Monday, October 19, 2009

A Way to Win the War on Drugs?

To date it would be difficult to effectively argue that the war on drugs has been a success and unfortunately it does not appear that any success will be forthcoming at any point in the near future. Direct information regarding spending on combating use and distribution of illegal drugs is somewhat sketchy, but it seems that in 2002 the federal government spent 13.6 billion dollars in drug enforcement which can be adjusted to 15.2 billion dollars gross in 2006 dollars, when taking inflation into account (13.8 billion net due to drug use based fines).1 State and local governments spent a combined 30.3 billion dollars in 2006.1 The reason the war on drugs has failed for so long is that the primary focus was and currently still is on the supply side. It should be rather obvious that as long as profit margins for drug distribution and sales remain high it will be nearly impossible to eliminate even a significant percentage of drug houses and fields. Such a sentiment is especially true in third world countries where the choice between growing drugs or a drug precursor, which has a huge market vs. growing a food crop, which may not have viable market, is really no choice at all. Also the rise in the number of individuals that elect to grow marijuana plants in the United States for profit demonstrates that as long as a market exists with a high enough revenue potential, individuals will fill that market even if it violates the law. When money is involved morality tends to vanish rather quickly.

Basic economics offers the solution to the reducing the revenue for the sale of illegal drugs, reduce the demand for a product and either the supply or the price of the product will have to fall in kind. There have been noble, but naïve attempts in the past to reduce demand through pre-teen and teenage education programs like Drug Abuse Resistance Education (DARE), which were designed to teach children early in life that there was little benefit to consuming illegal drugs and demonstrate techniques that could be used to extricate oneself from a situation involving drug use. Unfortunately these programs have not worked as well as intended and most do not even exist anymore due to lack of funding and/or lack of success. Although it would be unrealistic to expect these programs to completely derail drug use among those individuals exposed to them, it is fair to ask the question why these programs were not as successful as anticipated?

Two reasons immediately come to mind to potentially explain why neutralization/prevention programs do not appear to work at effectively. First, the general rebellious nature of drug use can easily eclipse the perception of a low combined percentage of severity and certainty of both biological/psychological and legal consequence. This perception is a difficult idea to combat because for a lot of teenagers making decisions that defy authority can be viewed not only as a means of self-expression, albeit not a very unique one, but also as a means of stress relief from the rigors of the daily grind. Without direct demonstration to the consequences of drug use, it seems unlikely that any passive level of education will change the predisposed mindset that an individual has when entering a drug awareness/education program.

One strategy that has been suggested to confront this motivation and also end the perceived futility of the war on drugs is to eliminate the illegality of those drugs generally defined as experimental with less intensive addictive qualities either through decriminalization (distribution is still a crime, possession is not) or complete legalization. In theory legalization aids the war on drugs in two ways: first, legalization should diminish the aspect of rebellion in the use of these drugs because now they are no longer taboo following the reasoning that some individuals are attracted to drug use because it is against the law. Second, allowing big pharmaceutical companies to enter the marketplace will lead to a huge gut of new supply, which will drive prices downward significantly making it difficult for individual players to profit forcing them to leave the market. Even so-called ‘drug lords’ would find it hard to continue to deal drugs because of the hypothesized price collapse unless they diversify their industry.

Unfortunately there are some reservations about beginning a policy of legalization. Regardless of the level of addictive components available in any currently illegal drug there is a potential for addiction at an unhealthy level. In addition it would be reasonable to assume that if certain drugs were made legal then there would be more individuals that would become casual users of those newly legalized drugs increasing the probability of drug abusers. It can be argued that there are some individuals that are deterred from using 'recreational' drugs due to their illegality and the associated legal consequences. Also there are individuals that may not use these types of drugs because they are not widely available. For some it is difficult to proposition an interest in purchase if one does not know the nuances in which to do it and the illegality of the action itself reduces the probability of inquiry without a high probability of success. With an increase in the number of drug abusers one may see a slight to moderate increase in low-level crime such as robbery and vandalism. Finally there is the lingering question of any potential increase in medical costs or procedures due to the increased use of the newly legalized drugs. The change in medical costs is the biggest question mark in any legalization policy because it may transfer a bulk, if not proportionally more, strain from the currently strained court system to the already strained medical care system resulting in legalization costing more capital than drug enforcement.

Of course the counter-argument could be made regarding alcohol and cigarettes, but any direct comparison between these two elements without considering their current status in society would be inherently flawed. The restriction of alcohol has already occurred once in our society and was not effective, largely because it made a legal product of wide use illegal; obviously no illegal drug shares such a circumstance. Also illegal drugs have a much higher probability of fostering genuine addiction than alcohol in which a genetic predisposition is almost always required. Cigarettes have already started to be displaced from public places, which is appropriate due to the potential health risk to non-smokers. So support for the legalization of drugs cannot look at examples provided by alcohol or cigarettes in a general fashion. However, in the end legalization is a difficult question with multiple viewpoints, although both proponents and opponents of legalization think otherwise frequently offering illogical and simplistic arguments, and this particular blog post is not the venue to further elaborate on the pros and cons of those viewpoints.

The second reason education and prevention programs do not work is that for some individuals the ephemeral psychotropic effects of drugs are perceived to outweigh any potential economic or health detriments. Under such a circumstance, exclusion tactics such as those encouraged by DARE, do not have a high probability of success because simple cost/benefit arguments would have little influence on dissuading those individuals from using drugs. Instead one would need to utilize substitution tactics, finding alternative strategies to generate similar euphoric feelings. For example if one can introduce non-drug based activities to an individual that produce a sufficient level of enjoyment at a lower resource expenditure then cost/benefit arguments become more effective. Basically instead of denying the individual a pleasurable experience the detrimental one is substituted with a less/non-detrimental one. Unfortunately these methods are difficult to apply on a consistent basis.

Finally another positive strategy for reducing demand is expansion and administration of drug treatment programs as a requirement for those incarcerated for drug offenses. Due to the fact that drug use is not typically a single time event, simply incarcerating an individual for use of illegal drugs and not giving that individual an opportunity or assistance to attempt to change the behavior is not a logical course of action. However, opportunities for treatment should not be limited to inmates or those just recently released, but also must be made available to anyone that wants to participate. Initiating widespread treatment programs for illegal drug use should not only reduce demand for these drugs, but also reduce the total cost of the war on drugs. Unfortunately the public seems more interested in punishing non-violent drug users than assisting them even if treatment is almost always more cost-effective.

Despite the positive attributes associated with these alternative options there has been resistance to their widespread deployment. With this lack of alternative option application to reduce demand there is reason to understand why the war on drugs continues to attack the supply side of the drug question. However, another option is becoming more and more viable for reducing the demand side of the drug use curve. If the neurotoxic influence of a drug can be eliminated then there is no opportunity to induce any change in neuronal firing patterns which leads to addiction.

Most drugs that facilitate addiction do so via similar neuronal influence. For example cocaine affects both dopamine and glutamate transmission to generate addiction (GABA transmission could also influence addiction via its inhibitory influence on glutamate). The dopamine angle has widely been acknowledged due to the rewarding and pleasurable effects of cocaine. The dopaminergic pathway influenced by the pharmacological action of cocaine functions through enhanced dopamine transmission from neurons projecting from the prefrontal cortex, nucleus accumbens and amygdala.2,3 The anterior cingulate and ventral orbital cortex appear to be the regions in the prefrontal cortex most commonly associated with addiction and the amygdala is the primary component responsible for drug related relapse.4,5,6

Whereas dopamine enhancement is primarily responsible for short-term influences in cocaine use, glutamate enhancement is primarily responsible for long-term influences in cocaine use and behavior.7,8 This influence is understandable when one considers that long-term potentiation and long-term depression are primarily driven by changes in glutamate concentration and its interaction with AMPA and NMDA receptors. Most long-term addictive behavior for cocaine abusers seem to flow between the interaction of the core compartment of the nucleus accumbens and the amygdala where both the projecting and receiving neurons between those regions are glutamatergic.4 The prefrontal cortex also plays a role in the gluamatergic transmission between these two locations. There is evidence that suggests increased blood flow into the amygdala during a drug-induced craving.5 Antagonist blocking of AMPA receptors in the nucleus accumbens or GABA receptor agonists in the prefrontal cortex significantly reduce the probability of relapse.3,9,10

Although there are therapeutic targets available for reducing the probability of addiction from cocaine use and corresponding treatments like disulfiram and amantadine, those targets also play important roles in normal brain function and their over or under-activation can produce side effects that can lead the patient to cease treatment after only a short period of time.

Based on the neuronal mechanism behind addiction another strategy for reducing/eliminating a drug’s neurotoxic influence is to bind the drug molecule with an antibody, which would change its structure and disallow it from passing through the blood brain barrier to bind with the appropriate neuronal receptor. Currently most of the advancement in developing a vaccine for illegal drug use has occurred for cocaine largely driven by the widespread use of cocaine, the lack of a pharmacological treatment and the magnitude of its ill-health effects relative to other illegal drugs.

The basis behind the current cocaine vaccine uses succinylnorcocaine (SNC) molecules covalently linked to a carrier protein derived from the cholera B toxin (rCTB) strengthened by an aluminum hydroxide adjuvant.11,12 The idea is similar to other vaccines in that in response to the injection the body will successfully induce the development of specific IgG antibodies that can bind to cocaine in the future preventing cocaine molecules from crossing the blood brain barrier. Without the ability to cross the blood brain barrier the bound cocaine is left exposed allowing the various cholesterases in the body to interact with the bound molecule and break it down to inactive metabolites, which are later excreted from the body with other waste products. A useful attribute to a vaccine treatment is that the serum antibodies that are generated do not appear to be able to travel across the blood brain barrier either, which reduces any detrimental or unwarranted psychological effects from the immune response.

Phase I and II trials have already demonstrated that higher concentrations of vaccine increase the probability of less cocaine use12 as well as sufficient ability to neutralize the ability of cocaine to activate its neuronal dopaminergic pathway fostering addiction.13 However, there are questions regarding the inability of the vaccine to consistently generate a significant amount of antibodies to negate the ability of cocaine to maintain addiction.13 Also there are questions regarding the lifespan of the antibodies. Although lifespan issues can be dealt with booster shots every 2-3 months, it is currently unknown how long treatment would be required before an individual is no longer addicted to cocaine, thus it is difficult to gauge the total cost of such a treatment.

Another concern is that some individuals may increase their cocaine use after receiving the vaccine. The reason for this behavior change is that although the new antibodies are binding the cocaine, the addictive neuronal pathway that induces the individual to take cocaine is not neutralized in any way. In some context for these patients the vaccine generates an infinite tolerance level where no matter how much cocaine is taken no neuronal reaction is generated. Therefore, if these vaccines were used as a treatment method it would be possible that in the early stages of treatment some participants would demonstrate a significant increase in cocaine use. Fortunately because the cocaine is not having any biological effect due to the antibody there is almost no chance for the individual to overdose. Instead the only real detriment from this behavior is significant loss of the capital required to purchase the cocaine and multiple instances of possible legal ramifications for doing so.

One issue of exploration that does not receive much attention, if any at all, is the prospect of using a cocaine vaccine as a preventative measure instead of a therapeutic one. Of course with the current version of the vaccine the cocaine antibodies do not have a long enough residence time to warrant its use as a preventative measure, but it stands to reason that the lifespan issue will improve in the future. Improvement of antibody lifespan would make a drug vaccine eligible for administration in consort with other childhood vaccines. For example it makes sense that non-cocaine using parents would be interested in eliminating the possibility that their children become cocaine addicts in the future. Administration of the vaccine before the individual can form the neuronal addiction pathways for cocaine would significantly increase the probability that the individual would not become addicted to cocaine even if consumed later in life. Without the addiction pathways and with no euphoria generated from the consumption of the cocaine there would be no rational reason for the individual to begin consuming cocaine. The potential profitability of such a vaccine in a preventative context should be high, which would suggest that it presents a quality investment opportunity for a pharmaceutical company. In time it stands to reason that multiple drug vaccines could be created which would neutralize the influence of those drugs and in the end these vaccines could be the game-changer that ends the war on drugs in victory.

1. Miron, Jeffrey. "The Budgetary Implications of Drug Prohibition.” 2008.

2. Berridge, K, and Robinson, T. “What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?” Brain Res Rev. 1998. 28: 309-369.

3. Kalivas, P. “Glutamate systems in cocaine addiction.” Current Opinion in Pharmacology. 2004. 4: 23–29.

4. Kalivas, P, and McFarland, K. “Brain circuitry and the reinstatement of cocaine-seeking behavior.” Psychopharmacology. 2003. 168: 44-56.

5. Goldstein, R, Volkow, N. “Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex.” Am. J. Psychiatry. 2002. 159: 1642-1652.

6. Kantak, K, et, Al. “Dissociable effects of lidocaine inactivation of the rostral and caudal basolateral amygdala on the maintenance and reinstatement of cocaine-seeking behavior in rates.” J Neurosci. 2002. 22: 1126-1136.

7. Winder, D, et, Al. “Synaptic plasticity in drug reward circuitry.” Curr. Mol. Med. 2002. 2: 667-676.

8. Tzschentke, T, and Schmidt W. “Glutamatergic mechanisms in addiction.” Mol Psychiatry. 2003. 8: 373-382.

9. McFarland, K, and Kalivas, P. “The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior.” J Neurosci. 2001. 21:8655-8663.

10. McLaughlin, J, and See, R. “Reversible inactivation of the dorsomedial prefrontal cortext attenuates conditioned reinstatement of cocaine-seeking behavior in rats.” Psychopharmacol. 2003. 168: 57-65.

11. Holmgren, J, et, Al. “Strategies for the induction of immune response at mucosal surfaces making use of cholera toxin B subunit as immunogen, carrier, and adjuvant.” Am J Trop Med Hyg. 1994. 50: 42-54.

12. Martell, Bridget, et, Al. “Vaccine pharmacotherapy for the treatment of cocaine dependence.” Biol Psychiatry. 2005. 58: 158-164.

13. Martell, Bridget, et, Al. “Cocaine Vaccine for the Treatment of Cocaine Dependence in Methadone-Maintained Patients.” Arch Gen Psychiatry. 2009. 66(10): 1116-1123.

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