The Addicted Brain and New Treatment Frontiers: 6th Annual Aspen Brain Forum

Resources

Websites

Life of the Party at UCSB

National Association of Drug Court Professionals. What Are Drug Courts?

The Marijuana and Cannabinoids: A Neuroscience Research Summit. National Institutes of Health. 2016.

The System We Need [video]. The Kennedy Forum.

Truth Initiative

Jeremy Waletzky. A Personal Story of Despair and Hope, and the Origin of the Jacob P. Waletzky Award. National Institute on Drug Abuse. December 2, 2015.

Journal Articles

24/7 Sobriety Program. RAND Corporation.

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DePoy L, Daut R, Brigman JL, et al. Chronic alcohol produces neuroadaptations to prime dorsal striatal learning. Proc Natl Acad Sci USA. 2013;110(36):14783-14788.

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Farsalinos KE, Polosa R. Safety evaluation and risk assessment of electronic cigarettes as tobacco cigarette substitutes: a systematic review. Ther Adv Drug Saf. 2014;5(2):67-86.

Feng J, Wilkinson M, Liu X, et al. Chronic cocaine-regulated epigenomic changes in mouse nucleus accumbens. Genome Biol. 2014;15(4):R65.

Funk CK, O'Dell LE, Crawford EF, Koob GF. Corticotropin-releasing factor within the central nucleus of the amygdala mediates enhanced ethanol self-administration in withdrawn, ethanol-dependent rats. J Neurosci. 2006;26(44):11324-11332.

Galvan A, Hare TA, Parra CE, et al. Earlier development of the accumbens relative to orbitofrontal cortex might underlie risk-taking behavior in adolescents. J Neurosci. 2006;26(25):6885-6892.

Garcia-Keller C, Kupchik YM, Gipson CD, et al. Glutamatergic mechanisms of comorbidity between acute stress and cocaine self-administration. Mol Psychiatry. 2015.

George O, Sanders C, Freiling J, et al. Recruitment of medial prefrontal cortex neurons during alcohol withdrawal predicts cognitive impairment and excessive alcohol drinking. Proc Natl Acad Sci USA. 2012;109(44):18156-18161.

Gipson CD, Kupchik YM, Shen H, Reissner KJ, Thomas CA, Kalivas PW. Relapse induced by cues predicting cocaine depends on rapid, transient synaptic potentiation. Neuron. 2013;77(5):867-872.

Govindan RM, Behen ME, Helder E, Makki MI, Chugani HT. Altered water diffusivity in cortical association tracts in children with early deprivation identified with Tract-Based Spatial Statistics (TBSS). Cereb Cortex. 2010;20(3):561-569.

Gremel CM, Costa RM. Orbitofrontal and striatal circuits dynamically encode the shift between goal-directed and habitual actions. Nat Commun. 2013;4:2264.

Gruber SA, Dahlgren MK, Sagar KA, Gonenc A, Lukas SE. Worth the wait: effects of age of onset of marijuana use on white matter and impulsivity. Psychopharmacology (Berl). 2014;231(8):1455-1465.

Hardin MG, Mandell D, Mueller SC, Dahl RE, Pine DS, Ernst M. Inhibitory control in anxious and healthy adolescents is modulated by incentive and incidental affective stimuli. J Child Psychol Psychiatry. 2009;50(12):1550-1558.

Hayashi T, Ko JH, Strafella AP, Dagher A. Dorsolateral prefrontal and orbitofrontal cortex interactions during self-control of cigarette craving. Proc Natl Acad Sci USA. 2013;110(11):4422-4427.

Heisler LK, Zhou L, Bajwa P, Hsu J, Tecott LH. Serotonin 5-HT(2C) receptors regulate anxiety-like behavior. Genes Brain Behav. 2007;6(5):491-496.

Hilario MR, Costa RM. High on habits. Front Neurosci. 2008;2(2):208-217.

Hurd YL, Michaelides M, Miller ML, Jutras-Aswad D. Trajectory of adolescent cannabis use on addiction vulnerability. Neuropharmacology. 2014;76 Pt B:416-424.

Jackson NJ, Isen JD, Khoddam R, et al. Impact of adolescent marijuana use on intelligence: Results from two longitudinal twin studies. Proc Natl Acad Sci USA. 2016;113(5):E500-508.

Jeong JW, McCall JG, Shin G, et al. Wireless optofluidic systems for programmable in vivo pharmacology and optogenetics. Cell. 2015;162(3):662-674.

Johnston LD, O'Malley PM, Miech RA, Bachman JG, Schulenberg JE. Monitoring the future national survey results on drug use, 1975–2015: overview, key findings on adolescent drug use. 2016.

Kash TL, Pleil KE, Marcinkiewcz CA, et al. Neuropeptide regulation of signaling and behavior in the BNST. Mol Cells. 2015;38(1):1-13.

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Knackstedt LA, Melendez RI, Kalivas PW. Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking. Biol Psychiatry. 2010;67(1):81-84.

Koob GF, Bloom FE. Cellular and molecular mechanisms of drug dependence. Science. 1988;242(4879):715-723.

Koob GF. A role for brain stress systems in addiction. Neuron. 2008;59(1):11-34.

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Lerman C, Schnoll RA, Hawk LW, Jr., et al. Use of the nicotine metabolite ratio as a genetically informed biomarker of response to nicotine patch or varenicline for smoking cessation: a randomised, double-blind placebo-controlled trial. Lancet Respir Med. 2015;3(2):131-138.

Lisdahl KM, Thayer R, Squeglia LM, McQueeny TM, Tapert SF. Recent binge drinking predicts smaller cerebellar volumes in adolescents. Psychiatry Res. 2013;211(1):17-23.

Lowery-Gionta EG, Marcinkiewcz CA, Kash TL. Functional alterations in the dorsal raphe nucleus following acute and chronic ethanol exposure. Neuropsychopharmacology. 2015;40(3):590-600.

Mackie K. Cannabinoid receptors as therapeutic targets. Annu Rev Pharmacol Toxicol. 2006;46:101-122.

McQueeny T, Schweinsburg BC, Schweinsburg AD, et al. Altered white matter integrity in adolescent binge drinkers. Alcohol Clin Exp Res. 2009;33(7):1278-1285.

Medina KL, Hanson KL, Schweinsburg AD, Cohen-Zion M, Nagel BJ, Tapert SF. Neuropsychological functioning in adolescent marijuana users: subtle deficits detectable after a month of abstinence. J Int Neuropsychol Soc. 2007;13(5):807-820.

Meier MH, Caspi A, Ambler A, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci USA. 2012;109(40):E2657-2664.

Merlo Pich E, Lorang M, Yeganeh M, et al. Increase of extracellular corticotropin-releasing factor-like immunoreactivity levels in the amygdala of awake rats during restraint stress and ethanol withdrawal as measured by microdialysis. J Neurosci. 1995;15(8):5439-5447.

Montague PR, Hyman SE, Cohen JD. Computational roles for dopamine in behavioural control. Nature. 2004;431(7010):760-767.

Murray JE, Belin-Rauscent A, Simon M, et al. Basolateral and central amygdala differentially recruit and maintain dorsolateral striatum-dependent cocaine-seeking habits. Nat Commun. 2015;6:10088.

Nazzaro C, Greco B, Cerovic M, et al. SK channel modulation rescues striatal plasticity and control over habit in cannabinoid tolerance. Nat Neurosci. 2012;15(2):284-293.

Nealey KA, Smith AW, Davis SM, Smith DG, Walker BM. Kappa-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent rats. Neuropharmacology. 2011;61(1-2):35-42.

Nestler EJ, Malenka RC. The addicted brain. Sci Am. 2004;290(3):78-85.

Nestler EJ. Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci. 2001;2(2):119-128.

Nicosia N, Kilmer B, Heaton P. Can a criminal justice alcohol abstention programme with swift, certain, and modest sanctions (24/7 Sobriety) reduce population mortality? A retrospective observational study. Lancet Psychiatry. 2016;3(3):226-232.

Park K, Volkow ND, Pan Y, Du C. Chronic cocaine dampens dopamine signaling during cocaine intoxication and unbalances D1 over D2 receptor signaling. J Neurosci. 2013;33(40):15827-15836.

Ramoa CP, Hiler MM, Spindle TR, et al. Electronic cigarette nicotine delivery can exceed that of combustible cigarettes: a preliminary report. Tob Control. 2016;25(e1):e6-9.

Ravinder S, Burghardt NS, Brodsky R, Bauer EP, Chattarji S. A role for the extended amygdala in the fear-enhancing effects of acute selective serotonin reuptake inhibitor treatment. Transl Psychiatry. 2013;3:e209.

Sagar KA, Dahlgren MK, Gonenc A, Racine MT, Dreman MW, Gruber SA. The impact of initiation: Early onset marijuana smokers demonstrate altered Stroop performance and brain activation. Dev Cogn Neurosci. 2015;16:84-92.

Sari Y, Smith KD, Ali PK, Rebec GV. Upregulation of GLT1 attenuates cue-induced reinstatement of cocaine-seeking behavior in rats. J Neurosci. 2009;29(29):9239-9243.

Schlosburg JE, Whitfield TW, Jr., Park PE, et al. Long-term antagonism of kappa opioid receptors prevents escalation of and increased motivation for heroin intake. J Neurosci. 2013;33(49):19384-19392.

Singh T, Arrazola RA, Corey CG, et al. Tobacco use among middle and high school students — United States, 2011–2015. MMWR Morb Mortal Wkly Rep. 2016;65(14):361-367.

Sink KS, Davis M, Walker DL. CGRP antagonist infused into the bed nucleus of the stria terminalis impairs the acquisition and expression of context but not discretely cued fear. Learn Mem. 2013;20(12):730-739.

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Smith RJ, Lobo MK, Spencer S, Kalivas PW. Cocaine-induced adaptations in D1 and D2 accumbens projection neurons (a dichotomy not necessarily synonymous with direct and indirect pathways). Curr Opin Neurobiol. 2013;23(4):546-552.

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Sponsors

Bronze Sponsor

Braeburn Pharmaceuticals

Academy Friends

Addiction Technology Transfer Centers

Gosnold on Cape Cod

The Newport Academy

The Peter G. Dodge Foundation

Grant Support

Indivior Inc. has provided unrestricted funding to support the program.

This event was supported by the National Institute On Drug Abuse of the National Institutes of Health under Award Number R13DA041813. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Substance use is common among teenagers and young adults. In the most recent Monitoring the Future survey of students across the United States in 2015, 35% of 12th grade students said they had tried alcohol in the past month, and nearly 40% said they had been drunk in the past year. Although alcohol and tobacco cigarette use are on the decline, use of illicit drugs has been steady, and a growing number of adolescents are using marijuana and electronic cigarettes. In 2015, more high school seniors said they smoked marijuana everyday (6%) than smoked tobacco cigarettes (5.5%).

Adolescents are at greater risk of developing a drug addiction than older adults. In adolescents the prefrontal cortex, which is the seat of executive function, is not yet fully developed, so it is difficult for them to make rational decisions and regulate emotions. In this group, there are also weaker connections between the prefrontal cortex and the nucleus accumbens, a component of the limbic system involved in reward, as Nora D. Volkow discussed in her keynote address. The role of dopamine in modulating the connections between the prefrontal cortex and nucleus accumbens has been well studied, but Peter W. Kalivas presented data on how the neurotransmitter glutamate could also modulate neuroplasticity in this network.

Some evidence shows that neuroplasticity and changes in activity in numerous brain networks contribute to addiction. Addiction turns on the stress system in the brain, which likely plays a critical role in the withdrawal stage, keynote speaker George F. Koob argued in his address. Barry J. Everitt and David M. Lovinger described specific brain networks that could be involved in the progression to addiction, and how they could be regulated by dopamine and the endocannabinoid system. Changes in brain network activity associated with drug use and withdrawal correlate with changes in gene expression profiles in neurons, according to speaker Eric J. Nestler.

Besides being more susceptible to drug addiction, adolescents may also suffer more harm from drug use than adults. Cross-sectional studies have found teens with a recent history of intense binge drinking have lower white and gray matter volumes in their cerebellums than non-drinking controls, based on brain imaging. In addition, young people who start using marijuana in their early teens have more changes in brain structure and function than their peers who start smoking later, as Staci A. Gruber outlined in her talk. However, it has been unclear whether drug use causes these changes or these changes precede and possibly predispose teens to drug use. Susan F. Tapert presented her longitudinal research exploring alterations in brain structure and function that coincide with the start of heavy alcohol use in middle and high school students.

In some cases, effective treatments are already available. The patch, bupropion, and varenicline help improve cigarette smoking quit rates, although genetics influence which treatment is most effective, said Rachel F. Tyndale. David R. Gastfriend talked about the important role of treatments such as methadone and naltrexone in reducing opioid use, but stressed that less than half of people in the U.S. who are addicted to opioids receive treatment. Research on new addiction treatments has also made exciting progress. Ronald G. Crystal presented his group's work to develop a cocaine vaccine, which they found reduces drug use in animal models. The team will soon start testing in humans.

Experts want to draw more attention to the effect of drug use among adolescents, and promote stricter regulations on access to legal drugs. The National Institutes of Health convened a landmark conference exploring what's known and what still needs to be studied about the effects of marijuana on the developing brain, according to Susan R. B. Weiss, who provided an overview of the event. Mark A. R. Kleiman argued that regulation of recreational marijuana has been inadequate, and the outcomes from this legal lassitude could be akin to those seen for alcohol. Four states have legalized recreational marijuana, and 24 states and the District of Columbia have legalized medical marijuana. Former congressman Patrick J. Kennedy concluded the forum by outlining the areas of mental health and addiction care that need improvements. It will take greater awareness and effort across sectors, including continued research, increased willingness on the part of clinicians and insurance providers to address addiction, and heightened interest among policymakers to make progress against the problem, he said.

Highlights

Young people are more susceptible than adults to developing drug addiction.

Researchers are studying vaccines and transcranial magnetic stimulation as possible treatments for addiction.

Policy makers need to create more public education programs directed at young people.

Drug courts are cost effective and could help people recover from drug addiction.

From neuroscience to criminal justice

The panel that opened the forum represented diverse perspectives on substance abuse in adolescents, from the neuroscience of addiction to policy and criminal justice. Moderator Claudia Wallis started by asking the panelists to briefly summarize their views on the topic. Jeremy Waletzy shared the tragic story of losing his son Jacob at the age of 29 to cocaine use. "One of the things that was so clear to me was that if there were a treatment that would work, Jacob would have taken it," Waletzy said. To support the development of such treatments, Waletzy and his wife created the Society for Neuroscience Jacob P. Waletzky Memorial Award for Innovative Research in Drug Addiction and Alcoholism to recognize young scientists who have made important contributions to understanding drug addiction.

Nora D. Volkow, who has pioneered the use of brain imaging to study how drugs affect the brain, explained how even children such as Jacob who grow up in a supportive environment can become addicted. In response to a question from the moderator about research on treatments, Volkow said "we are very excited about ... the possibility of using vaccines to actually treat [substance use disorder]." The technical challenge right now, she added, "is to create more potent vaccines." Volkow also mentioned transcranial magnetic stimulation (TMS) as a potential strategy to strengthen connections in brain networks that are weaker in people who are addicted.

In the criminal justice system, drug courts are a relatively new way to handle people who have been convicted of dealing illegal drugs. They are an alternative to the "revolving door" of sending addicted people to jail or prison where they do not receive treatment, get released, and commit the same crimes, said Gregory P. Canova. Felons entering drug court avoid prison and receive treatment and close monitoring, such as meeting regularly with a judge and receiving random biweekly urine tests. King County, Washington, where Canova was a drug court judge, became the twelfth drug court in the U.S. in 1994; now there are 2100 drug courts across the country. Peer-reviewed studies indicate that drug courts help addicts reclaim their lives and save taxpayer dollars compared to the traditional criminal court approach.

But how effective drug courts are at keeping people from using drugs? Canova said that those data are limited, especially for young adults, because few drug courts work with this age group. However, efforts to track drug court graduates overall at the county and national level by the National Association of Drug Court Professionals suggest these programs reduce the recidivism rate by 40% to 45%. Currently many individuals are in drug court because they committed property offenses to support their habit rather than drug offenses, Canova noted.

Cheryl Healton addressed drug use from a public health perspective, discussing how little emphasis has been put on public education and cultural tactics to prevent people from trying drugs in the first place, or from becoming regular users. The Philip Morris campaign, "Think, don't smoke!" was an ineffective way to appeal to adolescents who are rebellious and sensation seekers, she said. The Truth Campaign, which Healton worked on and which focused on teens' rebelling against the tobacco industry, has reduced youth smoking by 22%.

Responding to Wallis's question about applying her approach to other substances, Healton said that alcohol would be most applicable because of its analogies with tobacco in terms of marketing and young people's motivations for using it. Nevertheless, "it would be one more grand experiment," akin to the Truth Campaign, Healton said. Another "grand social experiment," she said, is the legalization of recreational marijuana.

Several audience members discussed policy changes that could prevent youth from starting to use drugs. Volkow agreed that advertising contributes to prescription drug overuse, stating that advertising leads to more patients asking for drugs and more drugs being prescribed, often to patients who shouldn't be taking them.

In response to a question about whether stressful school environments affect drug use among young people, Volkow said studies have shown that young people are more likely to experiment with drugs if they are in a school where they perceive others are using drugs. Nevertheless, even though the school environment is stressful, it can create a rewarding social support system for young people. An audience member asked for the panel's opinion on UCSB's Life of the Party program, which advises students how to socialize safely. Healton responded that, although it is possible these programs could be an effective harm reduction strategy, other approaches such as programs in which students self-police and take a pledge to abstain from unsafe behavior in social settings could be more effective.

Highlights

PET imaging studies have revealed dopamine levels are lower in the brains of people who are addicted to drugs.

Reduced expression of dopamine D2 receptors, which regulate dopamine's rewarding effects, could contribute to the development of addiction.

Adolescents have weaker connections between dopamine cells and the prefrontal cortex.

Greater social support could strengthen these connections and reduce the risk of addiction.

In her keynote address, Nora D. Volkow of the National Institute on Drug Abuse described brain imaging studies revealing how the dopamine system is hijacked in the brains of people addicted to drugs, and how this system is more likely to become disrupted in children and adolescents.

Unique vulnerabilities of adolescent brains

In PET imaging studies, Volkow and her colleagues found that, dopamine levels are less strongly induced in the nucleus accumbens and striatum of people addicted to cocaine after exposure to cocaine or methylphenidate, compared with non-addicted people. This dampening of dopamine induction is likely why people who are addicted to drugs continue to take them even though they are less rewarding, Volkow said.

People who are addicted to drugs regularly encounter stimuli that trigger cravings. The decision to take the drug is regulated by the prefrontal cortex, and the balance between dopamine D1 receptors, which stimulate the rewarding effects of drugs, and dopamine D2 receptors that counteract the D1 pathway. Studies by Volkow's group and others have demonstrated that expression levels of D2 receptors are lower in people addicted to drugs. This reduced expression could be involved in the process of addiction, as overexpressing D2 receptors in rats that self-administer high levels of alcohol or cocaine led to animals reducing their drug intake.

Volkow presented a model in which D2 receptors prevent compulsive drug consumption by inhibiting GABA cells in the striatum, which in turn inhibit the thalamus from stimulating the prefrontal cortex. As this model would predict, studies of people addicted to drugs show a link between low D2 levels and low activity in the prefrontal cortex.

Lower levels of dopamine D2 receptors could reduce prefrontal cortex activity and increase the risk of addiction.

This is your brain on family

Adolescents, a group at higher risk of addiction than adults, have weaker connectivity between dopamine cells and the prefrontal cortex compared with young adults. This connectivity is even weaker in adolescents who have attention deficit hyperactivity disorder and in children who have been neglected. However, some evidence suggests that these differences could be reversed. A study of orphans in Romania found that children who went to live with supportive families had stronger connections with the frontal areas of their brains than children who stayed at the orphanage. "You may not choose your genes, you may not choose where you are born, but we can create a supportive system that can help us counteract some of the negative effects of the environment or that may come from a genetic vulnerability," Volkow said.

Adolescents who have experienced social neglect have weaker connectivity between dopamine cells in the limbic system and the prefrontal cortex that drives decision making and control.

Highlights

Glutamate release in the tetrapartite synapse could underlie drug-seeking behavior.

The development of habitual behavior is associated with a shift from the ventral to the dorsolateral striatum.

The orbitofrontal cortex and the dorsal medial striatum synapse, mediated by the endocannabionid system, could also drive habitual behavior.

New optogenetics tools allow researchers to manipulate neural circuits and deliver drugs in freely moving animals.

Thinking of drinking

When people with a history of addiction are exposed to drug cues, such as an invitation from a friend to meet at the bar, they have difficulty deciding not to pursue the drug, explained Peter W. Kalivas, of the Medical University of South Carolina. The neural basis for this loss of inhibition is the tetrapartite synapse between the prefrontal cortex, the nucleus accumbens, the astroglial process, and the extracellular matrix. In response to food or drug cues, the prefrontal cortex releases glutamate, which the nucleus accumbens take up via NMDA receptors and the glutamate transporter on the surface of astroglial cells. Drug cues, unlike food cues, inhibit expression of the glutamate transporter, causing glutamate to spill out of the synapse.

A subpopulation of interneuron cells called nNOS neurons takes up this glutamate via mGluR5 receptors. As a result, these neurons release nitric oxide, which is important for the activation of the extracellular matrix metalloproteinase enzyme MMP-9, which in turn cleaves and activates a small peptide ligand called RGD (named for its RGD, or Arg-Gly-Asp, domains). Once activated, RGD binds to beta-3 integrin on the surface of nucleus accumbens cells, which increases the spine head diameter and glutamate receptor levels in these cells, potentiating or exciting the postsynaptic terminus and inducing drug seeking, as Michael Scofield, a postdoctoral fellow in the Kalivas lab, explained in his Hot Topic Talk. The researchers found that about 25% of nucleus accumbens cells are potentiated following drug cues, possibly creating a strong signal for drug seeking and overwhelming the signal to engage in other behaviors.

These findings suggest new approaches for treating drug addiction, Kalivas said. Studies have found that restoring glutamate transporter levels on glial cells using N-acetylcysteine prevents relapse in animal models of drug addiction, and a number of studies suggest it could reduce cocaine craving and cigarette and marijuana use in humans, although it is still considered experimental.

Many clinical trials are underway testing this compound and a phase 2 trial was completed in 2015 that addressed the ability of N-acetylcysteine to prevent drug relapse among military veterans with PTSD and substance abuse disorder.

Drug use increases glutamate release at the tetrapartite synapse could set off a cascade of events that signal drug seeking behavior.

Wired for addiction

The development of an addiction involves engaging in a goal-directed behavior to obtain an outcome such as a drug effect, and then repeating that behavior until it becomes habitual. "The key thing for addiction is some individuals lose control over those habitual behaviors and become compulsive," said Barry J. Everitt of the University of Cambridge.

Everitt's group modeled the progression from goal-directed to habitual and then compulsive cocaine use in rats. In one setup, rats learn to press one lever to gain access to a second lever, which they can then press to receive an infusion of cocaine. This goal-directed behavior requires the nucleus accumbens in the ventral striatum and the basolateral amygdala. However, if rats train long enough on this task, they will start pressing the levers even if no cocaine is produced, indicating their behavior has become habitual. Researchers have determined the shift from goal-directed to habitual behavior correlates with a shift from activity in the ventral striatum to the dorsolateral striatum. Disconnecting the dorsolateral striatum from the ventral striatum prevents animals from developing a cocaine-seeking habit.

Trying to measure how a habit becomes a compulsive behavior is "at the heart of what we are doing now," Everitt said. His team has created a system in which rats receive a mild foot shock if they press the levers for cocaine. Although most of the rats abstain from seeking cocaine, even after training on the task for several weeks, about 20% persist despite the punishment. Everitt and other researchers have observed several factors associated with this compulsive behavior in rats, including low dopamine D2 receptors in the ventral striatum, a smaller nucleus accumbens, and lower activity in the prefrontal cortex. These findings suggest strategies for treating addiction, such as transcranial magnetic stimulation and cognitive behavioral therapy, which could help restore inhibitory control, Everitt said.

The brain circuit that involves the orbitofrontal cortex (OFC) and the dorsal medial striatum (DMS) could also help determine the balance between goal-directed and habitual behavior. Experimentally blocking the activity of the OFC in mice shifts the balance toward habit-forming behavior. THC, the primary psychoactive ingredient in marijuana, and natural endocannabinoids appear to dampen the efficacy of the synapse between the OFC and DMS, which increases habit-directed behavior.

David M. Lovinger, of the National Institute on Alcohol Abuse and Alcoholism, determined that the endocannabinoid receptor CB1 could be involved in the OFC-DMS circuit and in suppressing goal-directed behavior. Deleting the gene for CB1 specifically in the OFC of mice diminished synaptic activity. "If you can disrupt this inhibition [of CB1] in some way, you may be able to restore goal-directedness even in the face of ... drugs that push you toward habit," Lovinger said.

Alcohol can also dampen the OFC-DMS synapse, Lovinger said. His group found that putting mice in chambers where they inhaled alcohol vapor for three weeks hindered their ability to learn goal-directed behaviors in subsequent training sessions. Numerous studies suggest that G-protein coupled receptors at presynaptic OFC terminals, including CB1 and mGluR and opiate receptors, could be involved in regulating the switch between goal-driven and habitual behavior.

The endocannabinoid receptor CB1 in the orbitofrontal cortex (OFC) and dorsal medial striatum (DMS) synapse could suppress goal-directed behavior.

A third neural circuit involved in addiction is serotonin, which has a "dark side" in aversive behavior, as Thomas L. Kash, of the University of North Carolina School of Medicine, explained. Serotonin, or 5HT, is a complex neuromodulator produced by a brain region called the dorsal raphe nucleus, which projects to many brain regions involved in reward, stress and anxiety, impulsivity, and other functions.

One area that receives serotonergic input from the dorsal raphe nucleus is the bed nucleus stria terminalis or BNST, which is activated in response to stress and is thought to produce anxiety and the conditioned fear response in mice and people. Kash and his lab found that both the nucleus and BNST are activated in DBA/2J mice, which have a robust anxiety response, following a five-day exposure to ethanol vapor. These animals exhibited anxiety and fear in behavioral assays, which appeared to be mediated by serotonin; injecting the mice with a serotonin receptor antagonist blocked the response. Conversely, stimulating the rapid release of serotonin into the BNST using optogenetics, which is the use of light, can induce anxiety.

In subsequent experiments, Kash's lab identified a subpopulation of BNST neurons called corticotropin-releasing factor (CRF) neurons that are activated by serotonin and inhibit the ventral tegmental area and lateral hypothalamus, and mediate the aversive effects of alcohol in mice.

Lighting up the brain

Optogenetic approaches use optical probes to manipulate neural circuits letting researchers study the function of receptors and neuromodulators in live animals in real time. Channelrhodopsin, an algae-derived ion channel that depolarizes neurons in response to blue light, and inhibitory pumps, which can hyperpolarize and silence neurons, are the main molecular tools for this technique, said Michael R. Bruchas at Washington University School of Medicine.

Advances in material sciences have made it possible for Bruchas and his colleague John A. Rogers at the University of Illinois to create needle-like probes printed with LED devices, as well as detectors and sensors, that are fully implantable. This allows them to study freely moving animals in behavioral assays, without having them tethered to fiber optic cables. An additional benefit of these small probes is that they do not require much voltage, allowing them to run wirelessly on radio frequency energy. Taking the platform one step further, Bruchas and Rogers added microfluidic channels to the probe that can deliver drugs selectively to the brain. Drug administration from this optofluidic probe can also be controlled wirelessly in free moving animals, using a design that heats the probe and drives a piston to push drugs from the channels.

Highlights

Changes in gene expression profiles occur following drug use and withdrawal in animal studies.

Longitudinal research suggests heavy alcohol consumption could cause reductions in brain volume in teenagers.

Smoking marijuana early in adolescence is linked with changes in brain volume and structure and poorer performance on executive function tests.

Interventions that decrease stress could change the trajectory of brain development and reduce addiction risk.

Use of electronic cigarettes among adolescents has surpassed that of tobacco cigarettes, but long-term health effects are not known.

Promoting plasticity

For many years, researchers have thought drug addiction could induce neuroplasticity, as chronic exposure to drugs of abuse leads to changes in synaptic activity and neuronal excitability and structure. Eric J. Nestler, of the Icahn School of Medicine at Mount Sinai Hospital discussed the changes in gene expression and chromatin modifications that could underlie this neuroplasticity.

Through a series of RNA sequencing experiments, Nestler's lab has demonstrated that gene expression changes correspond with behavioral changes in male and female mice in response to cocaine. Pups showed an increase in place preference following cocaine administration, although there were sex differences in the effect of social isolation. In both sexes, there were clear signatures of gene expression in the nucleus accumbens associated with place preference behavior.

A number of cellular changes occur in response to drug withdrawal, and gene expression studies have helped detail the molecular mechanisms associated with these changes. Short periods of withdrawal from cocaine or other drugs of abuse are associated with an increase in dendritic spine density in nucleus accumbens cells and thinner spiny heads that have less functional glutamate response. In contrast, long periods of withdrawal correlate with larger and more functional spiny heads. Nestler's lab identified a signaling pathway that promotes actin polymerization and the transcriptional upregulation of the Rap1b gene, causing a switch from larger, mushroom heads to thin spiny heads.

Short periods of withdrawal are associated with thinner, denser spiny heads in nucleus accumbens cells, whereas long periods of withdrawal are linked with larger more functional synapses.

Drinks, drugs, and development

Moving the focus to people, Susan F. Tapert of the University of California San Diego discussed research on whether alcohol consumption causes changes in brain development. She and her colleagues began a longitudinal study in the early 2000s, involving about 300 students from middle schools around San Diego who were not drinking alcohol or using drugs. The researchers are still following participants, and conducting interviews, memory and attention tests, and brain imaging scans.

Approximately 30% of the individuals in the study have started heavy alcohol use. Although this group had smaller volumes in the cerebellum and other brain regions prior to drinking, they also had larger reductions in gray matter in temporal lobe areas and less growth in gray matter in the corpus callosum and other areas, suggesting that heavy alcohol consumption can alter brain development.

Tapert concluded her talk by highlighting two large ongoing longitudinal studies that she is leading, the Adolescent Brain Cognitive Development (ABCD) study and the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) study. Both will conduct neuropsychological tests and brain imaging scans over time among adolescents who have started heavy drinking.

In her Hot Topic Talk, Lindsay M. Squeglia discussed her research in the Tapert lab to identify factors that could predict which students in the San Diego study would start drinking heavily in adolescence. Males were more likely to become heavy drinkers by age 18, as were teens who began dating before age 14, and those who had conduct disorders and high socioeconomic status. Other important predictors were poor performance on executive functioning tasks, thinner cerebral cortices, and less brain activation during working memory tests. Although it is too soon to put kids in a scanner to determine who will start drinking heavily, "one of my favorite parts about this [research] is that we are publishing the scripts that we used with the hopes that other groups will try to replicate these findings," said Squeglia, who is now at the Medical University of South Carolina.

Heavy drinking in teens is linked with increased reduction gray matter and reduced growth in white matter.

There is a growing use of marijuana among high school seniors, as reported in the 2015 Monitoring the Future survey, in which 68% of adolescents said they did not think regular marijuana use was harmful. "Perception of risk and harm continues to drop among our youth," said Staci A. Gruber of McLean Hospital at Harvard Medical School, asking "is marijuana really as harmless as our youth clearly believe?"

Research has found that adolescents who use marijuana before the age of 18 perform worse on tests of memory, attention, and in some studies, IQ. But what are the differences between teens who start smoking early and those who start later in adolescence? In a study of 50 heavy marijuana users, Gruber and her colleagues found that those who started smoking before the age of 16 smoked almost twice as frequently and more than 2.5 times as much marijuana as later onset smokers. Early onset smokers also differed from late onset smokers and a group of 34 nonsmokers in brain function and structure, including having worse performance on the Stroop test of executive function and less white matter integrity based on diffusion tensor imaging.

These findings are "really important since states that are considering legislation for recreational and medical [marijuana] need to determine safe guidelines, particularly during critical periods of neurodevelopment," Gruber said. She also noted that recreational marijuana products have become more potent over the last two decades. In 2014 marijuana samples averaged about 12% delta-9 THC, the product's primary psychoactive component, compared with 4% in 1995.

Heading off addiction

Understanding brain development in children and adolescents can inform prevention strategies for drug addiction in these groups, said Diana H. Fishbein of Pennsylvania State University. Adolescents do not have a fully developed prefrontal cortex, and compared with adults, have more activity in the nucleus accumbens and less activity in the amygdala, the brain's threat-detection system. Environmental factors such as chronic stress could also alter the trajectory of adolescent brain development through neurobiologic and epigenetic changes.

"There are some very good emerging articles on this that lead us to believe that with intervention we can alter trajectories for children who have been exposed to stress," Fishbein said. One of those interventions is the PATHS Curriculum, which teaches self-regulation. In her study of students in kindergarten through second-grade students in Baltimore City schools, she found PATHS improved inhibitory control, stress physiology and emotion regulation, thereby reducing behavioral problems. Fishbein has conducted other studies in adolescents and adults showing moderation of intervention effects by level of executive functioning and suggest that these processes are improved by intervention. Other studies have tested executive function-promoting interventions among four-year-olds in Head Start programs, and a family-based stress intervention among preschool-age children.

Another promising intervention is mindfulness-based stress reduction. Although most studies have examined its effect on brain function in adults, one study found an association between mindfulness and greater inhibitory control among fourth and fifth-grade students. Fishbein and her colleagues are working to determine the emotional and neurocognitive mediators of intervention responsivity. Although there are many evidence-based preventive interventions, their effect sizes are no more than small to modest. Such findings suggest that the process of identifying mediators and moderators is critical to guide program refinements to better target underlying generators of the behavior they aim to prevent. Only then can a greater number of recipients benefit, Fishbein said.

In adolescents, reward sensitivity develops before inhibitory control in the prefrontal cortex, leading to increases in risk-taking behaviors.

Addressing unknowns of e-cigarettes

Whereas the number of U.S. high school students that use tobacco cigarettes has been decreasing over the last decade, the number using electronic cigarettes has been on the rise since 2011. In 2015, 16% of high school students said they used e-cigarettes in the last month, whereas only 9.3% reported using tobacco cigarettes, according to the National Youth Tobacco Survey. These devices deliver nicotine, which can lead to structural and chemical structures in the brains of adolescents, however very little is known about the long-term health effects of e-cigarettes.

Some of the many questions surrounding these devices concern the amount of nicotine they deliver, as Thomas Eissenberg, of Virginia Commonwealth University, explained. Studies have found big variations in the amount of nicotine delivered by e-cigarettes depending on the power of the device. Certain devices deliver very low levels of nicotine to the body, and Eissenberg worries the tobacco industry is using these products to introduce youth to nicotine, whereas other devices deliver much more nicotine than tobacco cigarettes.

Another question about these devices concerns the flavorings. The nicotine is dissolved in propylene glycol, vegetable glycerine, or a combination of the two, and it almost always contain flavorants that have been tested for food safety but not for inhalation safety. But with vape shops selling flavors such as blue cotton candy and Apple Jacks cereal, "you have got to wonder who are these flavors designed to appeal to," Eissenberg said.

Highlights

Addiction is associated with shift from activity in the brain's reward system to the stress system.

The peptides corticotropin-releasing factor and dynorphin increase in response to stress and reward system activity, respectively.

Antagonists that block these peptides reduce alcohol intake in rats.

Striving for balance

Addiction correlates with decreased activity in the reward system in the brain and increased activity in the stress system. The brain's attempt to reestablish the balance between the two systems drives addictive behavior, said George F. Koob of the National Institute on Alcohol Abuse and Alcoholism, in his keynote. Repeated exposure to drugs of abuse activates the stress system, which then contributes to the negative emotional state of withdrawal. Koob argued that this is one of the three stages of addiction, along with binge/intoxication and preoccupation.

Activation of the brain's stress system could play an important role in addiction.

At the heart of the stress system are two peptides: corticotropin-releasing factor (CRF) in the amygdala and dynorphin in the ventral striatum. Acute stress causes the release of high levels of CRF. Research by Koob's group and others has found that a CRF antagonist can block excessive use of alcohol and other addictive drugs in rats. Glucocorticoids increase CRF levels in the amygdala, but block CRF in the paraventricular nucleus, which has the same effect as the CRF antagonist in blocking alcohol intake and dependence.

Activation of the dopamine or opioid receptor reward system induces expression of the neurotransmitter dynorphin, which in turn shuts off the dopamine system in which Koob said could be one of the mechanisms for the decrease in dopamine that Volkow discussed in her presentation. His group demonstrated that blocking dynorphin signaling through the kappa-opioid receptor, by injecting rats with an antagonist of the receptor, prevents animals from escalating their alcohol intake.

"These two systems provide a potentially rich framework for not only medication development but for behavioral treatments for addiction," such as cognitive behavioral therapy, Koob said.

The peptide corticotropin-releasing factor (CRF) and dynorphin, which are increased in response to the stress and reward system respectively, drive the consumption of drugs of abuse.

Highlights

Deep brain stimulation inspired by optogenetics tools reverses cocaine-induced neuroplasticity in mice.

A cocaine vaccine reduces drug-seeking behavior in animal models and will soon enter clinical testing in cocaine users.

Methadone, buprenorphine, and extended-release naltrexone all reduce opioid death rates; the best treatment choice depends on patient factors.

Nicotine metabolism genes influence the effectiveness of smoking cessation therapies.

The anti-drug

Even after prolonged periods of abstinence, exposure to drug cues can induce craving and behavioral changes in addicted people. Underlying this effect is the synaptic plasticity caused by cocaine and other drugs of abuse in the brain's reward system, driven by shifts in the AMPA receptor subunits that change the amount and type of synaptic transmission. "Can we reverse this cocaine-evoked synaptic plasticity and thus abolish the drug adaptive behavior?" asked Meaghan Creed of the University of Geneva.

To answer this question, Creed and her colleagues used optogenetics in mice. If cocaine is potentiating the strength of excitatory transmissions, then inducing depotentiation through optogenetics could reverse the drug-seeking behavior in mice. They expressed channelrhodopsin in the medial prefrontal cortex which, in response to light illumination, caused the release of glutamate specifically into the nucleus accumbens and depotentiation that successfully abolished the drug-adapted behavior in mice.

Next, Creed asked "can we achieve this with a more readily translatable therapy?" She and her colleagues were able to demonstrate the same reversal of drug-adapted behavior in mice using deep brain stimulation (DBS), along with a D1 antagonist, instead of channelrhodopsin and light illumination. They call the system optogenetic-inspired DBS, or OiDBS.

Optogenetic-inspired deep brain stimulation (OiDBS) combines low frequency stimulation and a D1 receptor antagonist to restore normal synaptic plasticity in cocaine addicted mice.

Vaccines could provide an effective option for preventing addiction by keeping drugs of addiction from getting to the brain. However, drugs of abuse are small molecules that would be poorly recognized by the immune system, as Ronald G. Crystal of Weill Cornell Medical College explained.

Crystal's lab is working to develop a cocaine vaccine using a replication-deficient adenovirus, which is highly immunogenic, as a delivery system. An analog of cocaine, either GNC or GNE, is coupled to the viral capsid protein to produce dAd5GNC or dAd5GNE, respectively. Studies in rhesus macaques found that vaccinated animals developed antibodies against the compounds, but these antibodies had short half-lives, so the animals had to be injected every month to maintain immunity. In both vaccinated mice and monkeys, there was a shift in distribution of cocaine following injection of the drug from the brain to the blood stream.

Vaccination with dAd5GNE correlated with reduced drug seeking behavior in rats and monkeys, supporting the vaccine's effectiveness. The Food and Drug Administration has approved dAd5GNE for clinical testing and Crystal's group will begin studying it in a cohort of people who use cocaine.

The other strategy to develop a cocaine vaccine, so far only tested in rodents, is to use an adeno-associated virus to deliver genes expressing anti-cocaine antibodies to the liver. One advantage of this strategy is that the expression could persist for many years so a single dose of vaccine might suffice.

Two strategies to develop cocaine vaccines that are being pursued involve adenoviruses (left) and adeno-associated viruses (right).

Using what we have

Treating opioid addiction involves managing withdrawal symptoms and cravings as well as normalizing the stress response. "The problem is when we only detoxify an individual, which is the actual dominant mode in this country, we are not really providing adequate care," said David R. Gastfriend, of the Treatment Research Institute at the American Society of Addiction Medicine. He outlined the role of the three existing treatments for opioid addiction: methadone, buprenorphine, and extended-release naltrexone.

Opioids bind the mu-opioid receptor, and methadone and buprenorphine work as full or partial agonists of this system, respectively, while naltrexoneis an antagonist. All three reduce overdose and death rates compared with counseling alone, but there are important differences between the treatments that could make one more acceptable to a patient than another. Methadone, which has to be taken every day and requires daily clinic visits, has higher rates of retaining people in treatment than buprenorphine, which is longer lasting and does not require daily visits to a clinic. However access to both is inadequate; methadone is not available in many areas of the country, and many physicians do not have waivers to prescribe buprenorphine, a DEA Schedule C-III substance.

An injected extended-release naltrexone (XR-NTX) was developed because the oral form failed to increase abstinence rates among addicts compared with placebo. Individuals have to be opioid free before starting XR-NTX, Gastfriend said. Yet because naltrexone is not a controlled substance, it can be easier to access for those motivated to be opioid-free. Naltrexone therapy is more expensive per day of treatment than methadone or buprenorphine, but could be more cost-effective.

Drug addiction has a strong genetic component. Among cigarette smokers, genetic factors account for about 86% of the variation between individuals in amount of cigarette consumption and 60% of the variation in quitting rates. People who have variants of the nicotine metabolism gene CYP2A6 that confer slower metabolism are about 3.7 times more likely to quit smoking compared with fast metabolizers, explained Rachel F. Tyndale of the Centre for Addiction and Mental Health at the University of Toronto.

But there's still hope for people who are fast or normal nicotine metabolizers; in this group, nicotine has a half-life of about two hours instead of three hours. The nicotine patch is more effective among slow metabolizers, but fast and normal metabolizers respond well to bupropion and varenicline, respectively. Nicotine metabolism status also seems to affect the risk of side effects of smoking cessation therapy. Varenicline is associated with an increase in abnormal dreams among slow metabolizers compared with normal metabolizers, and a decrease in irritability and anxiety among normal metabolizers.

Tyndale and her colleagues are trying to understand the neural basis for these differences. "By two or three days of stopping smoking all that nicotine is essentially gone, so why are we having these really substantial[ly] different quit rates way out at six weeks or six months?" Tyndale asked. Two factors that could contribute are that fast metabolizers had stronger reactions to smoking cues, based on fMRI studies, whereas slow metabolizers had decreased availability of nicotinic receptors.

People with variants of the CYP2A6 gene that confer slow nicotine metabolism are nearly four times more likely to quit than fast metabolizers.

Highlights

In March, the NIH convened a landmark conference to discuss neuroscience and policy research on marijuana.

Marijuana use during pregnancy has been associated with expression changes in genes involved in drug use in babies.

Models of neuronal activity could help predict individual behavior and the effect of drug use.

More regulations are needed on the sale and use of alcohol and marijuana.

Collaborating on cannabis

On March 22, the National Institutes of Health convened five of its institutes in a two-day conference called "Marijuana and Cannabinoids: A Neuroscience Research Summit." "It is really a landmark event because NIDA for a long time has been trying to get other institutes interested in cannabis and cannabis research because not all of the questions are those that fall within our mission," said Susan R. B. Weiss of the National Institute on Drug Abuse (NIDA).

The summit covered the state of the science and areas where more research is needed on the endocannabinoid system, the developing brain, psychosis, and policy research. "We have come a long way in understanding the endocannabinoid system and in thinking about how it may have potential for a wide variety of therapeutic indications, but we have come much less far in looking at the therapeutic effects of cannabis the plant," Weiss said. One of the most exciting new directions in therapeutic development is tweaking the endocannabinoid system, such as by inhibiting enzymes that break down endogenous cannabinoids, Weiss said.

Weiss summarized conflicting research on marijuana's effects on cognitive impairments in adolescents. A study in a Dunedin, New Zealand, cohort linked marijuana use with decreases in IQ, but a recent twin study found no difference in IQ among teens that used marijuana. "The dose, the strain, the potency, all of these things may be giving us very different effects," Weiss said. Data are more consistent on psychosis, with several studies suggesting that early cannabis use could increase the risk of developing schizophrenia in people who have genetic risk factors for the disease.

The policy discussion at the summit was well received, Weiss said. Speakers discussed challenges in policy research due to differences between states, and some states have recently changed their marijuana policies.

Many studies have linked early cannabis use with increased risk of schizophrenia among those with genetic risk factors.

Baby's first dose

Yasmin Hurd of the Icahn School of Medicine at Mount Sinai Hospital discussed transcriptional and epigenetic profiles associated with drug use that could help elucidate the neurobiology of addiction and improve treatments.

In a study of post-mortem brain samples, Hurd and her colleagues have found stark differences between heroin users and control individuals in the transcriptional profile in the nucleus accumbens, particularly for glutamatergic genes, and in the epigenetic profile, such as histone acetylation at the GluA1 glutamate receptor subunit. Studies in rats found the same transcriptional and epigenetic changes occurred after animals started using heroin, suggesting drug use could be causing these changes. Inhibitors of bromodomain protein complexes, which are involved in transcription at acetylated histones, decreased heroin self-administration in rats.

Hurd's group is also studying the effects of marijuana on the developing fetal brain. Almost 20% of newborns in the U.S. have THC in their meconia. Hurd and her colleagues found reductions in expression levels of dopamine D2 receptor and other genes involved in substance use in babies born to mothers that reported smoking marijuana during pregnancy. The research also suggests there could be germline transmission of cannabis effects, as rats exposed to low doses of THC during adolescence had offspring that were more likely to self-administer heroin. "It is not only during your lifetime [but] there is indeed vulnerability both in humans and our animal models and this cuts across generations," Hurd said.

Babies born to mothers who smoked marijuana during pregnancy have lower levels of dopamine D2 receptors.

Great expectations

Can the behavior of neurons be modeled computationally to predict individual behavior and the influence of drug addiction? P. Read Montague of Virginia Polytechnic Institute and University College London hopes to answer that question. Focusing on midbrain dopamine neurons, his hypothesis was that neurons fire, releasing dopamine and serotonin, at rates that reflect the expectation of reward. The rate stays the same if the expectation does not change, but increases or decreases with the expectation. "They are always emitting information even when they are quiet," Montague said.

Montague's group has focused on the neural signature underlying reward-based errors that people make when they engage in betting tasks. They found that the signature associated with error was similar between smokers and nonsmokers, based on fMRI studies, but that "in smokers' brain[s], it is decoupled from having an impact on their behavior," Montague said.

The group also adapted a technique used in rats called fast-scan cyclic voltammetry to allow them to see sub-second fluctuations in dopamine and serotonin firing simultaneously from midbrain dopamine neurons. In a group of Parkinson's disease patients with electrodes implanted for deep brain stimulation, they showed that dopamine levels tracked very closely with the betting task, underscoring the role of dopamine in gambling addiction.

The expectation of reward is thought to lead to changes in spikes of dopamine release.

Uncontrolled substances

Moving beyond the brain, Mark A. R. Kleiman of New York University discussed the myriad effects that drug addiction has at the individual and societal level. Kleiman disclosed that his firm works for the Washington State cannabis board, and he would probably profit personally from the legalization of cannabis.

Kleiman focused on three drugs of abuse in his talk: alcohol, nicotine, and cannabis. He called alcohol the "classic case" of inadequate control; since Prohibition, its availability has become virtually uncontrolled. Kleiman highlighted two effective strategies for reducing the harms of alcohol abuse: federal alcohol tax increases and the 24/7 Sobriety Project, which establishes zero tolerance for repeat drunk driving offenders. These strategies lead to substantial decreases in rates of homicide, mortality, and automobile crashes. For tobacco, Kleiman explained that big variations in state taxes have driven up the rates of smuggling in the last decade, and that market is expected to continue to grow.

Although cannabis use is lower than alcohol use, it has rapidly expanded in the past 20 years. More than 80% of cannabis use in the U.S. is only weekly or less often, and there is no evidence of harm with that infrequent use. However, the remaining 20% are heavy users, and are a rapidly growing group. "We are moving toward an alcohol model of essentially unregulated legalization: modest taxes, a rule against selling to minors, and not much else," Kleiman said. The policy goal should instead be to make cannabis legal for moderate use among adults, such as by allowing only government stores to sell it, he added.

Highlights

The Kennedy Forum advocates improvements in five broad areas of mental health care, from parity to screening and diagnosis.

The main barriers to better mental health care are political disinterest and unwillingness of clinicians to work together.

Legalizing cannabis will disproportionately affect minority groups who have less access to health care.

Five pillars

Treatment for mental health and substance use disorders is separate and unequal from the rest of health care, declared Patrick J. Kennedy, Former United States Representative of Rhode Island, co-founder of One Mind and founder of the Kennedy Forum, in his closing keynote address.

Kennedy opened his talk with a video that the Kennedy Forum created to illustrate the five pillars needed to improve mental health and addiction treatment. One of the pillars is parity, which is addressed by the Mental Health Parity and Addiction Equity Act that Kennedy wrote when he was in Congress. It requires insurance providers to cover mental health treatments like they would other health conditions. The other pillars are early screening and diagnosis of mental health disorders, brain fitness and training, technology to help patients manage and find care, and coordinating health care providers.

The biggest challenges to achieving improvements in mental health care are politics, and bringing together disparate groups of clinicians, said Kennedy, who has struggled with addiction. No one in Washington is sounding the alarm about problems with mental health care, such as not having enough doctors, and poor reimbursement rates and prescribing restrictions for doctors that do provide care, he said. There is also not enough focus on insurance providers, especially for self-insured plans, measuring outcomes and not just following up when a person returns to a rehabilitation program.

Although Kennedy has led efforts in Congress for drug courts and does not support incarcerating people with addictions, he opposes the legalization and commercializing of cannabis. He argues it will disproportionately affect minorities and the poor, like alcohol does. "If you are a progressive liberal who cares about public health, you cannot stand by and watch a new industry like big tobacco take over and addict poor people who don't have access to the Mayo Clinic [and addiction psychiatrists] like I do, and they are going to be out there struggling," Kennedy said.

What are the differences in brain networks in adolescents that put them at higher risk of addiction?

How do stress and other environmental exposures influence the connectivity of the prefrontal cortex in adolescents?

Can neurotransmitters that mediate drug-evoked neuroplasticity serve as therapeutic targets?

What are the epigenetic and transcriptional changes that accompany drug-evoked neuroplasticity?

What are the long-term consequences of early use of alcohol, marijuana, and electronic cigarettes in adolescents?

Are the differences in brain structure and function associated with drug use in adolescents caused by drug use or risk factors that precede drug use?

Can stress-reduction interventions in children and adolescents change the trajectory of brain development?

Will vaccines be an effective strategy to prevent drug use?

How can we increase the uptake and retention of effective treatments among opioid users?

How can research on the effects of marijuana legalization better account for policy differences between and within states?

Could taxation and other strategies shown to be effective for reducing harms of alcohol use be applied to marijuana use?

How can policy makers, clinicians, and politicians improve access to and quality of care for mental health and substance use disorders?