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group_2_presentation_1_-_effects_of_the_cocaine_on_the_brain [2016/09/30 13:33] khanba3 |
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| - | Cocaine acts on the brain’s limbic system by producing psychoactive and addictive effects. One initial short-term effect is the build-up of the neurochemical, dopamine in chemical synapses of the brain. This effect is what drives cocaine users to take the drug repeatedly due to the increasing levels of euphoria (2). A high volume of research today is focused on understanding how cocaine’s many long term effects produce addictions, cravings and risk of relapse (2). | + | Cocaine acts on the brain’s limbic system by producing psychoactive and addictive effects. One initial short-term effect is the build-up of the neurochemical, dopamine in chemical synapses of the brain. This effect is what drives cocaine users to take the drug repeatedly due to the increasing levels of euphoria [6]. A high volume of research today is focused on understanding how cocaine’s many long term effects produce addictions, cravings and risk of relapse [6]. |
| - | The effects of cocaine appear shortly after taking the first single dose and can disappear within a few minutes to an hour. The reality of cocaine hits after the high. Cocaine has powerful negative effects on the heart, brain and emotions. Many users become addicted quickly, with long term and life threatening consequences. Cocaine produces it's powerful "high" by acting on the brain but also affects the whole body as it travels through the blood. This drug is responsible for more U.S. emergency room visits than any other illegal drug (1). Cocaine predominately harms the brain, lungs, neural vessels and heart. Cocaine acts in the deep areas of the brain. These are the areas that give an individual the feeling of “reward” from highly pleasurable behaviours. Stimulating these areas in the brain causes users to feel good and it can create a powerful craving to use more cocaine. Regular use can lead to tolerance. This means that increasingly higher doses are needed to attain the same effects, this often results in addiction (1). | + | The effects of cocaine appear shortly after taking the first single dose and can disappear within a few minutes to an hour. The reality of cocaine hits after the high. Cocaine has powerful negative effects on the heart, brain and emotions. Many users become addicted quickly, with long term and life threatening consequences. Cocaine produces it's powerful "high" by acting on the brain but also affects the whole body as it travels through the blood. This drug is responsible for more U.S. emergency room visits than any other illegal drug [7]. Cocaine predominately harms the brain, lungs, neural vessels and heart. Cocaine acts in the deep areas of the brain. These are the areas that give an individual the feeling of “reward” from highly pleasurable behaviors. Stimulating these areas in the brain causes users to feel good and it can create a powerful craving to use more cocaine. Regular use can lead to tolerance. This means that increasingly higher doses are needed to attain the same effects, this often results in addiction [7]. |
| - | {{:1344e382ce14b3c370847e620b4f6931.jpg|}} | + | {{:cocaine.jpg|}} |
| //Figure 3 Low frontal metabolism may contribute to the loss of control seen in addiction// | //Figure 3 Low frontal metabolism may contribute to the loss of control seen in addiction// | ||
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| - | Cocaine acts by affecting the limbic system in the brain, as shown below in Figure 4. The limbic system consists of several regions in the brain associated with emotions, such as fear and anger, pleasure-seeking behaviour (which is related to survival), such as eating and sex, and motivation. Specifically, the subcortical structures and areas of the forebrain that are integrated into limbic circuitry include: the amygdala, hippocampus, basal ganglia, hypothalamus, cingulate gyrus, thalamus, and the pallidum. These areas are involved in peripheral nervous system and endocrine system activation. Normally, since the amygdala and hippocampus are involved with memory, they recognize which events or behaviours activate the reward circuitry in the limbic system, thus determining which events are emotionally significant [8]. The two components of the basal ganglia that are most affected by cocaine administration are the ventral tegmental area (VTA) and the ventral striatum, which contains the nucleus accumbens. During normal rewarding behaviours, the cortex stimulates these regions, activating the reward pathway. This is primarily done by stimulatory glutamatergic input sent to both the VTA and the ventral striatum. The VTA further stimulates the nucleus accumbens region of the ventral striatum through dopaminergic projection neurons. Specifically, these neurons in the nucleus accumbens region are GABAergic inhibitory neurons, called medium spiny neurons (MSNs). When stimulated, these inhibit the neurons of the Pallidum, which are tonically inhibiting the thalamus. By doing this, the inhibition onto the thalamus by the pallidum is stopped, allowing the thalamus neurons to be stimulated. This release of inhibition on the thalamus is called disinhibition. Stimulation of thalamic glutamatergic neurons positively feeds back into regions of the cortex, such as the motor cortex, amygdala and hippocampus With enough stimulation of this pathway, the behaviour or event that causes stimulation of the reward pathway is associated with feelings of pleasure, and the brain increases the frequency of the behaviour. In the case of cocaine administration, cocaine increases the dopaminergic stimulation onto the nucleus accumbens, leading to disinhibition of the thalamus, and stimulation of the reward pathway. With enough stimulation, cocaine administration is paired with euphoric feelings, so the brain increases the frequency of behaviour, which can eventually lead to addiction [8]. | + | Cocaine acts by affecting the limbic system in the brain, as shown below in Figure 4. The limbic system consists of several regions in the brain associated with emotions, such as fear and anger, pleasure-seeking behaviour (which is related to survival), such as eating and sex, and motivation [8]. Specifically, the subcortical structures and areas of the forebrain that are integrated into limbic circuitry include: the amygdala, hippocampus, basal ganglia, hypothalamus, cingulate gyrus, thalamus, and the pallidum. These areas are involved in peripheral nervous system and endocrine system activation. Normally, since the amygdala and hippocampus are involved with memory, they recognize which events or behaviours activate the reward circuitry in the limbic system, thus determining which events are emotionally significant [9]. The two components of the basal ganglia that are most affected by cocaine administration are the ventral tegmental area (VTA) and the ventral striatum, which contains the nucleus accumbens. During normal rewarding behaviours, the cortex stimulates these regions, activating the reward pathway. This is primarily done by stimulatory glutamatergic input sent to both the VTA and the ventral striatum. The VTA further stimulates the nucleus accumbens region of the ventral striatum through dopaminergic projection neurons. Specifically, these neurons in the nucleus accumbens region are GABAergic inhibitory neurons, called medium spiny neurons (MSNs). When stimulated, these inhibit the neurons of the Pallidum, which are tonically inhibiting the thalamus. By doing this, the inhibition onto the thalamus by the pallidum is stopped, allowing the thalamus neurons to be stimulated. This release of inhibition on the thalamus is called disinhibition. Stimulation of thalamic glutamatergic neurons positively feeds back into regions of the cortex, such as the motor cortex, amygdala and hippocampus With enough stimulation of this pathway, the behaviour or event that causes stimulation of the reward pathway is associated with feelings of pleasure, and the brain increases the frequency of the behaviour [8]. In the case of cocaine administration, cocaine increases the dopaminergic stimulation onto the nucleus accumbens, leading to disinhibition of the thalamus, and stimulation of the reward pathway. With enough stimulation, cocaine administration is paired with euphoric feelings, so the brain increases the frequency of behaviour, which can eventually lead to addiction [9]. |
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| ===== Changes in Brain Morphology after Cocaine usage ===== | ===== Changes in Brain Morphology after Cocaine usage ===== | ||
| - | Extensive research has been carried out in studying the effects of cocaine on the morphology of the brain, yet many discrepancies exist in the clinical literature as to what specific parts of the brain are influenced by cocaine usage. A multitude of studies have found differences in in the amount of grey and white matter when comparing the cocaine-dependent brains and brain tissue of control groups, yet these inconsistencies make it difficult to determine exactly what regions are affected<sup>10</sup>; nonetheless, the nucleus accumbens, the cerebellum, and the orbitofrontal cortex are three regions that have become apparent as the areas most often affected by cocaine administration. | + | Extensive research has been carried out in studying the effects of cocaine on the morphology of the brain, yet many discrepancies exist in the clinical literature as to what specific parts of the brain are influenced by cocaine usage. A multitude of studies have found differences in in the amount of grey and white matter when comparing the cocaine-dependent brains and brain tissue of control groups, yet these inconsistencies make it difficult to determine exactly what regions are affected [10]; nonetheless, the nucleus accumbens, the cerebellum, and the orbitofrontal cortex are three regions that have become apparent as the areas most often affected by cocaine administration. |
| - | The nucleus accumbens plays a central role in the reward circuitry of the brain<sup> 11 </sup>, and has been determined to be the “most important site of cocaine high” (12). A 2001 study by the University of Michigan and the University of Lethbridge investigated the influence of cocaine usage on the nucleus accumbens. They executed this research by allowing the rats in the experimental group to self-administer cocaine for 1 hour a day for one month, and left the control group undisturbed for the same period of time. From this study, the researchers determined that rats who self-administered cocaine experienced an increase in the dendritic branching and an increased dendritic density in the nucleus accumbens (12). Although the exact mechanism of how cocaine triggers the nerve cells in the nucleus accumbens to branch off and extend is still unknown, it has been hypothesized that this change will pick up more signals from other regions such as the hippocampus, the amygdala, and the frontal cortex (12). This allows these regions to have greater control over the functions of the nucleus accumbens, causing long-standing changes in behaviour such as intense drug cravings when drug-associated memories are stimulated (11). | + | The nucleus accumbens plays a central role in the reward circuitry of the brain [11], and has been determined to be the “most important site of cocaine high” [12]. A 2001 study by the University of Michigan and the University of Lethbridge investigated the influence of cocaine usage on the nucleus accumbens. They executed this research by allowing the rats in the experimental group to self-administer cocaine for 1 hour a day for one month, and left the control group undisturbed for the same period of time. From this study, the researchers determined that rats who self-administered cocaine experienced an increase in the dendritic branching and an increased dendritic density in the nucleus accumbens [12]. Although the exact mechanism of how cocaine triggers the nerve cells in the nucleus accumbens to branch off and extend is still unknown, it has been hypothesized that this change will pick up more signals from other regions such as the hippocampus, the amygdala, and the frontal cortex [12]. This allows these regions to have greater control over the functions of the nucleus accumbens, causing long-standing changes in behaviour such as intense drug cravings when drug-associated memories are stimulated [11]. |
| - | The cerebellum, a region of the brain involved in motor control and movement coordination, has also been found to be impacted by chronic exposure to cocaine (13, 14). Specifically, multiple studies have reported cocaine users to experience an increase in cerebellar activity. A 2014 study on the effect of cocaine on task execution in rhesus monkeys compared the working memory performance between a group that had previously self-administered cocaine for 12 months, and a control group that self-administered water for that length of time. Both groups were drug-free for 20 months prior to the start of the study. The researchers found no differences in the execution of the tasks, but detect an increase in cerebellar metabolic activity in the cocaine group whilst executing the aforementioned tasks. This finding matches the results of previous literature (13), and has been previously suggested to be a means of compensating for hypoactivity in cortical areas of the brain (10). | + | The cerebellum, a region of the brain involved in motor control and movement coordination, has also been found to be impacted by chronic exposure to cocaine [13][14]. Specifically, multiple studies have reported cocaine users to experience an increase in cerebellar activity. A 2014 study on the effect of cocaine on task execution in rhesus monkeys compared the working memory performance between a group that had previously self-administered cocaine for 12 months, and a control group that self-administered water for that length of time. Both groups were drug-free for 20 months prior to the start of the study. The researchers found no differences in the execution of the tasks, but detect an increase in cerebellar metabolic activity in the cocaine group whilst executing the aforementioned tasks. This finding matches the results of previous literature [13], and has been previously suggested to be a means of compensating for hypoactivity in cortical areas of the brain [10]. |
| - | Finally, the orbitofrontal cortex (OFC) is a critical structure in the process of decision making and emotional regulation (15). A number of studies have found a decrease in grey matter in this brain region with the chronic usage of cocaine, which has been used hypothesized to cause behavioural changes in users, such as engaging in risky behaviour (16). A 2014 study done by Federica Lucantonio and collegues compared the synaptic activity in the orbitofrontal cortex between rats fed cocaine for 14 days, and a control group that was trained to self-administer oral sucrose for the same amount of time (17). The rats were then trained with a Pavlovian-style task, where they were taught to respond to several cues by means of reward. This training required the rats to use insight to determine the likely outcomes of an event in order guide their response. The control group was found to experience change in neural activity in the OFC between task training- specifically, an increased conditioned response which led to the appropriate behaviour. This confirmed that the neural activity in the orbitofrontal cortex induced the resulting behaviour of the sucrose-ingesting rats. However, this pattern was not seen in rats that were fed cocaine. The study therefore concluded that the self-administration of cocaine resulted in the “loss of neural integration” in the OFC, thus inhibiting the rat’s ability to use insight and predict outcomes to guide their responding behaviour (17). | + | Finally, the orbitofrontal cortex (OFC) is a critical structure in the process of decision making and emotional regulation [15]. A number of studies have found a decrease in grey matter in this brain region with the chronic usage of cocaine, which has been used hypothesized to cause behavioural changes in users, such as engaging in risky behaviour [16]. A 2014 study done by Federica Lucantonio and collegues compared the synaptic activity in the orbitofrontal cortex between rats fed cocaine for 14 days, and a control group that was trained to self-administer oral sucrose for the same amount of time [17]. The rats were then trained with a Pavlovian-style task, where they were taught to respond to several cues by means of reward. This training required the rats to use insight to determine the likely outcomes of an event in order guide their response. The control group was found to experience change in neural activity in the OFC between task training- specifically, an increased conditioned response which led to the appropriate behaviour. This confirmed that the neural activity in the orbitofrontal cortex induced the resulting behaviour of the sucrose-ingesting rats. However, this pattern was not seen in rats that were fed cocaine. The study therefore concluded that the self-administration of cocaine resulted in the “loss of neural integration” in the OFC, thus inhibiting the rat’s ability to use insight and predict outcomes to guide their responding behaviour [17]. |
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| The risk for becoming dependant in the first two years of use is 5-6%, while becoming dependant within 10 years of first use increases to 15-16%. Studies show that the chances of becoming dependant on cocaine was lower when individuals snorted cocaine; higher when smoking, and much higher for injecting. Women are 3.3 times more likely to become dependent when compared to men. Those who started at a younger age, 12-13, were four times more likely to become dependent when compared to those who started at ages 18-20. The peak age for dependence is at ages 23-25. [21] | The risk for becoming dependant in the first two years of use is 5-6%, while becoming dependant within 10 years of first use increases to 15-16%. Studies show that the chances of becoming dependant on cocaine was lower when individuals snorted cocaine; higher when smoking, and much higher for injecting. Women are 3.3 times more likely to become dependent when compared to men. Those who started at a younger age, 12-13, were four times more likely to become dependent when compared to those who started at ages 18-20. The peak age for dependence is at ages 23-25. [21] | ||
| - | {{:meoww.jpg|}} | + | {{:figure_71_cocaine.jpg|}} |
| - | //Figure 7: Graph showing dependance on Cocaine use relative to age group // | + | |
| - | http://www.nature.com/npp/journal/v26/n4/full/1395810a.html | + | |
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| ====== Treatment ====== | ====== Treatment ====== | ||
| - | ==== Medical ==== | + | ==== Pharmacological Treatment==== |
| Presently there are not any medications that are approved for formal treatment of cocaine addiction. Many medications have been proven to be ineffective while others showed limited evidence of seeing improvement in cocaine abuse relief. Ibogaine is a pharmacological drug that has been under vigorous investigation recently, and is used in Canadian clinics as a treatment for cocaine use.Other medications used and currently under research include Gabapentin, which makes cocaine cravings easier to overcome and relapses less severe. It increases the neurotransmitter, GABA, which increases relaxation and reduces stress and anxiety. Vigabatrin is another drug that reduces GABA in the brain and reduces cocaine cravings. Baclofen which is still under vigorous research is a muscle relaxant that helps curb cocaine cravings, especially for chronic heavy users. Nocaine provides a weaker version of cocaine's effects, however it is only used by participating research trials. Each drug has its own set of side effects and availability, with most undergoing continuous research. [22] | Presently there are not any medications that are approved for formal treatment of cocaine addiction. Many medications have been proven to be ineffective while others showed limited evidence of seeing improvement in cocaine abuse relief. Ibogaine is a pharmacological drug that has been under vigorous investigation recently, and is used in Canadian clinics as a treatment for cocaine use.Other medications used and currently under research include Gabapentin, which makes cocaine cravings easier to overcome and relapses less severe. It increases the neurotransmitter, GABA, which increases relaxation and reduces stress and anxiety. Vigabatrin is another drug that reduces GABA in the brain and reduces cocaine cravings. Baclofen which is still under vigorous research is a muscle relaxant that helps curb cocaine cravings, especially for chronic heavy users. Nocaine provides a weaker version of cocaine's effects, however it is only used by participating research trials. Each drug has its own set of side effects and availability, with most undergoing continuous research. [22] | ||
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| - National Institute on Drug Abuse. (n.d.). Cocaine. Retrieved from https://www.drugabuse.gov/publications/drugfacts/cocaine | - National Institute on Drug Abuse. (n.d.). Cocaine. Retrieved from https://www.drugabuse.gov/publications/drugfacts/cocaine | ||
| - Johnston, A. J., Busch, S., Pardo, L. C., Callear, S. K., McLain, S. E. (2016). On the atomic structure of cocaine in solution. Physical Chemistry Chemical Physics, 18, 991- 999. doi: 10.1039/c5cp06090g. | - Johnston, A. J., Busch, S., Pardo, L. C., Callear, S. K., McLain, S. E. (2016). On the atomic structure of cocaine in solution. Physical Chemistry Chemical Physics, 18, 991- 999. doi: 10.1039/c5cp06090g. | ||
| - | - Methoide. (n.d.). Cocaine: Pharmacology. Retrieved from http://methoide.fcm.arizona.edu/infocenter/index.cfm?stid=168 | + | - Methoide. (n.d.). Cocaine: Pharmacology. Retrieved from http://methoide.fcm.arizona.edu/infocenter/index.cfm?stid=168 |
| - | - National Center for Biotechnology Information. (n.d.) PubChem Compound Database. Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/cocaine#section=Top | + | |
| - Stewart, D. J., Inaba, T., Lucassen, M., Kalow, W. (1979). Cocaine metabolism: cocaine and norcocaine hydrolysis by liver and serum esterases. Clinical Pharamcology and Therapeutics, 25, 464-468. | - Stewart, D. J., Inaba, T., Lucassen, M., Kalow, W. (1979). Cocaine metabolism: cocaine and norcocaine hydrolysis by liver and serum esterases. Clinical Pharamcology and Therapeutics, 25, 464-468. | ||
| + | - Nestler, E. (2005). The Neurobiology of Cocaine Addiction. Science & Practice Perspectives, 3(1), 4-10. http://dx.doi.org/10.1151/spp05314 Center for Behavioral Health Statistics and Quality. (2015). | ||
| + | - Goldberg, J. (2016). Cocaine Use and Its Effects. WebMD. Retrieved 23 September 2016, from http://www.webmd.com/mental-health/addiction/cocaine-use-and-its- effects?page=3 | ||
| - Nicholls, J.G., Mar5n, A.R., Wallace, B.G. & Fuchs, P.A. (2001) From Neuron to Brain, 4th Ed. | - Nicholls, J.G., Mar5n, A.R., Wallace, B.G. & Fuchs, P.A. (2001) From Neuron to Brain, 4th Ed. | ||
| - Breiter, Hans C., et al. "Acute effects of cocaine on human brain activity and emotion." Neuron 19.3 (1997): 591-611. | - Breiter, Hans C., et al. "Acute effects of cocaine on human brain activity and emotion." Neuron 19.3 (1997): 591-611. | ||
| + | - Mackey, S., & Paulus, M. (2013, March). Are there volumetric brain differences associated with the use of cocaine and amphetamine-type stimulants? Neuroscience & Biobehavioral Reviews, 37(3), 300-316. doi:10.1016/j.neubiorev.2012.12.003 | ||
| + | - Dubuc, B. (n.d.). THE BRAIN FROM TOP TO BOTTOM. Retrieved September 21, 2016, from http://thebrain.mcgill.ca/flash/i/i_03/i_03_cr/i_03_cr_par/i_03_cr_par.html | ||
| - Robinson, T. E., Gorny, G., Mitton, E., & Kolb, B. (2001). Cocaine self‐administration alters the morphology of dendrites and dendritic spines in the nucleus accumbens- and neocortex. Synapse, 39(3), 257-266. doi:10.1002/1098 2396(20010301)39:33.3.co;2-t | - Robinson, T. E., Gorny, G., Mitton, E., & Kolb, B. (2001). Cocaine self‐administration alters the morphology of dendrites and dendritic spines in the nucleus accumbens- and neocortex. Synapse, 39(3), 257-266. doi:10.1002/1098 2396(20010301)39:33.3.co;2-t | ||
| - | - Dubuc, B. (n.d.). THE BRAIN FROM TOP TO BOTTOM. Retrieved September 21, 2016, from http://thebrain.mcgill.ca/flash/i/i_03/i_03_cr/i_03_cr_par/i_03_cr_par.html | ||
| - Porter, J. N., Minhas, D., Lopresti, B. J., Price, J. C., & Bradberry, C. W. (2014). Altered cerebellar and prefrontal cortex function in rhesus monkeys that previously self- administered cocaine. Psychopharmacology, 231(21), 4211-4218. doi:10.1007/s00213-014-3560- | - Porter, J. N., Minhas, D., Lopresti, B. J., Price, J. C., & Bradberry, C. W. (2014). Altered cerebellar and prefrontal cortex function in rhesus monkeys that previously self- administered cocaine. Psychopharmacology, 231(21), 4211-4218. doi:10.1007/s00213-014-3560- | ||
| + | - Paulin, M.G. (1993). The Role of the Cerebellum in Motor Control and Perception. Brain Behav Evol, 41(1), 39-50 1993. http://www.otago.ac.nz/neurozoo/documents/Paulin%201993%20-%20role%20of%20the%20cerebellum.pdf | ||
| - Bechara, A. (2000). Emotion, Decision Making and the Orbitofrontal Cortex. Cerebral Cortex, 10(3), 295-307. doi:10.1093/cercor/10.3.295 | - Bechara, A. (2000). Emotion, Decision Making and the Orbitofrontal Cortex. Cerebral Cortex, 10(3), 295-307. doi:10.1093/cercor/10.3.295 | ||
| - Hester, R. (2004). Executive Dysfunction in Cocaine Addiction: Evidence for Discordant Frontal, Cingulate, and Cerebellar Activity. Journal of Neuroscience, 24(49), 11017-11022. doi:10.1523/jneurosci.3321-04.2004 | - Hester, R. (2004). Executive Dysfunction in Cocaine Addiction: Evidence for Discordant Frontal, Cingulate, and Cerebellar Activity. Journal of Neuroscience, 24(49), 11017-11022. doi:10.1523/jneurosci.3321-04.2004 | ||
| - Lucantonio, F., Takahashi, Y. K., Hoffman, A. F., Chang, C., Bali-Chaudhary, S., Shaham, Y., Schoenbaum, G. (2014). Erratum: Orbitofrontal activation restores insight lost after cocaine use. Nature Neuroscience Nat Neurosci, 17(9), 1287-1287. doi:10.1038/nn0914-1287e | - Lucantonio, F., Takahashi, Y. K., Hoffman, A. F., Chang, C., Bali-Chaudhary, S., Shaham, Y., Schoenbaum, G. (2014). Erratum: Orbitofrontal activation restores insight lost after cocaine use. Nature Neuroscience Nat Neurosci, 17(9), 1287-1287. doi:10.1038/nn0914-1287e | ||
| - | - Bechara, A. (2000). Emotion, Decision Making and the Orbitofrontal Cortex. Cerebral Cortex, 10(3), 295-307. doi:10.1093/cercor/10.3.295 | ||
| - | - Goldberg, J. (2016). Cocaine Use and Its Effects. WebMD. Retrieved 23 September 2016, from http://www.webmd.com/mental-health/addiction/cocaine-use-and-its- effects?page=3 | ||
| - | - Nestler, E. (2005). The Neurobiology of Cocaine Addiction. Science & Practice Perspectives, 3(1), 4-10. http://dx.doi.org/10.1151/spp05314 Center for Behavioral Health Statistics and Quality. (2015). | ||
| - Behavioral health trends in the United States: Results from the 2014 National Survey on Drug Use and Health (HHS Publication No. SMA 15-4927, NSDUH Series H-50). Retrieved from http://www.samhsa.gov/ data/ | - Behavioral health trends in the United States: Results from the 2014 National Survey on Drug Use and Health (HHS Publication No. SMA 15-4927, NSDUH Series H-50). Retrieved from http://www.samhsa.gov/ data/ | ||
| - What is the scope of cocaine use in the United States? (2016). Drugabuse.gov. Retrieved 23 September 2016, from https://www.drugabuse.gov/publications/research-reports/cocaine/what-scope-cocaine-use-in-united-states | - What is the scope of cocaine use in the United States? (2016). Drugabuse.gov. Retrieved 23 September 2016, from https://www.drugabuse.gov/publications/research-reports/cocaine/what-scope-cocaine-use-in-united-states | ||
