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Primary Care Corner with Geoffrey Modest MD: Marijuana passing through the generations…

29 Jul, 15 | by EBM

By: Dr. Geoffrey Modest

A pretty striking basic science article was recently published looking at the epigenetic effects of marijuana on rats, which seems to be inherited in the next generation (see doi:10.1038/npp.2015.155​).  There have been a slew of recent articles on marijuana suggesting that its adverse effects are more profound than many of us (myself included) thought (eg, structural changes to the brain, psychosis/scizophrenia, longer-term cognitive problems, risk of addiction to other drugs, lung diseases, etc — see here for some of these articles and critiques), and the positive effects are perhaps overstated by poor-quality studies (see blog, which reviews the data on the beneficial effects of medical marijuana). And, as noted, the marijuana issue is increasingly of concern as marijuana is being promoted as a “safe drug” and is now more commonly smoked than cigarettes by teenagers and young adults. In this context, the rats show us that there may be profound epigenetic effects of marijuana in the offspring of those exposed.  I do not presume to be very knowledgeable about the biochemistry here, so will present the extent of my primitive understanding: basically epigenetics differs from genetics in that there are heritable phenotypic changes that do not reflect genotypic changes (as a brief summary, see here). What I mean is that there can be profound changes in gene expression based on chemical changes to the DNA which typically either turn off or on some section of DNA, resulting in fundamental changes in gene expression. These epigenetic changes, for example, can result from aging, environment, lifestyle, and diseases themselves, and often are mediated by changes in areas of DNA which become methylated (there are other mechanisms as well, such as histone modification). The first epigenetic phenomenon studied in humans was in colon cancer, where DNA hypomethylation can lead to oncogene activation and hypermethylation to silencing tumor suppression genes (in general methylation silences gene expression). There are data from human lung cancers that those with cancer subsequently develop changes in oncogenes and tumor suppressor genes in the lung tissue, which can lead to increasing the potency of the cancer and decreasing the efficacy of chemotherapy (see here for example). There are human data that find that epigenetic modifications are important in the clinical expression of even identified genetic diseases leading to cognitive impairment (eg Prader-Willi syndrome), perhaps in autoimmune diseases, an array of neuropsych problems (schizophrenia, bipolar disease, mood disorders, dementia), etc.  So, as a primary care provider, why is this important???? I think epigenetics really opens the door to the link between the environment/lifestyle and the development of potentially many human effects, including an array of diseases. So, back to the rats…

The impetus of this study was the finding that there were cross-generational effects of parental cannabis exposure in adolescent rats leading to offspring who were more prone to self-administer heroin, have enhanced acute heroin withdrawal, altered striatal synaptic plasticity, and changes in the expression of cannabinoid, dopamine, and glutamatergic receptors (see Neuropsychopharmacology (2014) 39, 1315–1323). The current study used the same rat model, finding that of 16 adolescent rats exposed to tetrahydrocannabinol (THC) before mating, vs 16 non-exposed rats (all rat offspring were raised by non-THC exposed mothers) there were dramatic alterations in differentially methylated regions of the offspring’s brain (specifically, a depletion in gene promotors). They focused on glutmatergic synaptic regulation in the nucleus accumbens (a key area of the brain involved in reward processing and the area most linked to addiction vulnerability), finding profound methylation differences and associated altered mRNA expression in these offspring.

So, basic observations from above:

–the epigenetic effects of various stimuli, including those resulting from environmental exposures, can have profound effects on turning on or off different sections of the DNA, with resulting effects on protein production, etc, and may be associated with a variety of diseases

–although there is “reprogramming” of DNA methylation in offspring to preserve reasonably clean genetic transmission (see 10.1126/science.1229277), there are clearly times when these epigenetic changes do pass through to subsequent generations (well-documented in these rats)

–although I  am not a biological determinist, I think these types of studies do raise important issues about the potential for parental actions to affect offspring directly through epigenetic changes (which is not to say that they determine the behavior of kids. That is really complex and, undoubtedly, the social environment of the kids will play a large role in their own development, including subsequent epigenetic changes)

–it is pretty clear to me in inner-city Boston, that a huge number of people are exposed to the very potent marijuana on the streets now and using that regularly, especially but not only in adolescents. And that usage might increase with the acceptance/legalization of medical marijuana, with perhaps overstated benefits, but providing a more “socially-acceptable” aura, as with cigarettes and alcohol over the years.


–but, bottom line, we should be aware of these epigenetic changes, aware that they can be passed on to offspring even in the context of not using THC during pregnancy itself, and that the effects on the offspring might at least put them at a significant disadvantage in the longrun.

–and, I wouldn’t be surprised to find these types of epigenetic play a significant role in our common chronic diseases (obesity, hypertension, hyperlipidemia, diabetes…..) in individuals, and perhaps in their offspring as well (ie, it may not just be the genes themselves that predispose people to these diseases, but environmentally-induced changes in methylation etc of the genes which play a big role)



Primary Care Corner with Geoffrey Modest MD: Medical use of marijuana

27 Jul, 15 | by EBM

By: Dr. Geoffrey Modest

JAMA published a systematic review and meta-analysis of the medical use of cannabinoids (see JAMA. 2015;313(24):2456-2473.). This is rather timely as several states are moving forward implementing new procedures for use of medical marijuana (as of may 2015, 23 states and Washington DC). The researchers evaluated 79 studies with 6462 participants.



–Nausea/vomiting from chemotherapy: 28 studies, most with high risk of bias.

-all studies showed cannabinoid benefit (some not reaching statistical significance), whether vs placebo or active comparator (procholorperizine, chlorpromazine, domperidone, and with single studies on alizapride, hydroxyzine, metoclopramide and ondansetron)

-cannabinoids vs placebo: also higher average number of patients showing complete response with cannabinoids [OR 3.82 (1.55-9.42); 3 trials]

–Appetite stimulation in HIV infection. 4 studies, all at high risk of bias

-some evidence that cannabinoids led to increased weight vs placebo, though the one trial comparing it to megastrol found the latter led to more weight gain [by the way, I have had pretty good success with cyproheptadine, with many fewer adverse effects vs megastrol]

-there is also limited evidence that cannabinoids are associated with increased appetite, greater percentage of body fat, reduced nausea and improved functional status.

–Chronic Pain, 28 studies, 2 of which were at low risk of bias

-cannabinoids better than placebo, assessing reduction of pain of at least 30%  [OR 1.41 (0.99-2.00); 8 trials]. Greatest benefit in the 1 trial using smoked THC, with OR 3.4 (1.03-11.48). This was true using a variety of pain scales and measurements.

-no difference in benefit if neuropathic pain [OR 1.38 (0.93-2.03); 6 trials] vs cancer pain [OR 1.41 (0.99-2.00); 2 trials].

–Spasticity from multiple sclerosis or paraplegia, 14 studies, 2 of which had low risk of bias

-cannabinoids demonstrated greater improvement of spasticity by Ashworth scale, vs placebo, though not reach statistical significance.

-greater average improvement in spasticity

–Depression, no good studies.

-secondary analysis of studies for other indications did not find improvement in depression

–Anxiety disorder, 1 trial at high risk of bias

-cannabinoids associated with statistically significant decrease in anxiety on a visual analog scale (p=0.01)

–Sleep disorder, 2 studies

        -improvement in sleep apnea/hypopnea index (mean difference -19.64, p=0.02)

-compared to amitriptyline in patients with fibromyalgia, cannabinoids were associated with improvements in insomnia but amitriptyline had greater sleep restfulness.

-in cannabinoid trials for other indications (MS, pain), secondary analysis noted improvement in sleep quality and sleep disturbance

–Psychosis, 2 studies both at high risk of bias

-no benefit

–Glaucoma, 1 remarkably small trial (n=6)

-no difference in intraocular pressures in patients with glaucoma [rather surprising to me, but a really small and therefore suspect study]

–Movement disorder from Tourette syndrome, 2 studies, 36 participants

-significant improvement in tic severity

–Adverse events (AEs)

-in 29 studies, risk of any AE had OR 3.03 (2.42-3.80)

-in 34 studies, risk of serious AE had OR 1.41 (1.04-1.92)

-in 29 studies, risk withdrawal due to AE had OR 2.94 (2.18-3.96)

-major AEs were dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, disorientation, drowsiness, confusion, balance, hallucination, paranoia [newer studies which I have blogged on over the past couple of years have raised significant questions about longer-term cognitive problems, some finding structural brain changes, and psychosis – though it is hard to know for sure which came first: the marijuana leading to anatomic and physiologic brain changes or vice-versa]

So, overall not great data (pretty poor-quality data, per the Cochrane risk of bias tool). The best quality data supporting cannabinoid use were for chronic neuropathic or cancer pain, and spasticity from MS. Less good data supported use for nausea/vomiting from chemotherapy, weight gain in HIV, sleep disorders and tics from Tourette syndrome. Very low quality data for anxiety disorders. Other outstanding issues include: whether there are significant differences either between different cannabinoids or their mode of administration (orally, sublingually, topically; or if smoked, inhaled, mixed with food or made into tea). It should be emphasized that any medication with so many AEs make it very difficult to have a real placebo control (ie, the patients are pretty likely to know if they are on the active med vs placebo….)​

Primary Care Corner with Geoffrey Modest MD: Substance use and mental health in youth and adults 2014

2 Apr, 15 | by EBM

By: Dr. Geoffrey Modest

SAMHSA (Substance Abuse and Mental Health Services Administration) just released a 2014 report on where we are at in the US regarding substance abuse and mental health issues (see here). A pretty brief summary:

Youth substance use/mental health (note: there are different surveys used for these data):

–Past month marijuana use, 2002-2013

–slight decrease in adolescents 12-17 to 7.1% (peak in 2011 at 7.9%)

–9th-12th graders without much change, at 23%. 8th-10th graders at 12.5% (sl increase)

–Past-year nonmedical pain reliever use, 2002-2013

–12th grade males: significant decrease, was up to 11.6% in 2002, decreased to mid-10 range til 2009, now down to 8.4%

–12th grade females: pretty flat at around 8% til 2011, then decreased to 5.6%

–age 12-17 males and females was in the 7.2% range, now decreased to 4.5-4.8%

–Past-month illicit drug use, 2009-2013

–age 12-17 with overall decrease in total, White, Latino to 8.8%, but no change in black, at 10.5%

–comparing the different illicits: marijuana most common at 7.1%; nonmedical use of psychotherapeutics next at 2.2%; then hallucinogens, inhalants, cocaine and heroin, all 0.6% or less.

–Past-month cigarette use, 2009-2013

–age 12-17: decreasing in all ethnicities, but highest in white (7.2%), then latino (3.7%), then black (3.2%)

–Past month binge alcohol use, 2008-2013

​–age 12-17: similar in males and females, decreasing to 6.2%. highest in White (7.3%), then Latino (6.3%), then Native American/Alaskan (5.6%), then Black (3.9%), then Asian (2.8%)

–Past year initiated substance use, in age 12-17, from 2009-2013

–alcohol: dec from 10.8% to 9.7%

–marijuana: dec from 5.5% to 4.8%

–cigarettes: dec from 5.2% to 3.7%

–nonmedical use of psychotherapeutics: dec from 3.5% to 2.4%

–and pretty similar %’s of above for white, black, latino

–Major depressive disorders, in age 12-17,in 2013

–overall: 10.7% (2.6 million…)

​–males: highest in Asian (6.5%), then Latino (5.7%) and White (5.6%), then Black (3.0%)

–females: highest in Latino (17.4%), then White (16.3%), then Black (14.4%), and Asian (13.9%)

–Past year depression treatment for major depressive disorder, among age 12-17, in 2103

–around 60-70% did not receive treatment (males 70%, females 59%), and White 58%, Black 71%, Latino 63%

Adult substance use/mental health

–Suicidal thoughts, age 18 and older, in 2013

–highest in 18-25 (7.4%), then decreasing to 4.0% age 26-44, 3.7% age 45-64, and 1.5% if older than 65

–also higher in those not insured (5.7% vs 3.6%) and in those <100% of federal poverty level (6.6% vs 3.5%)

–Serious mental illness, age 18 and older, in 2103

–more female (4.9% vs 3.5%), more in uninsured (5.9% vs 3.9%), and more in those <100% of poverty level (7.7% vs 3.6%)

–did not receive treatment: more men (36.4% vs 28.4%), and more younger (46% in 18-25 yo vs 24% in 45-64), and (not a shocker) more without insurance (49.4% vs 28.6%)

–Alcohol dependence and abuse, age 12 and older, in 2103

–more male (8.7% vs 4.6%), most in the 18-25 age group (13%) then decreasing stepwise through the >65 yo group (2.1%)

–more in uninsured (9.7% vs 6.0%)

–trend decreasing from 2009-2013 (eg, in those 18-25, decreased from 16.1% to 13.0%)

–Illicit drug use, aged 12 and older, in 2013

–highest in 18-25 yo (7.4%),  then decreasing stepwise through the >65 yo group (0.4%)

–Enrollment in substance abuse treatment (single-day counts 2009-2013)

–increasing from 2010 to 2013, from 1.175 million to 1.250 million, pretty evenly divided between “drug use only” at 39.6% and “both drug and alcohol use” at 43.0%

–Past-year treatment for alcohol use, age 12 and older, in 2013

–Highest in 12-17yo (9.8%), then rest in 5.3%-7.3% range

–Of note, 90.6% did not receive treatment and did not perceive a need for treatment!

–People in opioid treatment programs 2009-2013

–methadone: increase from 2009 from 283K to 330K in 2013

–buprenorphine: increase from 2009 from 24K to 48K in 2013

–in 2013, only 13.4% were in treatment, 5.7% perceived need for treatment but did not receive it, and 80.9% did not perceive need for treatment.  those in treatment tended to be older (26-44 yo group, at 18.2%)

So, a few issues from the mass of numbers above:

–These surveys are subject to many biases in terms of reporting, both by sample selection and the general cultural issues (in the largest sense, including those related to ethnicity, as well as those relating to gender, age, local social environment, peer pressure, etc which affect one’s level of introspection/ability to verbalize it as well as interpreting what is “normal”)…all limiting the generalizability and interpretation of the results

–The trends for most of the above regarding substances are in fact getting better!! as well as the use of methadone/buprenorphine, etc

​–One sore point is the psych data: large numbers of people with serious mental illnesses. with lots who are poor and without insurance (there is certainly an aspect of “social drift”, in that those with serious mental illnesses tend to “drift” into poverty, but there is undoubtedly a component of poverty leading to lack of insurance, leading to lack of treatment, leading to lack of ability to function in society, leading to lack of ability to improve the situation…..


Primary Care Corner with Geoffrey Modest MD: “Feel-good gene”

16 Mar, 15 | by EBM

By: Dr. Geoffrey Modest 

Untitled5Interesting article in Sunday NY Times on human genetic variability and different responses to mind-altering drugs. In brief:

–the brain is full of receptors for the various psychoactive drugs, as well as endogenous stimulants for those receptors: the opiates (including the endogenous endorphins) stimulate the mu receptor, the cannabinoids (including the endogenous anandamide; its name by the way is taken from the Sanskrit word ananda, meaning “bliss”) stimulate the endocannabinoid system, the benzodiazepines (including the endogenous GABA, though not a benzo itself) bind close to the benzodiazepine binding site and affects benzodiazepine binding in the CNS, and nicotine which binds to brain acetylcholine receptors leading to stress reduction, pleasure and improved cognition.

–some people have lower levels of an enzyme called FAAH (fatty acid amide hydrolase, which deactivates the endocannabinoid anandamide) through a genetic variant, leading to increased levels of anandamide. These people, about 20% of the US population (21% of Americans from European background, 14% of Han Chinese, 45% of Nigerians), overall are less anxious, less likely to use marijuana, and get less of a blissful effect from marijuana. There was an article this week in Nature Communications (doi:10.1038/ncomms7395​)​ which showed that the presence of  the FAAH variant allele “enhances fronto-amygdala connectivity and fear extinction learning, and decreases anxiety-like behaviours.” Of some interest, they were able to implant this human genetic variant into mice and showed that in both humans and mice, there was enhanced fear-extinction and decreased levels of anxiety.

–these genetic differences may be reflected in drug use/self-medicating, eg patients without this mutation are more likely to use daily marijuana to decrease their anxiety symptoms, and are also more likely to suffer withdrawal from marijuana on stopping ingestion. In fact a study of 2100 healthy volunteers found that those with 2 copies of the mutant gene had lower rates of cannabis dependence (11% vs 26%)

–there are also many articles in the literature on mu opioid receptor variants (eg, see doi:10.1111/j.1471-4159.2007.04738.x) on the single nucleotide polymorphism A118G, which  is variably common in the general population (from 1-2% in African-Americans to 50% in Japanese). This variant of the mu receptor affects endorphin binding and signaling of the receptor and clinically is associated with improved clinical outcomes in alcoholic patients treated with naltrexone. Other data show that mu-receptor polymorphisms are associated with higher requirements of morphine for pain relief ( –This may help explain the variability in opiate dosages needed in clinical practice and perhaps in developing addiction??

–the article does take pains to point out that the environment does play a key role here (ie, it is not just biological determinism), noting that primates at low risk genetic of addiction can easily become compulsive drug users in the setting of stress and access to cocaine.  The primates lose their dopamine D2 receptors — I assume by down-regulation from excessive cocaine stimulation, but most of the primates are able to recover them on stopping the cocaine.

So, one implication of the genetic variations is that the concept of “just say no” is a tad more complex, given that there are apparently significant hard-wired differences in the drive to use drugs and maybe with the potential to addiction. Also these types of genetic differences could explain in part, for example, why when there is a significant trauma witness by many people, only some of them develop PTSD. It is also interesting that cannabinoid receptors are among the most numerous in the brain, which reinforces the evolutionary importance of the fear/anxiety (“fight or flight”) response and the ability to modulate it — eg, it is important to understand and protect oneself from dangerous situations, but also to be able to modulate that response (or else one just cowers in a dark corner shaking in fear of potential predators and starves to death…..). The point is that there are very developed intrinsic systems in the human body which regulate responses to external stimuli. Some of these involve the fear/anxiety and reward systems, as above. External psychoactive chemicals can overwhelm these intrinsic systems and have unfortunate adverse effects in this excessive, unregulated manner (affecting addiction, and the clinical sequelae of the many levels of functional and cognitive impairment).

Primary Care Corner with Geoffrey Modest MD: Marijuana Adverse Effects Review

6 Aug, 14 | by EBM

there have been several concerning studies about the adverse effects of marijuana, of increasing importance now as legalization becomes more of an issue (which is not to say that other legal substances, such as alcohol or cigarettes, are better than marijuana. just that there are several newer studies showing that adverse effects of marijuana are more impressive than was understood before, and, with more widespread access, may lead to significant morbidity). in addition, the potency of marijuana has increased dramatically (THC content in 1980s of 3%, now it’s 12%). the natl institute on drug abuse (NIDA), a division of NIH, just published an overall review (see DOI: 10.1056/NEJMra1402309). Findings:

short-term effects:

–impaired short-term memory, making it difficult to learn and retain information
–impaired motor coordination, increasing risk of injury (esp motor vehicular). relationship between blood THC levels and performance in driving-simulation studies. more car accidents if use marijuana, but alcohol is worse.
–altered judgment, esp increase in high-risk sexual behaviors
–paranoia and psychosis, esp with higher doses

long-term effects:

–risk of addiction: approx 9% of users become addicted (per DSM-IV criteria), increasing to 1 in 6 in those who start as teenager and to 25-50% of those who smoke daily (2.7 million people in US over age 12 meet criteria for addiction, and 8.6 million meet addiction criteria for alcohol). withdrawal symptoms include irritability, sleeping difficulties, dysphoria, craving, anxiety. in general, adolescents seem to be more susceptible to adverse long-term effects, perhaps because the brain, including the endocannabinoid system, is actively developing in adolescence. cannabinoid dependence is 2-4 times more likely if begin marijuana as adolescent vs adult.

–brain development: brain is actively developing until around age 21. adults who smoked marijuana regularly as adolescents have fewer neural connections in specific brain regions, 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). and, not surprisingly, frequent findings of decreased IQ in frequent users. also, poorer educational outcomes and increased likelihood of dropping out of school.

–gateway drug: unclear if marijuana use leads to other drug use, or if those inclined to drug use just start with marijuana (cheap, accessible). but, some of the animal studies are concerning: those exposed to marijuana when young have alterations in their mesolimbic dopamine reward systems, which can prime the brain for enhanced responses to other drugs

–relation to mental illness: some data that there is increase in psychosis, esp in those with genetic predisposition, though hard to establish causality. heavy use associated with earlier first psychotic episode than otherwise expected.

–cancer: lung cancer possibly associated, but nowhere near level of cigarettes. seems to be more chronic bronchitis (and inflammation of large airways, increased airway resistance, lung hyperinflation) in chronic marijuana smokers. some increase in respiratory infections and pneumonia. association with vascular disease (MI, stroke), with noted acute changes in vascular resistance and coronary microcirculation.

positive effects (ie, the rationale for medicinal marijuana):

–stimulate appetite, esp in those with AIDS (though there are some data that marijuana could exacerbate HIV-associated cognitive deficits)
–combating nausea/vomiting, esp in those on chemotherapy
–helping relieve severe pain and some types of spasticity
–decreasing intraocular pressure in those with glaucoma
–anti-inflammatory effects –role in IBD or rheumatoid arthritis (some data on cannabidol, which is devoid of psychoactive effects)
–MS — some efficacy for neuropathic pain, sleep disturbance, and spasticity

so, the brain effects are particularly concerning. also, the old mantra that marijuana is non-addicting seems to be wrong. at the health center, we are certainly seeing lots of patients, adolescents but also 70 year olds, smoking marijuana regularly. a few are able to decrease or stop just by engaging them in discussion (more so, in my experience, in adults than teens). others may benefit from psychosocial support, including cognitive behavioral therapy and motivational interviewing.


Primary Care Corner with Geoffrey Modest MD: Marijuana psych effects

9 Apr, 14 | by EBM

a recent animal study assessed the effects of cannabinoid receptor stimulation on adolescent rats, finding  brain changes similar to those found in schizophrenia (see  here). this study adds physiologic plausibility to the observed increased incidence of psychosis in human marijuana users in observational cohort studies (see below). given the current remarkable increase in marijuana potency, increasing usage overall, and new legalization, i thought it was useful to review some of the newer data on adverse effects, concentrating on the psych ones. it is notable that the onset of both addiction-related syndromes and psychosis typically occur in adolescence. in the rat study (i will not go into all of the gory details):

 –rats with persistent stimulation of the cannabinoid 1 receptor, but only during specific windows of adolescence (ie, only in early or mid adolescence and not during late adolescence or adulthood), develop a long-lasting prefrontal cortex disinhibition, with a functional downregulation of GABAergic transmission. One key finding is that this disinhibition is enduring into adulthood in rats but only if stimulated during these susceptible developmental times of early to mid adolescence.
–other studies find an important role of impaired GABA transmission in schizophrenia

an older lancet study provided a meta-analysis of longitudinal studies to assess the relationship between marijuana use in adolescence and psychosis (see here). although these were observational studies (so can’t really draw ironclad conclusions), these studies were long-term, so as to minimize the likelihood of reverse causality (eg, patients with imminent psychosis using more marijuana) and are not related to the acute, transitory, psychotic-like effect of acute marijuana usage. their findings:

–after thorough literature search, 7 cohort studies identified which were population-based longitudinal studies, including 2 birth cohorts from Dunedin
–there was a consistent relationship in these studies, finding an average 41% increased risk of schizophrenia (or schizophreniform disorder) with cannabis use. the most rigorous studies (swedish study and dunedin study) found an odds ratio of 2.58.
–6 studies looked at cannabis use frequencies, consistently finding that increased usage was associated with increased risk (50-200% increase)
–the Dunedin study found a stronger effect of cannabis on psychotic symptoms in those who used cannabis prior to age 16
–several studies assessed the presence of psychotic symptoms lasting longer than one month and another only looked at hospital admissions for schizophrenia, making acute intoxication as cause of psychotic symptoms unlikely
–by eliminating patients with known psychosis or predisposition to psychosis at baseline, controlling for up to 60 potential covariates (other substance use, mental health problems, personality traits, sociodemographic markers, etc), and following cohort for years before using cannabis, there was less likelihood for reverse causality (eg, Dunedin study adjusted for psychotic symptoms at age 11, looked at cannabis and psychosis measures at age 15 and 18)
–data on depression/affective disorders, suicidal thoughts, anxiety were examined separately, but marijuana usage was less consistently associated than for psychosis

 so, these 2 studies suggest that :

–especially during early adolescence (in rats and humans) there seems to be increased risk of long-term psychotic effects of marijuana use and this increase is dose-dependent.
–the implications seem pretty profound, since 20% of young people report using marijuana at least once a week and this increased use reported now is especially during early adolescence
–there can never be a randomized controlled trial of marijuana use and psychotic outcomes to prove causation.  but, this meta-analysis is one of the most careful i have seen, and the results are consistent over the several studies analyzed.
–in light of the physiologic possibility (in rats) and the potential increase in psychosis for the huge numbers of human marijuana users (40% of young adults report using marijuana in UK, which translates into a possible 14% of all psychotic outcomes might have been avoidable if marijuana not used), the better part of valor would be to inform young patients of psychosis as a potentially very serious complication of marijuana use.

 another review from the lancet (see here) reviewed the adverse effects of non-medical use of marijuana.  for psych effects, they note the well-accepted impairment in cognitive function in regular users, also noting deficits in verbal learning, memory and attention in heavy users (duration, frequency of use, cumulative dose of THC). there seems to be at least partial recovery after 2 years of abstinence in some but not all studies. also reported are structural brain changes (reduced hippocampus and amygdala volume in chronic users), as well as poor school performance, and early school leaving, with their attendant social consequences. again, most of this is based on observational studies, so cannot posit a direct causal relationship.

but, on the other hand, the American Academy of Neurology published guidelines on complementary/alternative medicine in multiple sclerosis, noting that cannabis has been shown to decrease spasticity and pain (excluding central neuropathic pain), and the spray seems to work for spasticity symptoms, pain and urinary frequency, though cannabis unlikely to improve objective measures of spasticity or urinary symptoms (see DOI 10.1212/WNL.0000000000000250).


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