Mehmet Sofuoglu

Sex and menstrual cycle differences in the subjective effects from smoked cocaine in humans

To investigate sex and menstrual cycle effects in response to cocaine administration, data from existing studies were analyzed. First, responses to a single delivery of 0.4 mg/kg smoked cocaine were investigated. Women reported lower ratings for measures of paranoid/suspicious and heart racing/pounding than did men. In addition, women in the luteal phase reported diminished ratings for a measure of feel high than did both women in the follicular phase of the menstrual cycle and men. Second, responses to up to 6 deliveries of 0.4 mg/kg smoked cocaine were investigated. Women, compared with men, had lower ratings on feel high, heart racing/pounding, and feel stimulated. Results suggest that there are significant sex and menstrual phase differences in the subjective effects of cocaine.

Neuroscience of behavioral and pharmacological treatments for addictions.

Although substantial advances have been made in behavioral and pharmacological treatments for addictions, moving treatment development to the next stage may require novel ways of approaching addictions, particularly ways based on new findings regarding the neurobiological underpinnings of addictions that also assimilate and incorporate relevant information from earlier approaches. In this review, we first briefly review theoretical and biological models of addiction and then describe existing behavioral and pharmacologic therapies for the addictions within this framework. We then propose new directions for treatment development and targets that are informed by recent evidence regarding the heterogeneity of addictions and the neurobiological contributions to these disorders.

Cognitive enhancement as a pharmacotherapy target for stimulant addiction.

BACKGROUND No medications have been proven to be effective for cocaine and methamphetamine addiction. Attenuation of drug reward has been the main strategy for medications development, but this approach has not led to effective treatments. Thus, there is a need to identify novel treatment targets in addition to the brain reward system. AIM To propose a novel treatment strategy for stimulant addiction that will focus on medications enhancing cognitive function and attenuating drug reward. METHODS Pre-clinical and clinical literature on potential use of cognitive enhancers for stimulant addiction pharmacotherapy was reviewed. RESULTS AND CONCLUSIONS Cocaine and methamphetamine users show significant cognitive impairments, especially in attention, working memory and response inhibition functions. The cognitive impairments seem to be predictive of poor treatment retention and outcome. Medications targeting acetylcholine and norepinephrine are particularly well suited for enhancing cognitive function in stimulant users. Many cholinergic and noradrenergic medications are on the market and have a good safety profile and low abuse potential. These include galantamine, donepezil and rivastigmine (cholinesterase inhibitors), varenicline (partial nicotine agonist), guanfacine (alpha(2)-adrenergic agonist) and atomoxetine (norepinephrine transporter inhibitor). Future clinical studies designed optimally to measure cognitive function as well as drug use behavior would be needed to test the efficacy of these cognitive enhancers for stimulant addiction.

Stress decreases the ability to resist smoking and potentiates smoking intensity and reward

We have developed a novel human laboratory model to examine two primary aspects of stress-precipitated tobacco relapse: (1) Does stress reduce the ability to resist the first cigarette? (2) Once the first cigarette is initiated, does stress facilitate subsequent smoking? Using a within-subject design, daily smokers (n = 37) who were nicotine deprived overnight received a personalized imagery induction (stress or neutral) on two separate days, and then had the option of initiating a tobacco self-administration session or delaying initiation for up to 50 min in exchange for three levels of monetary reinforcement. Subsequently, the tobacco self-administration session entailed a 1-hour period in which subjects could choose to smoke using a smoking topography system. Following the stress induction, subjects were less able to resist smoking, smoked more intensely (increased puffs, shorter inter-puff interval, and greater peak puff velocity), and perceived greater satisfaction and reward from smoking. Stress significantly increased hypothalamus–pituitary–adrenal (HPA) axis reactivity, tobacco craving, negative emotion, and physiologic reactivity relative to the neutral condition. In addition, increased cortisol, ACTH, and tobacco craving were associated with reduced ability to resist smoking following stress. These findings have implications for understanding the impact of stress on smoking relapse and model development to assess smoking lapse behavior.

Norepinephrine and stimulant addiction

No pharmacotherapies are approved for stimulant use disorders, which are an important public health problem. Stimulants increase synaptic levels of the monoamines dopamine (DA), serotonin and norepinephrine (NE). Stimulant reward is attributable mostly to increased DA in the reward circuitry, although DA stimulation alone cannot explain the rewarding effects of stimulants. The noradrenergic system, which uses NE as the main chemical messenger, serves multiple brain functions including arousal, attention, mood, learning, memory and stress response. In pre‐clinical models of addiction, NE is critically involved in mediating stimulant effects including sensitization, drug discrimination and reinstatement of drug seeking. In clinical studies, adrenergic blockers have shown promise as treatments for cocaine abuse and dependence, especially in patients experiencing severe withdrawal symptoms. Disulfiram, which blocks NE synthesis, increased the number of cocaine‐negative urines in five randomized clinical trials. Lofexidine, an α2‐adrenergic agonist, reduces the craving induced by stress and drug cues in drug users. In addition, the NE transporter (NET) inhibitor atomoxetine attenuates some of d‐amphetamines subjective and physiological effects in humans. These findings warrant further studies evaluating noradrenergic medications as treatments for stimulant addiction.

The Effect of Cannabis Compared with Alcohol on Driving

The prevalence of both alcohol and cannabis use and the high morbidity associated with motor vehicle crashes has lead to a plethora of research on the link between the two. Drunk drivers are involved in 25% of motor vehicle fatalities, and many accidents involve drivers who test positive for cannabis. Cannabis and alcohol acutely impair several driving-related skills in a dose-related fashion, but the effects of cannabis vary more between individuals than they do with alcohol because of tolerance, differences in smoking technique, and different absorptions of Delta(9)-tetrahydrocannabinol (THC), the active ingredient in marijuana. Detrimental effects of cannabis use vary in a dose-related fashion, and are more pronounced with highly automatic driving functions than with more complex tasks that require conscious control, whereas alcohol produces an opposite pattern of impairment. Because of both this and an increased awareness that they are impaired, marijuana smokers tend to compensate effectively while driving by utilizing a variety of behavioral strategies. Combining marijuana with alcohol eliminates the ability to use such strategies effectively, however, and results in impairment even at doses which would be insignificant were they of either drug alone. Epidemiological studies have been inconclusive regarding whether cannabis use causes an increased risk of accidents; in contrast, unanimity exists that alcohol use increases crash risk. Furthermore, the risk from driving under the influence of both alcohol and cannabis is greater than the risk of driving under the influence of either alone. Future research should focus on resolving contradictions posed by previous studies, and patients who smoke cannabis should be counseled to wait several hours before driving, and avoid combining the two drugs.

Novel Approaches to the Treatment of Cocaine Addiction

Cocaine addiction continues to be an important public health problem with over 1.7 million users in the US alone. Although there are no approved pharmacotherapies for cocaine addiction, a number of medications have been tested with some promising results. In this review, we summarise some of the emerging targets for cocaine pharmacotherapy including dopaminergic and GABA medications, adrenoceptor antagonists, vasodilators and immunotherapies. The brain dopamine system plays a significant role in mediating the rewarding effects of cocaine. Among dopaminergic agents tested for cocaine pharmacotherapy, disulfiram has decreased cocaine use in a number of studies. Amantadine, another medication with dopaminergic effects, may also be effective in cocaine users with high withdrawal severity. GABA is the main inhibitory neurotransmitter in the brain, and accumulating evidence suggests that the GABA system modulates the dopaminergic system and cocaine effects. Two anticonvulsant medications with GABAergic effects, tiagabine and topiramate, have yielded positive findings in clinical trials. Baclofen, a GABAb receptor agonist, is also promising, especially in those with more severe cocaine use. Some of the physiological and behavioural effects of cocaine are mediated by activation of the adrenergic system. In cocaine users, propranolol, a β-adrenoceptor antagonist, had promising effects in individuals with more severe cocaine withdrawal symptoms. Cerebral vasodilators are another potential target for cocaine pharmacotherapy. Cocaine users have reduced cerebral blood flow and cortical perfusion deficits. Treatment with the vasodilators amiloride or isradipine has reduced perfusion abnormalities found in cocaineusers. The functional significance of these improvements needs to be further investigated. All these proposed pharmacotherapies for cocaine addiction act on neural pathways. In contrast, immunotherapies for cocaine addiction are based on the blockade of cocaine effects peripherally, and as a result, prevent or at least slow the entry of cocaine into the brain. A cocaine vaccine is another promising treatment for cocaine addiction. The efficacy of this vaccine for relapse prevention is under investigation. Many initial promising findings need to be replicated in larger, controlled clinical trials.

Treatment Outcome Predictors for Cocaine Dependence

Over the past decade, a large number of potential medications have been examined in clinical trials for cocaine dependence. Unfortunately, no effective pharmacotherapies for cocaine dependence have been found to date. Although effective treatments for cocaine dependence are still being investigated, a few variables have been found to significantly predict cocaine treatment response. These variables include cocaine use variables, such as days of cocaine use in the month before treatment, baseline urine cocaine results, and cocaine withdrawal symptoms. Comorbid depression and alcohol use have also been shown to be risk factors for relapse. Among personality variables, impulsivity and similar personality traits may predict treatment response. Initial promising findings with genetic polymorphism, brain activation, and stress response have also been found and need to be replicated in future studies.

Emerging pharmacological strategies in the fight against cocaine addiction

Cocaine addiction continues to be an important public health problem worldwide. At present, there are no proven pharmacotherapies for cocaine addiction. The studies reviewed here revealed a number of emerging targets for cocaine pharmacotherapy. First, disulfiram, a medication with dopaminergic effects, reduced cocaine use in a number of clinical trials. Second, GABA medications, tiagabine and topiramate, were found promising in clinical trials. Third, a β-adrenergic blocker, propranolol, may be effective especially among cocaine-addicted individuals with high withdrawal severity. Fourth, treatment with a stimulant medication, modafinil, has reduced cocaine use. Last, a cocaine vaccine that slows entry of cocaine into the brain holds promise. These promising findings need to be further tested in controlled clinical trials.

Effects of progesterone treatment on cocaine responses in male and female cocaine users

We recently reported that progesterone treatment attenuated some of the subjective effects of smoked cocaine in female cocaine users. In this study, we further examined the interaction between progesterone and cocaine in both male and female cocaine users using subjective, physiological and behavioral outcomes. A total of 10 subjects, 6 male and 4 female cocaine users, had two experimental sessions. Before each session, participants received either two oral doses of 200 mg of progesterone or placebo. Two hours after the second dose of medication treatment, the participants received a 0.3 mg/kg dose of cocaine intravenously and started the self-administration period, in which five optional doses of cocaine were available. Progesterone treatment attenuated the cocaine-induced diastolic blood pressure increases without affecting the systolic blood pressure and heart rate increases. Progesterone treatment also attenuated the subjective ratings of high and feel the effect of last dose in response to cocaine but did not affect cocaine self-administration behavior. These results suggest that progesterone attenuates some of the physiological and subjective effects of cocaine in both male and female participants. The effects of progesterone treatment on cocaine dependence need to be further studied in controlled trials.