Building smart cannabis policy from the science up.

Social attitudes and cultural norms around the issue of substance abuse are shifting rapidly around the world, leading to complex and unpredictable consequences. On the positive side, efforts to more intensely disseminate the scientific evidence for the many connections between chronic substance use and the emergence of measurable and discrete brain dysfunctions, has ushered in an evolving climate of acceptance and a new era of improved access to more effective interventions, at least in the United States. On the negative side, there has been a steady erosion in the public perception of the harms associated with the use of popular drugs, especially cannabis. This worrisome trend has sprouted at the convergence of several forces that have combined, more or less fortuitously, to effectively change long-standing policies away from prohibition and toward decriminalization or legalization. These forces include the outsized popularity of the cannabis plant among recreational users, the unflagging campaign by corporate lobbyists and patient advocates to mainstream its medicinal use, and the honest realization in some quarters of the deleterious impact of the drug war and its draconian cannabis laws, in particular, on society's most vulnerable populations. Updating drug policies is a desirable goal, and significant changes may indeed be warranted. However, there is a real concern when policy changes are hurriedly implemented without the required input from the medical, scientific, or policy research communities. Regardless of how well intentioned, such initiatives are bound to magnify the potential for unintended adverse consequences in the form of far ranging health and social costs. To minimize this risk, science must be front and center in this important policy debate. Here, we review the state of the science on cannabis and cannabinoid health effects, both adverse and therapeutic. We focus on the prevalence of use in different populations, the mechanisms by which cannabis exerts its effects (i.e., via the endocannabinoid system), and the double-edged potential of this system to inspire new medications, on one hand, and to cause short and long term harmful effects on the other. By providing knowledge of cannabis' broad ranging effects, we hope to enable better decision making regarding cannabis legislation and policy implementation.

Don't Worry, Be Happy: Endocannabinoids and Cannabis at the Intersection of Stress and Reward.

Cannabis enables and enhances the subjective sense of well-being by stimulating the endocannabinoid system (ECS), which plays a key role in modulating the response to stress, reward, and their interactions. However, over time, repeated activation of the ECS by cannabis can trigger neuroadaptations that may impair the sensitivity to stress and reward. This effect, in vulnerable individuals, can lead to addiction and other adverse consequences. The recent shift toward legalization of medical or recreational cannabis has renewed interest in investigating the physiological role of the ECS as well as the potential health effects, both adverse and beneficial, of cannabis. Here we review our current understanding of the ECS and its complex physiological roles. We discuss the implications of this understanding vis-á-vis the ECS's modulation of stress and reward and its relevance to mental disorders in which these processes are disrupted (i.e., addiction, depression, posttraumatic stress disorder, schizophrenia), along with the therapeutic potential of strategies to manipulate the ECS for these conditions.

NOW vs LATER brain circuits: implications for obesity and addiction.

Balancing behaviors that provide a reward NOW versus behaviors that provide an advantage LATER is critical for survival. We propose a model in which dopamine (DA) can favor NOW processes through phasic signaling in reward circuits or LATER processes through tonic signaling in control circuits. At the same time, through its modulation of the orbitofrontal cortex, which processes salience attribution, DA also enables shifting from NOW to LATER, while its modulation of the insula, which processes interoceptive information, influences the probability of selecting NOW vs LATER actions on the basis of an individual's physiological state. Disruptions along these circuits contribute to diverse pathologies, including obesity and addiction.

The addictive dimensionality of obesity.

Our brains are hardwired to respond and seek immediate rewards. Thus, it is not surprising that many people overeat, which in some can result in obesity, whereas others take drugs, which in some can result in addiction. Though food intake and body weight are under homeostatic regulation, when highly palatable food is available, the ability to resist the urge to eat hinges on self-control. There is no homeostatic regulator to check the intake of drugs (including alcohol); thus, regulation of drug consumption is mostly driven by self-control or unwanted effects (i.e., sedation for alcohol). Disruption in both the neurobiological processes that underlie sensitivity to reward and those that underlie inhibitory control can lead to compulsive food intake in some individuals and compulsive drug intake in others. There is increasing evidence that disruption of energy homeostasis can affect the reward circuitry and that overconsumption of rewarding food can lead to changes in the reward circuitry that result in compulsive food intake akin to the phenotype seen with addiction. Addiction research has produced new evidence that hints at significant commonalities between the neural substrates underlying the disease of addiction and at least some forms of obesity. This recognition has spurred a healthy debate to try and ascertain the extent to which these complex and dimensional disorders overlap and whether or not a deeper understanding of the crosstalk between the homeostatic and reward systems will usher in unique opportunities for prevention and treatment of both obesity and drug addiction.

Unbalanced neuronal circuits in addiction.

Through sequential waves of drug-induced neurochemical stimulation, addiction co-opts the brain's neuronal circuits that mediate reward, motivation to behavioral inflexibility and a severe disruption of self-control and compulsive drug intake. Brain imaging technologies have allowed neuroscientists to map out the neural landscape of addiction in the human brain and to understand how drugs modify it.

The unrealized potential of addiction science in curbing the HIV epidemic.

The stubbornly high incidence of new HIV infections belies the overwhelming evidence showing that sustained highly active antiretroviral therapy (HAART) has the power to dramatically reduce the spread of HIV infection and forever change the face of this devastating epidemic. One of the main contributors to this public health paradox is the ongoing HIV epidemic among substance users who contribute significantly to HIV infection rates through injection drug use and high-risk sexual behaviours. Current evidence clearly shows that, in order to fill this gap, we need to integrate substance abuse treatment with HIV treatment programmes and provide substance abusers with universal access to HIV treatment through a focussed effort to seek, test, treat, and retain hard-to-reach high risk individuals. These aims will require structural changes in the health care system to overcome many of the obstacles that have inhibited the merging of substance abuse treatment with HIV programmes for far too long.

Addiction as a systems failure: focus on adolescence and smoking.

OBJECTIVE: Scientific advances in the field of addiction have forever debunked the notion that addiction reflects a character flaw under voluntary control, demonstrating instead that it is a bona fide disease of the brain. The aim of this review is to go beyond this consensus understanding and explore the most current evidence regarding the vast number of genetic, developmental, and environmental factors whose complex interactions modulate addiction risk and trajectory. METHOD: Focusing on childhood and adolescent smoking as a paradigm, we review the important risk factors for the development of addictions, starting at the level of genetics and closing with a focus on sociocultural and policy factors. RESULTS: A critical review of the pertinent literature provides a detailed view of the cumulative power of risk and protection factors across different phenomenological levels to modulate the risk of undesirable outcomes, particularly for young people. The result represents a compelling argument for the need to engage in comprehensive, multilevel approaches to promoting health. CONCLUSIONS: Today, the field of medicine understands more about disease than about health; however it need not be that way. The view of drug addiction as a systems failure should help refocus our general approach to developing dynamic models and early comprehensive interventions that optimize the ways in which we prevent and treat a complex, developmental disorder such as drug addiction.

Addiction: pulling at the neural threads of social behaviors.

Addiction coopts the brain's neuronal circuits necessary for insight, reward, motivation, and social behaviors. This functional overlap results in addicted individuals making poor choices despite awareness of the negative consequences; it explains why previously rewarding life situations and the threat of judicial punishment cannot stop drug taking and why a medical rather than a criminal approach is more effective in curtailing addiction.

Understanding the effects of stimulant medications on cognition in individuals with attention-deficit hyperactivity disorder: a decade of progress.

The use of stimulant drugs for the treatment of children with attention-deficit hyperactivity disorder (ADHD) is one of the most widespread pharmacological interventions in child psychiatry and behavioral pediatrics. This treatment is well grounded on controlled studies showing efficacy of low oral doses of methylphenidate and amphetamine in reducing the behavioral symptoms of the disorder as reported by parents and teachers, both for the cognitive (inattention and impulsivity) and non-cognitive (hyperactivity) domains. Our main aim is to review the objectively measured cognitive effects that accompany the subjectively assessed clinical responses to stimulant medications. Recently, methods from the cognitive neurosciences have been used to provide information about brain processes that underlie the cognitive deficits of ADHD and the cognitive effects of stimulant medications. We will review some key findings from the recent literature, and then offer interpretations of the progress that has been made over the past decade in understanding the cognitive effects of stimulant medication on individuals with ADHD.

Reward, dopamine and the control of food intake: implications for obesity.

The ability to resist the urge to eat requires the proper functioning of neuronal circuits involved in top-down control to oppose the conditioned responses that predict reward from eating the food and the desire to eat the food. Imaging studies show that obese subjects might have impairments in dopaminergic pathways that regulate neuronal systems associated with reward sensitivity, conditioning and control. It is known that the neuropeptides that regulate energy balance (homeostatic processes) through the hypothalamus also modulate the activity of dopamine cells and their projections into regions involved in the rewarding processes underlying food intake. It is postulated that this could also be a mechanism by which overeating and the resultant resistance to homoeostatic signals impairs the function of circuits involved in reward sensitivity, conditioning and cognitive control.

Is fetal brain monoamine oxidase inhibition the missing link between maternal smoking and conduct disorders?

Smoking is the leading cause of preventable illness in the world today. Prenatal cigarette smoke exposure (PCSE) is a particularly insidious form because so many of its associated health effects befall the unborn child and produce behavioural outcomes that manifest themselves only years later. Among these are the associations between PCSE and conduct disorders, which have been mostly ascribed to the deleterious effects of nicotine on the fetal brain. Here we hypothesize that inhibition of brain monoamine oxidase (MAO) during fetal brain development, secondary to maternal cigarette smoking and in addition to nicotine, is a likely contributor to this association. MAOs play a central role in monoaminergic balance in the brain, and their inhibition during fetal development - but not during adult life - is known to result in an aggressive phenotype in laboratory animals. This paper provides theoretical and experimental support for the notion that cigarette smoke-induced inhibition of MAO in the fetal brain, particularly when it occurs in combination with polymorphisms in the MAOA gene that lead to lower enzyme concentration in the brain, may result in brain morphologic and functional changes that enhance the risk of irritability, poor self-control and aggression in the offspring. It also encourages research to evaluate whether the interaction of smoking exposure during fetal development and MAOA genotype increases the risk for conduct disorder over that incurred by mere fetal exposure to tobacco smoke.

Drug addiction: the neurobiology of disrupted self-control.

The nature of addiction is often debated along moral versus biological lines. However, recent advances in neuroscience offer insights that might help bridge the gap between these opposing views. Current evidence shows that most drugs of abuse exert their initial reinforcing effects by inducing dopamine surges in limbic regions, affecting other neurotransmitter systems and leading to characteristic plastic adaptations. Importantly, there seem to be intimate relationships between the circuits disrupted by abused drugs and those that underlie self-control. Significant changes can be detected in circuits implicated in reward, motivation and/or drive, salience attribution, inhibitory control and memory consolidation. Therefore, addiction treatments should attempt to reduce the rewarding properties of drugs while enhancing those of alternative reinforcers, inhibit conditioned memories and strengthen cognitive control. We posit that the time has come to recognize that the process of addiction erodes the same neural scaffolds that enable self-control and appropriate decision making.