We found that that social impairment is corrected in two distinct mouse models by increasing anandamide activity through FAAH inhibition. This correction raises the immediate question of whether increasing anandamide activity in these mice is prosocial per se or simply anxiolytic. This question is particularly important in light of the known roles of endocannabinoids in stress modulation.In our case, we found that the prosocial action of anandamide is unlikely to be due to general anxiolysis, because FAAH inhibition did not alter BTBR performance in the elevated plus maze when tested in the dim lighting conditions of the social approach test. This result is in line with previous reports showing that FAAH inhibition results in anxiolytic-like effects only under ‘‘high-light’’ conditions.While this phenotype does not exclude more nuanced forms of social anxiety, it does support the idea that the modulation of stress reactivity and social behavior can be dissociable. In line with this notion, CB1 over expression in the medial prefrontal cortex alters social interactions without overtly changing the anxiety-related phenotype.In contrast to socially impaired mice, parallel experiments in normal mice indicated that increasing anandamide does not alter social approach. One explanation could be technical—namely, that the social approach test has a ceiling effect or is unable to capture more subtle qualities of social interaction.Indeed, the task is typically used as a screening tool rather than a continuous scale measure of sociability. Another explanation could be biological—that signaling systems in a healthy brain are able to compensate for endocannabinoid enhancement in a way that socially impaired brains cannot. These explanations are in line with previous reports of different social situations in which faah / mice demonstrated increased direct reciprocal interactions,as well as URB597-treated juvenile rats engaging in more social play.
Therefore, expanded investigation is warranted into how anandamide contributes to different social contexts and the qualities of social interactions. Nevertheless, our set of results suggests that the prosocial action of FAAH blockade is selective for social impairment in certain contexts,growers equipment which may be therapeutically advantageous for the spectral nature of ASD. Based on our results and the available literature, we can reasonably speculate on two possible scenarios improved by anandamide signaling that may underlie social impairment in BTBR and fmr1 / mice. First, oxytocin-driven anandamide activity in the NAc, which we previously demonstrated to be important for social reward,may be impaired in these mice. Consistent with this idea, BTBR mice were found to have abnormal oxytocin expression in the hypothalamus.BTBR mice were also reported to be deficient in conditioned place preference to social interactions.46 However, because social conditioned place preference is a relatively new construct, and the learning impairments in these mice make interpretation problematic, further support from the literature is lacking. A second possible scenario is that anandamide might correct an imbalance of excitatory and inhibitory neurotransmission in the cortex, which has been postulated to underlie ASD.Enhancing GABAergic activity in BTBR mice ameliorates their social impairment, and negative allosteric GABA modulation in C57Bl6J mice recapitulates social impairment.This suggests that a loss of balance between inhibitory and excitatory activity might contribute to social impairment. A simplified view of this result orients us to interpret our findings as indicating that anandamide could modulate such balance. This view is consistent with the presence of CB1 receptors on presynaptic terminals of both glutamatergic projection neurons and GABAergic interneurons.In conclusion, the present study provides new insights into the role of endocannabinoid signaling in social behavior and validates FAAH as a novel therapeutic target for the social impairment of ASD.The United States stands out among developed nations for both its extremely punitive illegal drug policy and the high percentages of its population that have consumed banned substances—particularly marijuana and cocaine. The war against the millions of Americans who use and sell these drugs has cost taxpayers billions of dollars each year and contributed substantially to America’s globally unmatched incarceration rate .
Yet it has failed to displace America from among the world leaders in use rates for illegal drugs even if escalating punitiveness may have contributed to declines in U.S. drug consumption from its peaks in the late 1970s and 1980s. To locate America’s illegal drug policy globally and along a spectrum of potential alternatives, it is helpful to consider three broad approaches governments may take toward drugs: legalization—a system in which possession and sale are lawful but subject to regulation and taxation ;criminalization—a system of proscriptions on possession and sale backed by criminal punishment, potentially including incarceration ; and depenalization—a hybrid system, in which sale and possession are proscribed, but the prohibition on possession is backed only by such sanctions as fines or mandatory substance abuse treatment, not incarceration.All three of these approaches have been implemented in the practices of various governments around the world, though to greater and lesser extents. Nearly all countries have criminalized a consistent set of proscribed substances including marijuana, cocaine, heroin, and methamphetamine; most have also legalized other drugs such as alcohol and tobacco; and some have adopted policies of depenalization for substances whose sale, and to some degree possession, remains prohibited.We begin our analysis in Section II by attempting to define America’s illegal drug problem, first sketching consumption patterns, current policy, and the social costs of illegal drugs under America’s basic regime of criminalization. Because America’s illegal drug policies are an integral part of the context in which those costs arise—and many of those costs, such as those associated with incarceration, would not exist but for America’s current policies—we consider current policies and social costs in tandem, distinguishing costs that stem from criminalization and costs that flow from psychopharmacological effects of drugs on their users. Following this overview, we focus in Section III on the particular cases of marijuana and cocaine. For both marijuana and cocaine, we analyze three potential regimes—criminalization, depenalization, and legalization. We also address the two most significant sources of social costs from cocaine: crime and incarceration.
Cocaine has been an especially acute problem in America, with the prevalence of this drug and its derivative, crack, providing the impetus for the escalation of the War on Drugs in the 1980s and Plan Colombia in the 1990s. We restrict our discussion to these two drugs partly because one of our principal contentions is that analysis of illegal drug policy from a perspective of minimizing social costs requires great focus on the varying burdens of individual drugs given their different toxicological and inherent criminogenic effects, and their distinct patterns of consumption and distribution. Under U.S. criminalization of marijuana, a large number of people are arrested and otherwise punished for possession of a substance that is routinely consumed in today’s developed world and is—by various expert accounts and along many measures—less dangerous to users and society than cigarettes or alcohol. This policy not only consumes criminal justice resources and crowds out other valuable social spending, it also creates hard-to-quantify costs in other forms: diminished respect for the law, loss of faith in government warnings about the serious dangers posed by more harmful drugs, and a morally arbitrary arrest lottery undermining the principle that like offenders be treated equally. On the other hand,plant benches cocaine is substantially more dangerous than marijuana and under criminalization it is much more socially costly in the aggregate, notwithstanding far lower rates of use. The costs of cocaine under criminalization overwhelmingly stem from crime, violence, and incarceration. The differing nature of the costs of criminalization for marijuana and cocaine is important because it suggests that the effect of a regime change would be different for marijuana than for cocaine. Depenalization and legalization could both potentially reduce perhaps the foremost cost of marijuana criminalization: the extremely high number of arrests for possession, and the concomitant burdens they impose on the criminal justice system’s resources and individual arrestees—many of whom are otherwise law-abiding.6 Legalization, to a much greater extent than depenalization, would reduce the costs of black-market violence and lengthy incarceration for sellers that weigh so heavily in the overall costs of cocaine. On the other hand, economic theory suggests that reductions in sanctions through depenalization or legalization would lower costs both implicit and explicit , and thereby increase demand and use. By more substantially reducing costs and government disapproval, and by potentially enabling advertising, legalization would be expected to lead to higher levels of consumption than under a regime of depenalization. The possible exception to this claim would be if legalization were accompanied by a sufficiently comprehensive taxation regime that would restrain consumption by maintaining a high enough price to the consumer. The psychopharmacological effects of cocaine are markedly more harmful than those of marijuana, and the costs per additional user would be higher for cocaine than marijuana. Moreover, marijuana consumption is much higher than cocaine consumption so the offsetting effect of tax revenues on the social costs of cocaine would be much less significant than for marijuana. In sum, legalizing cocaine would pose greater risks and offer greater potential rewards than legalizing marijuana: the decreases in certain categories of costs and increases in others would be much more substantial for cocaine than for marijuana. Not surprisingly, much of the debate over illegal drug policy and potential reforms hinges on two contentious questions. First, by how much would the prevalence and intensity of a drug’s use rise under a different regime?Second, would reductions in other social costs—particularly through lower rates of crime and criminal justice enforcement costs—outweigh the costs of increased consumption? Our nation’s experience with alcohol regulation is instructive. During Prohibition—a regime of decriminalization or extreme depenalization—alcohol consumption was suppressed to a degree that noticeably lowered the cost of alcohol abuse.
These gains, however, appear to have come at a high cost in terms of crime, which fell sharply after Prohibition ended. While criminal gangs no longer cause mayhem over alcohol distribution, alcohol abuse does lead to belligerence and crime as well as many other social costs ranging from impaired productivity and increased motor-vehicle deaths to higher levels of child abuse and neglect. The U.S. has vastly more alcoholics than drug addicts in part because we have allowed a free market coupled with extensive advertising to promote alcohol consumption, with taxation levels that are well below social costs. Conjectures from some sources that similarly free markets for cocaine could increase today’s relatively small number of cocaine addicts to levels beyond the current number of alcoholics are offered in support of the current war on drugs. Opponents counter by pointing to the enormous criminal violence—here and abroad—that this war has generated, as well as the 500,000 incarcerated Americans whose lost freedom and productivity are among the greatest casualties of the war on drugs. The stakes are high for illicit drug policy, yet unfortunately we must continually choose its contours with a less than ideal evidentiary base. Legalization would almost certainly reduce crime, but such a prospective gain must be weighed against the increase in the costs of substance abuse that would likely follow. The murder and violence of illegal drug dealing, and the hundreds of thousands of ruined lives of prison inmates must be assessed against increased motor vehicle deaths and potentially millions of lives impaired by addiction. These are not pretty or easy choices, and to a significant extent the consequences of various drug policy regimes will depend upon the specifics of design and implementation. Our effort here is directed toward clarifying the trade offs by exploring, in the contexts of marijuana and cocaine, the question of which regime—and what set of policies within that overarching framework—would minimize the total cost to society.8A recurring pattern in the distribution of consumption across users holds for a variety of recreational drugs: a small percentage of users account for a large percentage of consumption. This pattern is found for alcohol consumption in the United States , as well as for cocaine use. For example, one study found that the top 22 percent of users account for 70 percent of cocaine consumption . The top heaviness of the distribution of cocaine use among consumers is believed to have increased from the early 1980s when consumption was nearly evenly split between light users and heavy users .