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Understanding and Treating Cannabinoid Addiction

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Matters were a lot simpler in the 1960s and 1970s. In the US, homegrown marijuana had low THC (delta-9-tetrahydrocannabinol) content, and in order to get a better quality product people sought hashish from Germany or marijuana from Columbia, Jamaica or Southeast Asia. Working in medical research in the 1970s did, however, give me a glimpse of what was to come. THC has to be kept in something like vegetable oil because it will oxidize in air. On several occasions we took a milliliter of this oil and injected it into a regular cigarette. Six people could hallucinate on one of these cigarettes.

 

Fast forward to today, where THC content in marijuana is routinely in double digits and the various concentrated forms can be as high as 90 percent. Add to this the long (and getting longer) list of synthetic cannabinoids and it is no wonder crisis centers are seeing so many problems such as psychosis, mania, and extreme anxiety.

 

What We See Today

 

Known as “honey oil,” butane hash oil (BHO)—also called “hash oil,” “dabs,” “earwax,” “butter” or “shatter,” among other names—homemade marijuana concentrates have caught on quickly. The popularity and availability of e-cigarettes and vaporizer pens offer an easy, discrete way to use the drug. 

 

Nowadays marijuana is smoked through a vaporizer (vape) pen that gives the user a more pronounced high due to enhanced THC content. This process is called “vaping.” “Dabbing” requires heating the THC concentrate with an open flame until it turns to smoke. The smoke is collected in the device and breathed in by the user. Oil is the most commonly used form in vaporizer pens while wax and shatter are typically used in dabbing products.

 

Oil is a refined version of marijuana resembling honey. It is manufactured using liquids and gases such as alcohol and butane, producing THC contents as high as 60 to 80 percent depending upon the degree of solvent extraction. Wax is created using a similar process to that of oil, but the final step in the mixture involves stirring or “whipping” the liquid state to produce the waxy texture. Shatter is produced using the same methods as oil only the process is repeated several times. Extra filtration and purification increases the potency to 75 to 90 percent THC.

 

Synthetic Products

 

Synthetic cannabinoids such as Spice and K2 work in the brain just like marijuana and the naturally occurring cannabinoid neurotransmitters such as anandamide. By changing molecular structure, chemists are able to alter half-life and potency. Many are cannabinoid agonists produced in research laboratories.

 

When the molecule is changed there are also possibilities for enhanced toxicity. Due to poor quality control, the user does not truly know what they are getting. These products are often marketed in catchy, metal foil packets that typically contain around three grams of dried vegetable matter laced with one or more of the cannabinoids.

 

How Cannabinoids Affect the Brain

 

Many drugs selectively activate or inhibit areas of the brain. For example, opioids receptors are distributed in distinct patterns in the brain most concentrated in areas involved in pain pathways such as the substantia gelatinosa of the spinal cord, the medial area of the thalamus, the periaqueductal gray area of the midbrain, and the reward centers in the limbic area. 

 

The cannabinoids attach to CB1 brain receptors and serve as agonists. These receptors are located all over the brain, explaining the very diverse effects of using marijuana. Table 1 gives an overview of how CB1 agonists affect the brain, causing everything from the munchies to euphoria and impaired memory.

 

For example, THC stimulates the CB1 receptors in the ventromedial nucleus of the hypothalamus, which is the appetite center of the brain. THC also attaches to the CB1 receptors in the olfactory bulb, significantly increasing the user’s ability to smell food which causes salivation and a hunger response. 

 

 
It is easy to see why the pharmaceutical community is interested in marijuana. Both delta-9-tetrahydrocannabinol and another active ingredient called cannabidiol (CBD) have created interest therapeutically. THC stimulates appetite and reduces nausea, as well as decreases pain and inflammation. CBD is a nonpsychoactive cannabinoid that may be useful in reducing pain and inflammation, controlling seizures, and possibly treating psychosis. Additionally, finding a medication that would decrease appetite, feeding behavior, and body weight is highly desirable. The possibility of a CB1 agonist that might fill the void between the nonsteroidal anti-inflammatory medicines and the opioids would be highly marketable. In this age of living longer, a new medicine that could positively impact memory would be well worth the hundreds of millions of dollars necessary to bring a new drug to the market.

 

Cannabinoid Effects

 

Exogenous cannabis, including THC and CBD, act on the endogenous cannabinoid system—endocannabinoids such as anandamide—in the brain and other tissue by binding to two different types of cannabinoid receptors on cell membranes. The CB1 receptors are located primarily in presynaptic neurons of the central nervous system and are responsible for the acute psychological and cardiovascular effects of cannabis. CB2 receptors are located in other areas of the body and modulate immune function and inflammatory response. Action at the CB2 receptors is also of medicinal interest since it is the insidious nature of inflammation that is often related to our demise.

 

Every neurotransmitter I am aware of works the same way: starting from the presynaptic side, traveling across the synapse, and bonding to its receptor on the postsynaptic side of the synaptic cleft. However, endogenous cannabinoids seem to work backwards; they are released postsynaptically by a wide variety of stimuli upon demand, travel across the synaptic cleft, and then activate presynaptic CB receptors.

 

 
Cannabinoid receptors have been isolated in the central nucleus of the amygdala. This is a key emotional hub in the brain involved in regulating anxiety and the flight-or-fight response. This discovery may help explain why marijuana users say they select the drug mainly to reduce anxiety. The natural endocannabinoid system regulates anxiety and the response to stress by dampening excitatory signals that involve the neurotransmitter glutamate (Snyder, 2014).

 

Chronic stress such as that found in early life developmental trauma or acute, severe emotional trauma can cause a reduction in both the production of endocannabinoids and the responsiveness of the receptors. Without their “buffering” effect, anxiety can escalate.

 

While marijuana’s exogenous cannabinoids can diminish anxiety, chronic use of the drug down-regulates the receptors, paradoxically increasing anxiety. This action can trigger a vicious cycle of increasing marijuana use that may lead to cannabis use disorder (CUD; Ramikie et al., 2014).

 

A Drug with Addiction Potential

 

Cannabis or cannabinoids in all of its varieties represent the second most commonly used mood-altering substance. It is second only to ethyl alcohol consumption. About 7 percent of Americans are current users of marijuana in its various forms. This compares to less than 1 percent for cocaine, heroin, and methamphetamine (SAMHSA, 2011).
Although a lot of emphasis is placed upon the preteen and adolescent cannabis user, it is more common to see addiction develop during the eighteen to thirty-year- old age range. This population represents a third treatment population along with the traditional concept of adolescent and adult treatment groupings. Today the young adult population makes up the majority age group of those involved in addiction treatment. This is good news because in past history most addicts and alcoholics did not seek treatment until much later in life and generally with more disability.

 

Because they have greater degrees of freedom and are monitored less by authority figures such as parents, emerging adults can pursue more novel experiences than adolescents. Recent binge drinking and heavy alcohol use peak in emerging adulthood (42 percent), four times that found in the adolescent grouping (10 percent). Recent illicit drug use also peaks during emerging adulthood (20 percent) and is almost twice what is reported in adolescents. Rates of dependence on or abuse of any illicit drug or alcohol are highest in emerging adulthood. Dependency and abuse rates decline for both males and females after the age of twenty-five. Among emerging adults who reported abuse and dependence only 2.8 percent have received any treatment addressing abuse or associated conditions in the past year (Park, Mulye, Adams, Brindis, & Irwin, 2006).

 

Cannabis, like all drugs of addiction, leads to problems of scholastic, social, and occupational performance. While alcohol use is more commonly reported to compromise relationships with friends and significant others, marijuana use is more commonly reported to undermine relationships with teachers or supervisors. The result of use is a lowering of energy or interest, yielding lower school or job performance (Palamar et al., 2014).

 

The Effect on Women

 

Smoking today’s concentrated pot might create a greater risk for women. During the follicular phase of the menstrual cycle, where estrogen levels are markedly higher than progesterone levels, female rats are at least 30 percent more sensitive than males to the pain-relieving qualities of THC. Females also develop tolerance to THC more quickly. These enhanced sensitivities could increase vulnerability to negative effects like anxiety, paranoia, and addiction.

 

Margaret Haney at the Columbia University Medical Center has shown that women are more susceptible to cannabis abuse and dependence than men. Haney has documented a cannabis withdrawal syndrome of irritability, sleep disruption, and decreased food intake that tends to be more severe in women. Women also have a greater tendency to relapse when trying to stop using the drug. The research reveals with THC females gets a very clear spike in drug sensitivity when they are ovulating—right when their estrogen levels have peaked and are coming down. Other reports are showing the same increased jeopardy in the female cannabis user (Wakley, Wiley, & Craft, 2014; Washington State University, 2014).

 

Cannabis Use Disorder

 

It has really only been in the last five to ten years that treatment programs have started to see more and more adults, emerging adults, and adolescents seeking treatment primarily for CUD. From data collected in 2002, adults seeking treatment had typically been cannabis smokers for over ten years with repeated and failed attempts to quit. Their primary reasons for seeking treatment involved relationship problems, financial difficulties, problems of low self-esteem, sleep and memory problems, work performance issues, and decreased life satisfaction (Stephens, Babor, Kadden, & Miller, 2002). During the same time period, adolescents entering treatment did not readily admit any life problems due to marijuana. It is interesting to consider this perspective because if one is having difficulties at home or school and it is not due to the cannabis, it must be a problem with the individual.
 

 

The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5; APA, 2013, p. 509) describes cannabis as a drug of dependence with an intoxication syndrome, as well as a well-described acute abstinence syndrome. CUD will be described here while intoxication and withdrawal with be reviewed in the next section of this article.

 

According to the DSM-5, “Cannabis is the generic and perhaps the most appropriate scientific term for the psychoactive substance(s) derived from the plant, and as such it is used in this manual to refer to all forms of cannabis-like substances, including synthetic cannabinoid compounds” (APA, 2013, p. 510). Therefore, CUD can be applied to all of the CB1 agonists, regardless of whether they come from the natural plant or synthesized in a laboratory.

 

The DSM-5 describes CUD as a problematic pattern of cannabis use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a twelve-month period:

 

 
  • Cannabis is often taken in larger amounts or over a longer period than was intended
  • There is a persistent desire or unsuccessful efforts to cut down or control cannabis use
  • A great deal of time is spent in activities necessary to obtain cannabis, use cannabis or recover from its effects
  • Craving, or a strong desire or urge to use cannabis
  • Recurrent cannabis use resulting in a failure to fulfill major role obligations at work, school or home
  • Continued cannabis use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of cannabis
  • Important social, occupational or recreational activities are given up or reduced because of cannabis use
  • Recurrent cannabis use in situations in which it is physically hazardous
  • Cannabis use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by cannabis
  • Tolerance, as defined by either of the following: a need for markedly increased amounts of cannabis to achieve intoxication or desired effect or markedly diminished effect with continued use of the same amount of cannabis
  • Withdrawal, as manifested by either of the following: the characteristic withdrawal syndrome for cannabis or cannabis (or a closely related substance) is taken to relieve or avoid withdrawal symptoms

 

 

 

The DSM-5 describes certain specifiers to further help accurately describe the individual in regard to the course of their illness. 

 

 
  • In early remission: After full criteria for CUD were previously met, none of the criteria for CUD have been met for at least three months but for less than twelve months
  • In sustained remission: After full criteria for CUD were previously met, none of the criteria for CUD have been met at any time during a period of twelve months or longer
  • In a controlled environment

 

 

 

As more and more states are legalizing and/or decriminalizing cannabis use—and with cannabis being strongly lobbied as a treatment for medical conditions—the diagnosis of CUD will be affected. As DSM-5 states, “When a substance is taken as indicated for a medical condition, symptoms of tolerance and withdrawal will naturally occur and should not be used as the primary criteria for determining a diagnosis of a substance use disorder” (APA, 2013, p. 511–2). The medicinal uses of cannabis remain controversial and often lacking in scientific rigor. However, use for medical circumstances should be considered when a diagnosis is being made. 

 

Cannabis Intoxication and Withdrawal

 

As previously described, cannabis and related CB1 agonist drugs have a very diverse impact on the consumer’s brain. What is generally described as “intoxication syndrome” consists of the acute effects of THC ingestion. The most pronounced effects are as follows:

 

 
  • Euphoria
  • Enhanced perception of novelty
  • Distractedness
  • Decreased processing speed
  • Loss of short-term memory

 

 

 

The loss of short-term memory and the inability to consolidate information into long-term memory is of critical importance. Short-term memory can hold up to two things, and any mother knows this. When she is cooking dinner, speaking to someone at the office, and her child runs in experiencing a crisis, it’s always the third thing that takes her over the top. 

 

When the information is important and/or has a strong positive or negative emotions valence, it is consolidated into long-term memory. These memories can be drawn upon in the future when needed. At school or at work, cannabis users will typically not be able to convert important short-term memories into long-term memory. When it becomes necessary—such as an examination for school—the information cannot be retrieved, as it appears cannabis interrupts the memory storage. Those with higher IQs may be able to compensate.

 

Remember, THC is a fat-soluble drug and is stored in the body much longer than drugs such as alcohol or cocaine. How long THC stays in a user’s body depends on a lot of factors, such as age, weight, metabolism, amount, and potency of marijuana. Because of its fat solubility, as few as three marijuana cigarettes per week is considered high-dose usage.

 

At least eighty different metabolites are formed from THC. These metabolites are stored in body fat and are gradually eliminated from the body through feces and urine. However, some are stored in body fat and have an elimination half-life of ten to thirteen days. 

 

For those users who have established dependence upon the drug, coming off cannabis can be a difficult experience. There is no threat to life from cannabis withdrawal, but it does last approximately one to two weeks. Symptoms have their onset within the first twenty-four to seventy-two hours of cessation and the most predominant symptoms are as follows:

 

 
  • Irritability, anger or aggression
  • Nervousness or anxiety
  • Sleep difficulty (e.g., insomnia, disturbing dreams)
  • Decreased appetite or weight loss
  • Restlessness
  • Depressed mood
  • At least one of the following physical symptoms causing significant discomfort: abdominal pain, shakiness/tremors, sweating, fever

 

 

 

According to the DSM-5, three or more of these signs and symptoms must develop within approximately one week for cannabis withdrawal to be diagnosed (APA, 2013).

 

Sleep difficulties may last more than thirty days and have been documented among adolescents and adults. For a scoring system to test the severity of perceived withdrawal symptoms, I would suggest the Incidence and Severity of Perceived Withdrawal Symptoms (Budney, Novy, & Hughes, 1999). 

 

Dependence and withdrawal was historically considered to be more of an adult phenomenon, but with changes in toxicity and availability this seems to be changing. A study by Massachusetts General Hospital investigators found that 40 percent of cannabis-using adolescents receiving outpatient treatment for substance use disorder reported experiencing symptoms of withdrawal, which are considered a hallmark of drug dependence (Greene & Kelly, 2014). 

 

Medication-assisted treatment (MAT) has not been very effective in the treatment of CUD. Many pharmacological agents have been tried including the off-label use of baclofen (Lioresal), bupropion (Wellbutrin), divalproex (Depakote), mirtazapine (Remeron), nefazodone (Serzone), and quetiapine (Seroquel). Quetiapine actually caused increased use (Weinstein & Gorelick, 2011).

 

In a positive trial using gabapentin, patients received 1200 mg per day in divided doses for twelve weeks. Symptoms of withdrawal—mood, sleep problems, cravings, and others—were all improved compared to the placebo (Mason et al., 2012). 

 

N-Acetylcysteine (NAC), a product found in health food stores, was used in an eight-week, double-blind, randomized, placebo-controlled trial with fifteen- to twenty-one-year-olds addicted to cannabis. The patients were given 1200 mg of NAC or placebo twice daily along with contingency management. Those taking NAC had twice the odds of a negative urine drug test than those taking the placebo (Gray et al., 2012).

 

General Medical and Long-Term Health Effects

 

History reveals failed attempts to convince young people to avoid cannabis and other drugs of mood alteration. It has been difficult to counter responses such as, “marijuana is safer than alcohol.” I remember using that argument myself back in the 1960s and 1970s. Putting a wrecked car in front of the high school right before the prom probably didn’t change many people’s behaviors.

 

I believe that there are those adolescents and adults who will not use and there is that percentage often described in the range of ten to fifteen percent that will develop substance use problems. However, there is a large group of preadolescents, adolescents, and emerging adults who sit on a fence, potentially falling to one side or the other. This is the population where appropriate education and positive life opportunities can make such a great difference.

 

Studies are beginning to challenge the traditional concept that the teenage brain can’t plan because of an immature prefrontal cortex. Findings indicate that the prefrontal cortex of teens is not much different than of adults, but it can be easily overruled by heightened motivation centers in the brain. There is this mixture of newly gained executive control plus extra reward that is pulling teenagers toward immediate gratification (University of Pittsburgh Schools of the Health Sciences, 2015).

 

It is not that the young people are not capable of understanding the risks inherent in drug use; it is they experience the reward much more profoundly than older people. Therefore, it seems the correct route for prevention and treatment would involve helping adolescents or emerging adults find something in life that truly turns them on and gives their life meaning. 

 

With this being said, an understanding of the potential consequences of cannabis use and abuse should be made available to users, potential users, and their family and friends. As mentioned earlier, the cannabis of today is entirely different from that of fifty years ago; it is far more toxic and addicting. To this end, the following contains a brief summary of the general medical and long-term health effects of marijuana:

 

  • Heavy marijuana use predicts impairments in executive functioning and learning (Gruber, Sagar, Dahlgren, Racine, & Lukas, 2012).
  • Persistent users of marijuana, particularly those who started in adolescence, had significant decreases in IQ. There was a dose-response relationship (Meier et al., 2012). A loss of eight IQ points was found with heavy smoking during teen years. This is especially devastating to those with normal or below normal intelligence (NIDA, 2015).
  • There is a 1.5 to 2.0 increase in risk of psychotic disorders. It could well be that cannabis is the environmental stressor that causes a subclinical genetic condition to become fulminate (Moore et al., 2007).
  • The observed tendency for cannabis use to precede or coincide with rather than follow mania symptoms, and the more specific association between cannabis use and new onset manic symptoms was discovered. Cannabis use significantly worsened mania symptoms in people who had previously been diagnosed with bipolar disorder (Gibbs et al., 2015).
  • Exposing adolescent rats to THC can lead to molecular and behavioral alterations in the next generation of offspring, even though progeny were not directly exposed to the drug. Male offspring showed stronger motivation to self-administer heroin during their adulthood. Damage in the glutamate pathway, which regulates synaptic plasticity, has been linked to disturbances in goal-directed behavior and habit formation (Szutorisz et al., 2014).
  • Using marijuana in adolescence may do serious long-term damage to the immune system. This damage may result in autoimmune diseases and chronic inflammatory diseases such as multiple sclerosis, inflammatory bowel disease, and rheumatoid arthritis in adulthood (Moretti et al., 2014).
  • Consuming cannabis during pregnancy clearly results in defective development of nerve cells of the cerebral cortex, the part of the brain that orchestrates higher cognitive functions and drives memory formation. In particular, THC negatively impacts if and how the structural platform and conduit for communication between nerve cells, the synapses and axons, will develop and function. Even though not all children who have been exposed to cannabis will suffer immediate and obvious deficits, relatively subtle damage can significantly increase the risk of delayed neuropsychiatric diseases (Tortoriello et al., 2014).
  • Significant portion of individuals with CUD also have social anxiety disorder (SAD). Comorbid SAD is associated with greater severity of cannabis-related problems (Buckner et al., 2012).

 

 

Treating Cannabis Addiction

 

Most people entering treatment with CUD are in the precontemplative or contemplative stages of readiness for change. Assessment and education are the primary tools utilized to create discrepancy and move the user into preparation for change and beyond.

 

A full review of treatment approaches is well beyond the purview of this writing. However, an overview will be given.

 

The following three evidence-based interventions can be utilized singularly or in combination: motivational enhancement therapy (MET), cognitive behavioral therapy (CBT), and absintence-based contingency management (CM). 

 

Motivational Enhancement Therapy

 

The MET approach is grounded in research on processes of change. Prochaska and DiClemente (1984) described five stages of change people progress through in successfully navigating problem behaviors: precontemplation, contemplation, determination, action, and maintenance. 

 

Cognitive Behavioral Therapy

 

Cognitive behavioral therapy (CBT) is designed to reduce deficits in skills for coping with cues leading to marijuana use. Individuals who rely primarily on marijuana or other substances to cope have little choice but to resort to substance use when experiencing stress. The goal of this intervention is to teach basic skills needed to cope with situations that might lead to substance use. A major focus of CBT groups is the development and rehearsal of coping skills.

 

Contingency Management

 

Research has demonstrated the effectiveness of treatment approaches using contingency management (CM) principles. Tangible rewards are given to patients in order to reinforce positive behaviors such as abstinence. Studies conducted in both methadone programs and psychosocial counseling treatment programs demonstrate that incentive-based interventions are highly effective in increasing treatment retention and promoting abstinence from drugs.
Parental monitoring can help attenuate a number of negative adolescent behaviors, including gambling, sexual activity, and drug use. This involves parents knowing where their children are, who they are with, and what they are doing. There is a strong link between parental monitoring and decreased marijuana usage in adolescents. The strongest effects were seen in the female-only studies (Lac & Crano, 2009).

 

The largest clinical trial for CUD evaluated the following five manualized outpatient treatments for teens (Dennis et al., 2004): 

 

 
  • MET/CBT5 (two individual and three groups)
  • MET/CBT12 (two individual and ten groups)
  • MET/CBT12 plus family support network (six parent education sessions, four home visits, and case management)
  • Community Reinforcement  Approach (ten individual and four parent sessions)
  • Multidimensional Family Therapy (six individual, three parent sessions, and six with both patient and family)

 

 

 

The results of the Dennis et al. study revealed significant decreases in cannabis use and symptoms of dependence were observed across treatments; no between-treatment differences were clearly observed; and nearly two-thirds of teens continued to report significant problems (2004). 

 

There is plenty of information available to clinicians that can assist in the treatment of cannabis-addicted patients. For example, the Cannabis Youth Treatment Series is a free series of publications provided by the Substance Abuse and Mental Health Services Administration. 

 

Conclusion

 

Cannabis use in the second decade of this century is a very confusing picture. I hope this article gives readers a better understanding of how cannabis impacts the body and mind. I also hope this information will give accurate information to those who work daily with those whose lives have been compromised by their addiction to cannabis products. Thank you for your tireless dedication toward helping those whose lives have become unmanageable.

 

 
 

 

 

 

 

 
References

 

American Psychiatric Association (APA). (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: Author.
 
Budney, A. J., Novy, P. L., & Hughes, J. R. (1999). Marijuana withdrawal among adults seeking treatment for marijuana dependence. Addiction, 94(9), 1311–22.
 
Dennis, M., Godley, S. H., Diamond, G., Tims, F. M., Babor, T., Donaldson, J., . . . Funk, R. (2004). The Cannabis Youth Treatment (CYT) Study: Main findings from two randomized trials. Journal of Substance Abuse Treatment, 27(3), 197–213.
 
Gray, K. M., Carpenter, M. J., Baker, N. L., DeSantis, S. M., Kryway, E., Hatwell, K. J., . . . Brady, K. T. (2012). A double-blind randomized controlled trial of n-acetylcysteine in cannabis-dependent adolescents. The American Journal of Psychiatry, 169(8), 805–12.
 
Greene, M. C., & Kelly, J. F. (2014). The prevalence of cannabis withdrawal and its influence on adolescents’ treatment response and outcomes. Journal of Addiction Medicine, 8(5), 359–67.

Lac, A., & Crano, W. D. (2009). Monitoring matters: Meta-analytic review reveals the reliable linkage of parental monitoring with adolescent marijuana use. Perspectives on Psychological Science, 4(6), 578–86.

Mason, B. J., Crean, R., Goodell, V., Light, J. M., Quello, S., Shadan, F., . . . Rao, S. (2012). A proof-of-concept randomized controlled study of gabapentin: Effects on cannabis use, withdrawal, and executive function deficits in cannabis-dependent adults. Neuropsychopharmacology, 37(7), 1689–98.
 
Palamar, J. J., Fenstermaker, M., Kamboukos, D., Ompad, D. C., Cleland, C. M., & Weitzman, M. (2014). Adverse psychosocial outcomes associated with drug use among US high school seniors: A comparison of alcohol and marijuana. The American Journal of Drug and Alcohol Abuse, 40(6), 438–46.
 
Park, M. J., Mulye, T. P., Adams, S. H., Brindis, C. D., & Irwin, C. E. Jr. (2006). The health status of young adults in the United States. The Journal of Adolescent Health, 39(3), 305–17. 
 
Prochaska, J. O., & DiClemente, C. C. (1984). The transtheoretical approach: Crossing the traditional boundaries of therapy. Melbourne, FL: Krieger.

Ramikie, T. S., Nyilas, R., Bluett, R. J., Gamble-George, J. C., Hartley, N. D., Mackie, K., . . . Patel, S. (2014). Multiple mechanistically distinct modes of endocannabinoid mobilization at central amygdala glutamatergic synapses. Neuron, 81(5), 1111–25. 

Snyder, B. (2014). Discovery sheds new light on marijuana’s anxiety relief effects. Retrieved from http://news.vanderbilt.edu/2014/03/discovery-sheds-new-light-on-marijuana-anxiety-relief-effects/
 
Stephens, R. S., Babor, T. F., Kadden, R., Miller, M. (2002). The marijuana treatment project: Rationale, design, and participant characteristics. Addiction, 97(Suppl. 1), 109–24.
 
Substance Abuse and Mental Health Services Administration (SAMHSA). (2011). Results from the 2010 National Survey on Drug Use and Health: Summary of national findings. Retrieved from http://archive.samhsa.gov/data/NSDUH/2k10ResultsRev/NSDUHresultsRev2010.pdf
 
University of Pittsburgh Schools of the Health Sciences. (2015). Pitt expert talks teenage brain development at American Association for the Advancement of Science annual meeting. Retrieved from http://www.upmc.com/media/NewsReleases/2015/Pages/pitt-expert-aaas-meeting.aspx
 
Wakley, A. A., Wiley, J. L., & Craft, R. M. (2014). Sex differences in antinociceptive tolerance to delta-9-tetrahydrocannabinol in the rat. Drug and Alcohol Dependence, 143, 22–8.

Washington State University. (2014). Estrogen increases cannabis sensitivity. Retrieved from http://www.eurekalert.org/pub_releases/2014-09/wsu-eic082814.php

Weinstein, A. M., & Gorelick, D. A. (2011). Pharmacological treatment of cannabis dependence. Current Pharmaceutical Design, 17(14), 1351–8.
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