In an animal model, rats that were exposed to tetrahydrocannabinol during adolescence showed higher levels of opioid self-administration during adulthood than rats that had not been exposed.18 In humans, correlational twin studies have shown that regular use of marijuana during adolescence is associated with use of other illicit drugs in the future.19,20
Drugs of abuse cause specific interactions within the brain's most primitive and salience-provoking systems. They change the brain and can produce disease where none would have been without early use or exposure. Although the "gateway hypothesis" describes the progression from tobacco/marijuana use in adolescence to later abuse of "hard" drugs via attitude changes, it is possible that the earlier tobacco or marijuana use actually sensitizes the brain, making it remember the effects of drug use, and making it more susceptible to abuse of other drugs in the future. Indeed, preliminary research shows that anesthesiologists who experience long-term secondhand exposure to extremely low doses of opioids in the air of the operating room are at increased risk for opioid addiction.21 Furthermore, persons with a history of smoking marijuana or tobacco appear to be at highest risk.22
More research is needed to explore these hypotheses and determine the mechanism(s) involved. Until then, it may be safest to address patients' substance use/abuse (even with soft drugs such as marijuana) as early as possible. This approach is relatively inexpensive and could potentially decrease the likelihood of a long-term addiction developing without increasing risk to the patient.
Recently, methods of proteomics and genomics have been applied to the study of molecular mechanisms and neurobiological consequences of drug administration. Using animal models, advances in the understanding of neural circuitry and cellular mechanisms involved in addiction have paved the way for improved understanding of addiction in humans and may eventually provide information needed to develop more effective prevention and treatment methods. Nestler23 has demonstrated that drug addiction is associated with changes at the molecular level, which may be understood as a form of neural plasticity that results from long-term drug use.
Kobeissy and colleagues24 reviewed the existing animal and human proteomic research on the cellular effects of morphine(Drug information on morphine), methamphetamine, and alcohol(Drug information on alcohol), particularly in the prefrontal cortex, striatum, and hippocampus. They reported that morphine administration is associated with dysregulation of proteins involved with several crucial cellular functions (eg, metabolism, signal transduction, organization of the cytoskeleton, synaptic transmission). Similarly, acute methamphetamine administration appears to negatively alter cellular functioning in many ways (eg, oxidative stress, synaptic transmission, mitochondrial dysfunction, apoptosis). It is noteworthy that data assessing the impact of chronic alcohol administration demonstrate similar dysfunction in signaling and cytoskeleton organization, as well as increased oxidative stress. These data suggest that drug abuse may result in permanent damage to cellular structure and functioning, even in the absence of behavioral markers. Current proteomic studies are assessing inflammatory response and damage caused by drugs (eg, methamphetamine) and evaluating the length of time before brain functioning "recovers" following a drug binge.25,26
Stress and relapse
It is generally understood that among patients with addiction disorders, relapse is the rule rather than the exception. Drug dependence appears to be related to dysregulation of the reward system and withdrawal-related activation of the stress system.27 Stress hormones (eg, corticosterone, prolactin) increase in response to withdrawal from psychoactive drugs, increasing the aversive quality of the experience.28
Factors associated with classical and operant conditioning and social learning produce environmental and behavioral "cues" that may increase urges and encourage use. As a result, treatment efforts typically involve relapse prevention techniques that help individuals prepare for recovery by assessing personal antecedents of relapse and adjusting expectations.29 Psychoeducation, self-efficacy support, and coping skills training are important components of the intervention. The patient and clinician work together to identify situations associated with a high-risk for substance use and ways to avoid or minimize exposure to these situations. The clinician also helps the patient learn ways to manage urges, cravings, and withdrawal symptoms.