"Long before it's in the papers"
January 27, 2015


Adolescence may be key time when pot harms the brain

July 24, 2013
Courtesy of University of Maryland Medical Center
and World Science staff

Reg­u­lar ma­ri­jua­na use in ad­o­les­cence, but not adult­hood, may per­ma­nently im­pair the brain and raise the risk of be­com­ing men­tally ill, a new study in mice in­di­cates.

Al­though some pre­vi­ous re­search sug­gested si­m­i­lar con­clu­sions, the new work goes fur­ther in­to ex­plor­ing why the ef­fect oc­curs. Re­search­ers hope the stu­dy, pub­lished in the jour­nal Neu­ro­psy­chophar­ma­col­ogy, will help clar­i­fy the drug’s po­ten­tial long-term ef­fects as law­mak­ers in var­i­ous U.S. states con­tem­plate le­gal­iz­ing it.

“Over the past 20 years, there has been a ma­jor con­tro­ver­sy about the long-term ef­fects of ma­ri­jua­na, with some ev­i­dence that use in ad­o­les­cence could be dam­ag­ing,” said the stu­dy’s sen­ior au­thor, Asaf Kel­ler of the Uni­vers­ity of Mar­y­land School of Med­i­cine. 

“Ado­les­cence is the crit­i­cal pe­ri­od dur­ing which ma­ri­jua­na use can be dam­ag­ing,” added the stu­dy’s lead au­thor, Sylv­ina Mul­lins Rav­er, a Ph.D. can­di­date at the uni­vers­ity. “We wanted to iden­ti­fy the bi­o­log­i­cal un­der­pin­nings and de­ter­mine wheth­er there is a real, per­ma­nent health risk.”

“Pre­vi­ous re­search has shown that chil­dren who started us­ing ma­ri­jua­na be­fore the age of 16 are at great­er risk of per­ma­nent cog­ni­tive deficits, and have a sig­nif­i­cantly high­er in­ci­dence of psy­chi­at­ric dis­or­ders such as schiz­o­phre­nia,” Kel­ler said. “There likely is a ge­net­ic sus­cep­ti­bil­ity, and then you add ma­ri­jua­na dur­ing ad­o­les­cence and it be­comes the trig­ger.”

The sci­en­tists be­gan by ex­am­in­ing cor­ti­cal os­cilla­t­ions in mice. Cor­ti­cal os­cilla­t­ions are pat­terns of nerve cell ac­ti­vity in the brain and are be­lieved to un­der­lie the brain’s var­i­ous func­tions. These os­cilla­t­ions are very ab­nor­mal in schiz­o­phre­nia and in oth­er psy­chi­at­ric dis­or­ders. The sci­en­tists ex­posed young mice to very low doses of the ac­tive in­gre­di­ent in ma­ri­jua­na for 20 days, and then al­lowed them to re­turn to their sib­lings and de­vel­op nor­mal­ly.

“In the adult mice ex­posed to ma­ri­jua­na in­gre­di­ents in ad­o­les­cence... cor­ti­cal os­cilla­t­ions were grossly al­tered, and they ex­hib­ited im­paired cog­ni­tive abil­i­ties,” said Rav­er. “We al­so found im­paired cog­ni­tive be­hav­ior­al per­for­mance in those mice. The strik­ing find­ing is that, even though the mice were ex­posed to very low drug doses, and only for a brief pe­ri­od dur­ing ad­o­les­cence, their brain ab­nor­mal­i­ties per­sisted in­to adult­hood.”

The sci­en­tists re­peat­ed the ex­pe­ri­ment, this time ad­min­is­ter­ing ma­ri­jua­na in­gre­di­ents to nev­er-be­fore-ex­posed adult mice. Their cor­ti­cal os­cilla­t­ions and abil­ity to per­form cog­ni­tive be­hav­ior­al tasks ap­peared to stay nor­mal. 

The re­search­ers also tried to pin­point the mech­an­isms un­der­ly­ing the changes in young mice and the time pe­ri­od in which they oc­cur.

“We looked at the dif­fer­ent re­gions of the brain,” said Kel­ler. “The back of the brain de­vel­ops first, and the front­al parts of the brain de­vel­op dur­ing ad­o­les­cence. We found that the front­al cor­tex is much more af­fect­ed by the drugs dur­ing ad­o­les­cence. This is the ar­ea of the brain that con­trols ex­ec­u­tive func­tions such as plan­ning and im­pulse con­trol. It is al­so the ar­ea most af­fect­ed in schiz­o­phre­nia.”

Kel­ler’s team be­lieves the re­sults have im­plica­t­ions for hu­mans as well. “The pur­pose of stu­dying these mech­an­isms is to see wheth­er we can re­verse these ef­fects,” said Kel­ler. “We are hop­ing we will learn more about schiz­o­phre­nia and oth­er psy­chi­at­ric dis­or­ders, which are com­pli­cat­ed con­di­tions. These cog­ni­tive symp­toms are not af­fect­ed by med­ica­t­ion, but they might be af­fect­ed by con­trolling these cor­ti­cal os­cilla­t­ions.”

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Regular marijuana use in adolescence, but not adulthood, may permanently impair the brain and raise the risk of getting psychiatric illnesses such as schizophrenia, a new study in mice indicates. Although some previous research suggested similar conclusions, the new work goes further into exploring why the effect occurs. Researchers hope the study, published in the journal Neuropsychopharmacology, will help clarify the drug’s potential long-term effects as lawmakers in various U.S. states contemplate legalizing it. “Over the past 20 years, there has been a major controversy about the long-term effects of marijuana, with some evidence that use in adolescence could be damaging,” said the study’s senior author, Asaf Keller of the University of Maryland School of Medicine. “Adolescence is the critical period during which marijuana use can be damaging,” added the study’s lead author, Sylvina Mullins Raver, a Ph.D. candidate at the university. “We wanted to identify the biological underpinnings and determine whether there is a real, permanent health risk.” “Previous research has shown that children who started using marijuana before the age of 16 are at greater risk of permanent cognitive deficits, and have a significantly higher incidence of psychiatric disorders such as schizophrenia,” Keller said. “There likely is a genetic susceptibility, and then you add marijuana during adolescence and it becomes the trigger.” The scientists began by examining cortical oscillations in mice. Cortical oscillations are patterns of nerve cell activity in the brain and are believed to underlie the brain’s various functions. These oscillations are very abnormal in schizophrenia and in other psychiatric disorders. The scientists exposed young mice to very low doses of the active ingredient in marijuana for 20 days, and then allowed them to return to their siblings and develop normally. “In the adult mice exposed to marijuana ingredients in adolescence, we found that cortical oscillations were grossly altered, and they exhibited impaired cognitive abilities,” said Raver. “We also found impaired cognitive behavioral performance in those mice. The striking finding is that, even though the mice were exposed to very low drug doses, and only for a brief period during adolescence, their brain abnormalities persisted into adulthood.” The scientists repeated the experiment, this time administering marijuana ingredients to adult mice that had never been exposed to the drug before. Their cortical oscillations and ability to perform cognitive behavioral tasks remained normal, indicating that it was only drug exposure during the critical period of adolescence that impaired cognition through this mechanism. The researchers took the next step in their studies, trying to pinpoint the mechanisms underlying these changes and the time period in which they occur. “We looked at the different regions of the brain,” said Keller. “The back of the brain develops first, and the frontal parts of the brain develop during adolescence. We found that the frontal cortex is much more affected by the drugs during adolescence. This is the area of the brain controls executive functions such as planning and impulse control. It is also the area most affected in schizophrenia.” Keller’s team believes the results have implications for humans as well. “The purpose of studying these mechanisms is to see whether we can reverse these effects,” said Keller. “We are hoping we will learn more about schizophrenia and other psychiatric disorders, which are complicated conditions. These cognitive symptoms are not affected by medication, but they might be affected by controlling these cortical oscillations.”