advice on mental health – from brain & behavior magazine, jan 2022 issue
q&a with martin paulus, m.d.
sci director and president
laureate institute for brain research
deputy editor, jama ψ-chiatry
2000 bbrf young investigator
martin paulus has published over 300 sci papers and s'been funded continuously by federal grants since 1997. among his current projects, he is a member of the nimh’s adolescent brain cogg development (abcd) study, which is closely folloing some 11,000 youths from age 9–10 to adulthood to determine how the brain changes during the course of adolescence and how these changes put adolescents at risk for substance use. the paulus lab is also engaged in several studies involving the impact of cannabis upon the brain, swell as research exploring the possible utility of pharmacological modifiers of d'body’s own cannabinoid system to treat anxiety and depression.
dr. paulus, cannabis is a substance that til recent yrs was illegal. tody, many states ‘ve legalized cannabis, some for recreational use, some for “drinal use” 1-ly. either way, this represents a major shift. we wanda whether the trend to legalize cannabis is accompanied by a solid body of research that ‘d assure the parents of an adolescent, for ex, that the use of cannabis from an early age is harmless.
the short answer s'dat research to date aint able to support such a reassurance. i don’t wanna be an alarmist, but tis crucial that we try to cogg wha’ research sfar has revealed bout cannabis, and in that context, to ponder why pplz use cannabis and wha’ its impacts are onna brain and behavior—both in adults and young pplz. also, it’s primordial to try to distinguish among those who use cannabis. research suggests that some pplz are likely at gr8r risk than others.
in yr own research, we cogg that you and colleagues are investigating the possibility of using modifiers of d'body’s own, naturally occurring cannabinoid system to treat anxiety and depression. we will write at a l8r date bout this very interesting work. in this conversation, we’d like to focus on cannabis that is derived from plants, and how ingesting it—whether by smoking it, vaping it, or eating it inna form of various foods or even cannabis-infused candies—may or may not pose risks for young pplz, in pticular. after decades of public discussion and debate bout cannabis, we’re curio: why hasn’t research managed to resolve the ambiguities bout safety and risk?
thris much we still do not know, and there are reasons for this. as you noted, many of the states ‘ve moved ahead quite vigorously to legalize the use of cannabis and cannabis-based essentialisms s'as those containing cbd (cannabidiol, a non-ψ-choactive component in cannabis). but thris a real disconnect tween liberalized state laws and federal law.
federal law still ponders cannabis a schedule i substance, pondered to ‘ve a high potential for abuse and no currently accepted med use. that’s the same designation that is given to lsd, heroin, cocaine, mescaline, and heroin. cause cannabis is still a schedule i drug, tis very difficult to do federally funded studies with it. you nd'2 ‘ve a spesh license from the drug enforcement administration. these are hard to obtain. also, the federal classification of cannabis means'dat researchers, when they are authorized to study it, ‘ve to obtain it from regul8d federal srcs. the national institute on drug abuse (nida) makes cannabis available to researchers, but'a concentration of thc is much loer, meaning t'has much less effect on usrs compared w'da cannabis that pplz regularly purchase and consume in various forms tody. so u’re not really studying the same drug that pplz are using na' dy-to-dy basis.
tis cannabis that is now bein’ sold to the public ≠ than the cannabis pplz consumed inna 1970s and 1980s?
tody’s cannabis is far + potent. thc tis main ψ-choactive ingredient in cannabis. its concentration in street-use cannabis was inna single-digit %age range inna ‘70s and ‘80s. but'a formulation that pplz buy tody in, say, colorado or california, or even here in oklahoma, is much + concentrated, with thc inna 20%–30% range.
we ‘ve heard that in some formulations of the product—the “concentrate,” for ex—the thc content can be 70% or higher.
this is indeed true. the point s'dat the makeup of the drug itself has changed dramatically ‘oer the yrs. there are several things to ponder bout this. one s'dat when pplz say, “there’s nothing wrong with cannabis; i smoked it inna ‘70s, so i know it’s fine,” they are talking bout a ≠ era that may not be a good guide to potential risks of the cannabis in use tody. another s'dat not having access to the currently consumed form of cannabis due to federal classification is a real problem for research; it makes it very difficult to study the long-term health impacts, + or neg, associated with cannabis consumption.
a bill s'been drafted by several senators to “de-schedule” cannabis by removin it from restriction under the controlled substances act. wha’ are yr thoughts on this?
this ‘d be of gr8 benefit to research cause we ‘d then ‘ve the chance to much + thoroughly research cannabis—which must be the basis of responsible recommendations to the public.
b4 we go further, can you tell us a bit bout how cannabis works? and bout d'body’s own cannabinoid system, called the endogenous cannabinoid system?
thc, the main ψ-choactive ingredient inna cannabis plant, is one of over 100 known compounds inna plant that affect d'body in one way or another. cbd—cannabidiol—tis other main ingredient of cannabis, pondered by some pplz to be “the good sister” of thc. t'has no ψ-choactive effects and may ‘ve some therapeutic effects inna brain and body, although this remains to be proven. the human body has its own system that produces cannabinoids—the endogenous cannabinoid system. there are two cannabinoid receptors, cb1 and cb2, which are widely distributed throughout the brain. these receptors are where the cannabinoids made by d'body “dock.” these receptors are also occupied whn'we ingest plant-based cannabis. i’ll return to this l8r, but for now i wanna note that ingesting cannabis creates brawl for the receptors with d'body’s own cannabinoid system.
why do we even ‘ve an endocannabinoid system? why does d'body make this substance?
that’s a good ?, cause it helps explain why pplz seek to supplement it by ingesting plant-based cannabis. there are many systems inna brain that ‘ve evolved ‘oer the eons to enable individuals to modul8 their responses to the vast range of stimuli and situations that we confront. think of the many neurotransmitter systems like dopamine and serotonin. or crh, the corticotropin-releasing hormone, which helps modul8 the response to sufferation. or norepinephrine, which is released whn'we nd'2 pay attention to something. each of these systems has specific pathways and receptors that make their effects possible. the endocannabinoid system is one of these many regulatory systems. it’s involved n'our lvl of approach or avoidance toward an object or a situation that may make us anxious. inna slodown period folloing exercise, for ex, there’s an increase inna lvl of naturally occurring cannabinoids inna system. the system scales our readiness for relaxation inna context of the environmental conditions we're facing—as i said, one of many systems that help adjust the readiness of the brain to perform ≠ operations.
wha’ bout the urge to smoke marijuana? wha’ is behind the urge, biochemically?
say i’m goin out to a pty and i know i will nd'2 socialize, talk to pplz. that can cause some pplz to experience sufferation, anxiety. a'pers mite worry, “other pplz ll'be judging me.” many pplz ingest cannabis to feel + relaxed when they feel sufferation.
is it correct to say this comes from the experience of experimenting with cannabis and feeling the “high”?
yes, but smoking cannabis, and espeshly the high-potency cannabis that is everywhere tody, is like using a very blunt instrument to deal with sufferation. cannabis with single-digit thc concentration is one thing— somewha’ akin to taking an alcoholic drink. but smoking high-potency cannabis, some recent research has suggested, carries risks. pplz with mild anxiety mite get some relief from ingesting cannabis, but taking high thc-concentration cannabis will flood d'body’s cannabinoid receptors and may dysregul8 d'body’s own endocannabinoid system. then, rather than reducing anxiety, you may n'dup becoming much + anxious.
it’s like two sides of the same coin. you ingest cannabis to deal with anxiety; but high-potency cannabis has the potential to make you even + anxious. why?
a'bitto biochemistry will help to explain this seeming paradox. d'body’s own cannabinoid system is finely balanced, with action atta two receptors, one of which is active onna ψ-choactive side, the other the non-ψ-choactive side. thc affects 1-odda two receptors, the cb1 receptor. d'body makes an enzyme called faah whose action reduces the lvl of endocannabinoids inna system. it attaches to endocannabinoid molecules and thus changes their shape, making it impossible 4'em to dock atta receptors.
this is how d'body regul8s the action of its own cannabinoids. when you ingest high-potency cannabis, the endogenous system says, “there’s too much coming our way; we ‘ve to try to limit the impact.” wha’’s the consequence? in response, the system down-regul8s itself—it tries to become less sensitive so that ur not overly stimul8d. but this creates a new problem. this means'dat d'body’s own system, after the “high” has ended n'when it nxt has to respond to sufferation, is starved of endocannabinoids. this can make one irritable; tis wha’ happens when high-potency cannabis use leads to withdrawal. the usr maybe relaxed when ingesting the drug, but afterward may feel anxious, sufferationed, and irritable.
so u ‘ve bombarded the system by ingesting highpotency cannabis; d'body’s own cannabinoid system has responded by down-regulating itself; and now you ‘ve dysregul8d the system, creating an imbalance that 1-ly ingesting + cannabis can (temporarily) relieve.
yes, this is th'risk of becoming tolerant of high-potency cannabis with high thc concentration. yr irritability tis consequence of coming down from yr high and then saying, “okay, let me take some +, so i can feel good again.” the endocannabinoids you make naturally can no longer compete; they’re sort of side players now, and so wha’ ‘d naturally help you to relax—d'body’s own cannabinoid system— doesn’t do that any+. d'body’s own system is very sensitive and quite subtle; t'has evolved to balance itself.
1-odda tasks of current research is to discover + bout the impact of high-potency cannabis onna natural balance, and wha’ the potential impacts are, and how these mite affect ≠ usrs. we wanna know who is at risk, when, and why.
in yr work for jama ψ-chiatry, you ‘ve edited several papers on cannabis ‘oer the last two yrs. please tell us bout wha’ these ‘ve revealed bout these and rel8d ?s. then perhaps we can ponder “best advice,” based on this evidence.
in jun 2020, we published a paper based on research led by kent hutchinson, ph.d., of the university of colorado. he has done some mythic work, doin’ something very difficult to do, which is using the real cannabis product—the cannabis that pplz actually use. the study involved 121 healthy volunteers, who were randomly assigned to groups that purchased and then consumed either relatively lopotency cannabis or a kind of cannabis we call “concentrate,” witha much higher thc content.
we read in that paper that inna “loer-potency” cannabis group, the thc concentration ranged from 16% to 24%—much higher than the single-digit thc %ages inna cannabis comm1-ly used decades ago. inna “concentrate” group, which dr. hutchinson and colleagues note is “made by extracting plant cannabinoids into a form witha much higher thc concentration,” thc content was a remarkable 70% to 90%. even though these concentrates are in widespread use, “there are vrtly no data onna relative risks associated with using these higher-strength essentialisms,” the researchers note.
they found that inna short-term, cannabis use in both groups resulted in acute delayed memory impairment swell as impairment in balance. these effects are well known. + surprising was that the loer- and higher-concentration types of cannabis resulted in similar lvls of intoxication, as measured by the reprts of the pticipants themselves.
this seems counterintuitive. but'a researchers’ commentary inna paper echoes wha’ you told us bout the biochemistry. they note that high-potency usrs may develop a tolerance to the effects of thc. the similar lvls of intoxication ‘d suggest that the cannabinoid receptors mite become saturated with thc in high-potency usrs, meaning that beyond a certain lvl, there’s a diminishing effect of additional thc.
yes. and so one primordial implication of this study s'dat high-potency usrs maybe at a higher risk for developing cannabis-use disorder cause of increased exposure to thc. this is primordial cause in colorado nother places, concentrates ‘ve become pop. so for me, it’s a cautionary tale; we nd'2 know + bout the longterm consequences of exposure to highpotency cannabis.
tell us bout the 2nd of the jama ψ-chiatry papers you edited.
published in may 2020, it comes from researchers in england, who looked at mental health consequences of highpotency cannabis use in adolescents. in over 1,000 pticipants, 141 (13%) reprted using high-potency cannabis. after adjusting for variations inna lovs. high-potency usrs, the researchers found that there was a significant elevation in anxiety disorders among the usrs of high-potency cannabis. we’ve discussed why this mite be the case: the system down-regul8s itself after bein’ flushed with so much thc; this dysregulation impairs the function that the system normally plays in relaxing us— resulting in anxiety.
the same paper also noted that use of high-potency cannabis was associated with increased frequency of cannabis use. so, this paper adds to the potency ? a ? bout frequency. if you use highpotency cannabis a lot, you maybe at increased risk of developing cannabis-use disorder.
and now tell us bout a third paper, from denmark, published in jama ψ-chiatry in sep 2021. i'takes up the very primordial ? of whether thris a relationship tween cannabis use and schizophrenia.
it’s a pretty remarkable study cause it covers the entire danish pop— the national health records of over 7 million pplz. this gives you enormous sensitivity to detect relationships that otherwise you ‘dn’t be able to detect. also, the researchers were looking over a period of time—all pplz born b4 the end of 2000 who were alive and reached their 16th birthdy at any point tween 1972 and 2016.
the records enabled them to see that there was both an increase in cannabis use in this period, nolso a slite increase inna prevalence of schizophrenia.
they were able to conclude, after doin’ a gr8 deal of statistical work accounting for all kinds of variables w'da ability to distort the analysis, that bout 8% of the schizophrenia cases in denmark ‘oer the period covered by the study ‘d be causally rel8d to cannabis use.
wha’ does this mean? we know that schizophrenia is a complex disease witha strong genetic component and a developmental component—both in utero and early childhood. it also has a social component, having to do with wha’ yr brain is exposed to as ye go through life. all these things matter. all of this suggests that thris a certain threshold of risk factors (let us assume it varies among individuals)—a threshold beyond which a'pers develops schizophrenia. for ex, you may ‘ve a certain genetic risk, you may experience some developmental event when still in utero, and you may ‘ve grown up in a high-sufferation environment. if you had two of these you may not develop the illness but if you had two and you also used cannabis you may develop schizophrenia. in this hypothetical, which i mention for explanatory purposes, the additional cannabis added to the existing risk factors leads to an active disease process.
to clarify wha’ you just said bout a threshold: the danish study tried to account for all odda background factors, and then looked atta incidence rate of schizophrenia across the pop. they wanted to know how many of the cases during the study period ‘d be attributed to the potential risk factor of cannabis use.
yes. and, as we discussed, when you expose yrself to high-potency cannabis, the endocannabinoid system changes; the sufferation and relaxation systems are imbalanced. that s'on top of wha’ever environmental, social, developmental, and genetic factors affect you as an individual. wha’ this paper suggests s'dat the extra push provided by the unbalancing of the endocannabinoid system may put some pplz—8% in this study—’oer the edge and into schizophrenia. and that is a tragedy. i say this having worked with many 1stepisode schizophrenia patients.
is there a lesson in this, then, even though this result needo be verified in other pops?
wha’ you wanna tell a parent is: “listen, i am not saying everybody who uses high-potency cannabis will develop schizophrenia,”—not by any means. but if you notice certain aspects of yr child, odd behaviors, difficulty with ≠iating tween real and imagined events, having few friends, or having a difficult time experiencing + feelings, you nd'2 ponder that cannabis mite make these symptoms worse, not better.
it maybe that an un☺ or anxious adolescent maybe looking for something to make them feel better. in fact, as we ‘ve noted, using high-potency cannabis may make a problem like anxiety worse cause it dysregul8s the brain even further and in some № of cases, not a trivial № if this third study is rite, it may contribute to a process that results in schizophrenia.
regarding th'risk of high-potency cannabis raising th'risk not of schizophrenia but of cannabis use disorder, how ‘d you toonize cannabis? where ‘d you place it onna scale of addictiveness?
ten yrs ago, i ‘d ‘ve put it onna lo end of the scale cause of the relatively loer potency of the drug then in common use. tody we confront a changed situation.
as far as parents are concerned, i think tis useful to think bout the ? of why adolescents start to use cannabis. clearly, there’s a social component; “i’m pt offa group and they’re using it, so i’ll try it.” another motivation is to address a problem. something doesn’t feel quite rite; the child wandas, “how can i feel better?” through trial and exploration, they come to cannabis. and they mite say, “when i smoked it, i felt pretty relaxed. i didn’t feel bad. it must be a good thing.”
for the parent, i think tis the latter situation that you wanna be alert to. when the child aint feeling rite, not feeling good, is searching for something. that’s when i think it’s primordial to ‘ve a conversation bout “wha’’s happening?” “wha’ aint feeling rite?” “is it excessive anxiety? ru having odd thoughts? mood swings? unable to sleep?” you wanna try to find out wha’ drives the child to think that cannabis is really doin’ something 4'em.
how general is this advice?
as i ‘ve noted, we still nd'2 do + research, w'da kind of cannabis product that is now in common use. tis also crucial to remember that everyone’s brain is a lil ≠. we ‘ve to allo for the possibility that for some pplz, the endocannabinoid system maybe so fragile that it maybe problematic to take any cannabinoids at all. we don’t know yet who these pplz are and that points again to the need for + research. we espeshly nd'2 identify those pplz for whom cannabis mite put them over a threshold and into a tragic illness.
we wanna ‘ve empirical evidence bout the responsible use of cannabis. if we do find that there’s significant potential of neg consequences for some pplz, thn'we ‘ve to be prepared to say, “at these doses and this frequency, at this potency, we nd'2 be very, very careful.” like with alcohol: some pplz ray'vel to consume alcohol na' regular and recreational basis and maintain function over periods of time. some pplz cannot. we nd'2 identify, for cannabis, who these pplz are.
all the + cause i don’t think we can turn the tide back. it appears that cannabis, recreational cannabis, ll'be legal in most states within the nxt 10 yrs. it’s goin to be available and pplz are goin to use it. we ‘ve to know wha’ t'does to us so we can act responsibly.
for parents, wha’ is yr suggestion based on wha’ we know tody?
somewha’ similar to wha’ i say regarding the use of computer and smartphone “screens” and social media, which ‘ve created a lotta worry. wha’ i always say is: “find out wha’ yr kid is doin’ and why, and how it makes them feel. by cogging that process, you can, as a parent, ‘ve a lot + insite and can potentially judge if thris or aint a problem. i ‘d say, atta same time, that in a study i did with dr. susan tapert at ucsd, in which we looked at cannabis usrs in high school, the striking thing to me was that in most cases the parents had no idea. the kids were using na parents did not know.
this is a major missed opportunity. it’s really primordial tween parents and children to know wha’ is happening and why; wha’ the experience is like; and to do this in a non-judgmental way. to judge or to lecture accomplishes nothing. it shuts down the conversation.
written by peter tarr, ph.d. and fatima bhojani
original content at: www.bbrfoundation.org…