events were evident in some of these old studies when marijuana was so remarkably weak (THC content of 5%) vs the currently available and used marijuana (up to 99% THC), since we do know that many of these clinical conditions are dose-dependent!!!

-- the current data on the medical/psych/social disruptions (individual, family, community..) from marijuana are likely very under-reported (ie, much more common than we know)

-- which brings up (yet again) another failure of our public health system: there are pretty clearly some medical benefits from marijuana (eg nausea and vomiting associated with cancer chemotherapy, loss of appetite and weight loss associated with HIV/AIDS and other conditions, neuropathic and other pain, spasticity related to Parkinson’s, anxiety and sleep disorders, Crohn’s disease, PTSD and some others: https://www.ncbi.nlm.nih.gov/books/NBK430801/#:~:text=Marijuana%20is%20used%20to%20treat,Tourette%20syndrome%2C%20and%20Crohn%20disease, and https://gmodestmedblogs.blogspot.com/2015/06/medical-use-of-marijuana.html ), and these medical benefits were an important segue into the initial legalization of marijuana, but the marijuana industry has been able to dramatically increase the potency of the marijuana and its addiction potential along with above-noted adverse effects unchallenged for their own immense profit; this was unrelated to any of these medical benefits. And there has been essentially no oversight/control/regulation by our federal/state public health agencies….

geoff

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