Volume 4, Issue 1
Pharmacological treatment of addiction: Obstacles in identifying and testing medications
by Dr. Richard De La Garza
Our lab is involved in medications testing for cocaine- and methamphetamine-addiction in humans and we receive funding primarily from the National Institute on Drug Abuse. While Food and Drug Administration (FDA)-approved medications are available for alcohol, nicotine and heroin addiction, not one has been approved for the treatment of either cocaine or methamphetamine addiction. The absence of available medications is not a result of lack of effort or interest on the part of the National Institutes of Health, or scientists and clinicians in the field. The fact is that cocaine addiction (focusing on just that stimulant for the rest of this essay) is a heterogeneous disease and the process of identifying and testing medications for addiction, like any neuropsychiatric disease (e.g., depression), takes many years and costs hundreds of millions of dollars. The primary obstacle has been that pharmaceutical companies have never been that interested in addiction as a disease because of the stigma surrounding it. This has been complicated more recently by the fact that many companies are eliminating their neuroscience research programs. So, the hope for finding new medications is especially difficult to envision and requires a great deal of patience and fortitude from clinicians and patients alike.
With regard to “heterogeneity”, I often remind medical and graduate students that research on cocaine addiction is not like foot fungus research. Cocaine is a powerfully addictive stimulant that blocks the transporters for dopamine, norepinepherine, and serotonin in the brain. Take that bit of knowledge and couple it with the fact that the majority of cocaine-addicted individuals also smoke cigarettes (~80%), use alcohol (~70%), and use cannabis (~50%). Throw in the fact that the majority of these individuals have been subjected to serious adverse childhood experiences (e.g., physical and sexual abuse) and extraordinary stressors as adults (e.g., incarceration, homelessness), and the result is the brain of an individual that is unlikely to be fixed by a simple compound that targets a single protein in the brain.
Speaking vaguely and very broadly, the medications development process begins with organic and medicinal chemists who create novel compounds in the lab, followed by in vitro evaluation of affinity of these new small molecules for a slew of neuronal receptors, and this is followed by in vivo assessments of toxicology in a variety of animal species. Once these hurdles have been cleared, promising compounds move forward to in vivo testing in specific assays of reward and reinforcement (e.g., conditioned place preference and self-administration), which occurs in mice, rats and in non-human primates. All along, our lab is watching these developments as reports are published in the scientific literature. With time the initial list of 1000 compounds is whittled down to 100, then to just 10, and eventually 1 compound is selected as the most promising for evaluation in healthy human subjects (not literally - I’m just trying to give you a sense for how the process works). Believe it or not, this is still a step away from our lab and despite that proximity, it may be a year or two and at least a million dollars before a given compound makes it to our front door. Once the initial safety, pharmacokinetic and pharmacodynamic studies are complete, these compounds finally move into the population of interest – i.e., cocaine-dependent participants, and that is where our lab takes over.
We recruit non-treatment seeking, cocaine-dependent individuals who are willing to participate in an inpatient research study that takes place over several days (depending on the half-life of the compound and the planned experiments in the protocol). We recruit non-treatment seeking individuals because this phase of testing (called Phase Ib) includes exposing participants to low doses of their drug of choice as well as the medication of interest. This is done since the FDA is primarily interested in the safety of the co-administration of these compounds. They want to know what a given compound will do (i.e., adverse events) when cocaine is on board before the next phase of testing (Phase II and III outpatient clinical trials) can even be considered. The FDA, and any knowledgeable scientist or clinician, knows that these individuals are more likely than not to relapse even when they have the best intention to stop using. So, a typical study in our lab involves assessment of the safety and tolerability of the drug itself (1 or 2 doses versus placebo) as well as what happens when cocaine is co-administered. As you might expect, when you give cocaine to a cocaine-addicted individual, they self-report feelings of euphoria (e.g., ”high”, “stimulated”) and “desire” for more cocaine. Positive subjective effects are accompanied by increases in blood pressure and heart rate, but these are invariably transitory and wane within just a few minutes. All of that is simple and straightforward and we have seen these changes a 1000+ times. Even though these are double-blind studies, it does not take long before a participant blurts out (or smiles knowingly) that they have received “dope”. The funny thing is they call the placebo infusions “nope”. The blind is never really broken, however, since the guy who does the stats and writes the reports (me) is not the same one who is interacting with the patients during the infusion sessions (research coordinators).
Where things get interesting is how participants respond to cocaine infusions after they have received the candidate medication for several days - after steady state levels have been achieved. As scientists, we want to know whether the drug was able to block the “high” produced by cocaine, or the “desire” for cocaine. Again, let me remind you that the FDA is primarily interested in safety, so we dutifully collect lots of cardiovascular data, and self-reports of negative adjectives (bad feelings), and any self-reports of adverse events like nausea, headaches, dizziness, etc.
The most interesting, and perhaps relevant, data we acquire are derived from self-administration sessions. On those days, participants are first given a sample dose then using a patient-controlled infusion pump, participants make choices every 15 minutes for either an infusion identical to the one they received as a sample or a monetary alternative (usually $1). It is not surprising that when saline is in the syringe, participants choose money, but when cocaine is in the syringe they take most, if not all, of the available infusions. The excitement occurs for us when a medication has been on board for several days and we detect a reduction in the number of choices they make for cocaine. This is not very common, but when it happens, we are ecstatic because it tells us there is a chance that this compound may change not only how a participant “feels” when cocaine is on board, but that they may also choose to take less of it when it is available.
What I failed to mention is that the majority of compounds we evaluate are not novel and fresh off the chemist’s bench, but are typically FDA-approved compounds for other diseases. This is a common strategy and makes sense since it significantly reduces the time and costs of identifying an effective medication. When approaching it in this manner, we look through the scientific literature and think about what is already known about a compound and whether or not it would be able to do something important and useful for cocaine addiction. I will give one example. Modafinil is a wake-promoting agent that is approved by the FDA as a treatment for daytime sleepiness and narcolepsy. Modafinil increases brain dopamine (which could be useful for a cocaine-addicted individual who typically has low brain dopamine) and modafinil also improves cognitive function (this may also be useful for cocaine addicted individuals who often exhibit impairments in cognitive function and poor decision making). Modafinil has looked quite promising so far, but the most recent Phase II outpatient study reveals that it will not be a magic bullet. No surprise there. Notwithstanding, we know it does work for some people and the question we are addressing now is how can we augment the signal provided by modafinil, or what other compounds are available that are like modafinil (structurally/chemically) that might do a better job.
Beyond these studies, our lab uses 3-D fully immersive virtual reality to evaluate the effects of medications on cue-induced craving, functional magnetic resonance imaging to evaluate the neural substrates of reward, and a comprehensive battery of computerized tests of cognitive function. In short, we are pursuing medications testing from multiple angles.
So, this is my life in a nutshell and I am enjoying every minute. I love this line of research, I love where I work and the scientists with whom I interact daily, I love my staff and students, and I love our research participants. If you have never met a cocaine addict (seeing one on TV or in a movie does not count) you might be surprised to learn how much they are just like you and me. Their lives and ours started out pretty much the same. Somewhere along the way decisions were made, drugs were consumed, and some of us had the ability to keep moving forward and turned out OK. Others did not or could not stop using and they ended up on the wrong side of just about everything in life. This is an oversimplification and I do not make excuses for my patients, but I know enough about life, the world, the brain, genetics and the environment to understand that addiction is a very complicated disease (it’s not as simple as foot fungus). Interacting with these individuals keeps me coming to work every day. Knowing that they roam about this world and that no effective treatment exists often keeps me up at night, but it also motivates me to try, try, try again to find a medication or behavioral intervention that will help them stop using and hopefully regain some semblance of normality in their lives.