As a result, a young child treated with amphetamines would not necessarily have an increased risk for abuse of other stimulants by the time he or she reached adolescence – when illicit drugs are more readily found. In contrast, if the onset of treatment were to start in the early teens , drug-seeking behavior would peak just as illicit substances became more available. This hypothesis is supported by one study that found that ADHD individuals whose treatment persisted into adolescence were more likely to become dependent on cigarettes than those whose treatment ended earlier. The individuals whose treatment had stopped before adolescence went through the sensitization/withdrawal process before cigarettes became available to them, either through legal or illegal means. The effect of amphetamine is also hypothesized to be greater under both temporal and environmental cues previously associated with administration. It is likely that a child treated at a younger age would move out of an environment previously associated with amphetamine and therefore have a decreased sensitivity to amphetamine at an older age compared to an individual who started treatment in adolescence. The child treated at a younger age would therefore be less likely to abuse their prescription and eventually other illicit drugs. Thus, ADHD treatment at a younger age seems to have little or no effect on drug abuse during adolescence and adulthood,cannabis grow equipment while treatment that continues into adolescence may raise the risk of non-prescription stimulant abuse. Lastly, adolescents typically experience much more stressful environments as more responsibility is given to them at both home and school. The stress of adolescence may synergize with the effects described above, and thus further increase the likelihood of stimulant abuse. On the other hand, if amphetamine prescription is initiated before adolescence, the individual will not have the same added level of stress, and thus will be less driven to abuse their medication or drugs with similar effects.
Although much evidence points to an increased risk of substance abuse with amphetamine treatment, many investigators have concluded that amphetamine use does not increase a patient’s likelihood of later developing SUD, and that it may actually exert a protective effect against substance abuse later in life based on population-level studies – that is, some have concluded that stimulant-based treatment of ADHD early in life may decrease drug abuse later in life. For instance, Barkley and colleagues, the same group whose results indicated a significant increase in cocaine use amongst ADHD patients treated with stimulants, still concluded that treatment of ADHD had no effect on the likelihood of using a number of drugs. A similar study that followed 56 medicated and 19 unmedicated patients found that there was no association between treatment and drug abuse. A study that followed 285 treated and 84 untreated ADHD patients also concluded that SUD did not develop as a result of stimulant treatment. A meta-analysis of several studies also found that for any category of drug use, stimulant treatment decreased the risk that an individual would abuse drugs in general. Review papers on the subject of SUD and its relationship with ADHD have also come to the conclusion that childhood treatment with stimulants is negatively correlated with substance abuse.Although many studies conclude that stimulant treatment is protective against the development of SUD when prescribed to ADHD patients, the validity of these studies is questionable. For instance, many of the studies that come to this conclusion are funded in full or in part by drug companies such as Pfizer or Eli Lilly, which manufacture ADHD medications.Reviews and meta-analyses are particularly dubious when a conflicting financial interest exists, because they may select papers that suggest a desired result. In addition, studies with larger sample sizes and meta analyses tend to group all types of substance abuse into one category, or simply distinguish between “drug abuse” and “alcohol/ tobacco use” categories. Large bins of categorization produce a confounding variable, because stimulant drugs are known to reinforce and prime other stimulant drugs most reliably. The fact that amphetamine treatment has been suggested to protect against or have no correlation with the use of depressants such as marijuana or alcohol makes placing all drugs of abuse into one category especially problematic. The decreased risk factor for depressant use and the increased risk factor for stimulant use interfere with each other when considered together, thus concealing any specific trends that might exist.
Of two predominant studies that separated “substance abuse” into individual drugs or drug subcategories, one study found a significant increase in cocaine use, while the other found no significant increase. However, the latter study had a small sample size of 56 medicated ADHD patients and 19 non-medicated patients. It is possible that if larger sample sizes were obtained, a significant increase would have become apparent. This conclusion seems increasingly likely since the prevalence of stimulant abuse in society is generally not as high as for other drugs such as cannabis or alcohol, especially amongst ADHD patients in general. Therefore, a much larger sample size is needed to compare stimulant-specific abuse amongst ADHD patients. Furthermore, if treatment with stimulants does in fact exert a protective effect against general drug abuse and not illicit stimulant abuse, the analysis of drug abuse in general as a single category would actually downplay the increase in stimulant abuse amongst patients. Untreated subjects would be much more likely than treated subjects to participate in non-stimulant abuse, confounding a large portion of studies. Based on the idea that those with a later onset of treatment have a higher potential for stimulant abuse, it is probable that if the age of treatment onset were compared, patients with a later onset of treatment would show a specific increase in illicit stimulant abuse in adolescence and possibly into adulthood. However, those treated at a younger age may not have a statistically higher percentage of abuse of any drug. If it is true that subjects treated earlier are less likely to abuse stimulants than those treated later in adolescence, any study that does not compare age of onset and likelihood to develop stimulant-specific abuse possesses a significant weakness. Most of the studies that come to the conclusion of a negative correlation between amphetamine treatment and substance abuse fail to accurately assess age of treatment onset when evaluating data, thus mixing information from individuals that may have a higher risk of drug dependence with those that may have a lower risk of drug dependence because of age of treatment onset. Finally, none of these studies take into account the differences between methylphenidate and amphetamine. Since amphetamine has been shown to have an increased potential for abuse compared to methylphenidate and other ADHD medications, these studies therefore downplay the exposure to risk of substance dependence that is put forth with amphetamine prescription.
The majority of population studies that have concluded that stimulant-based treatment has no effect on the development of substance abuse later in life fail to take into account all of the factors necessary to produce accurate correlations.Current knowledge regarding the effects of amphetamines on stimulant-specific abuse in animals and general drug abuse in humans is not consistent. Studies on animal models have concluded that amphetamines specifically raise the tendency to self-administer stimulants, such as cocaine and nicotine,mobile vertical rack largely due to the sensitization of the rewarding effects of amphetamine that results in drug-seeking behavior.On the other hand, other population-level studies based on surveys and meta-analyses have concluded that stimulant prescription has no correlation with the development of substance abuse. These studies, however, all possess one or more of the following flaws: failing to distinguish between stimulants and depressants in terms of drugs abused by patients; failing to distinguish between amphetamine medication and other stimulant treatment; working with sample sizes far too small to accurately reflect the level of dependence that might develop to stimulants, specifically; and failing to consider the age of the patient at treatment onset. Taken together, evidence suggests that amphetamine treatment of ADHD causes a small increase in potential for stimulant drug abuse and possibly a decreased potential abuse of depressants. The risk for developing stimulant abuse is likely dependent on age of onset of stimulant prescription, with those treated in adolescence and young adulthood at a higher risk. However, there are no conclusive studies to verify this hypothesis. Considering that the amphetamine treatment for ADHD is on the rise, it would be prudent for an independent research group concerned with the health of ADHD patients to conduct a large scale study that accounts for the variables mentioned above, using a large population of both treated and untreated ADHD patients to test specific dependence of stimulant class drugs that arise from treatment with amphetamines. Another potential method of study might include comparing the number of formerly treated ADHD versus untreated ADHD patients amongst a population known to have abused stimulants, adjusting for the percentage of treated versus untreated ADHD individuals amongst the ADHD population. A conclusive study on this matter would allow parents, schools, and physicians to more accurately consider the treatments available for children with ADHD.The expression of cannabinoid receptors by human leukocytes suggests that both endogenous ligands and inhaled marijuana smoke might exert immuno regulatory properties that are distinct from their effects on the brain . Furthermore, while brain cells exclusively express cannabinoid receptor type 1 , leukocytes express both CB1 and CB2, with CB2 reported as the predominant sub-type .
Both CB1 and CB2 are transmembrane G-protein coupled receptors that inhibit the generation of cyclic adenosine monophosphate and can signal through a variety of pathways including PI3-kinase, MAP kinase, NF-κB, AP-1, and NF-AT . The resulting effects on host immunity have primarily been studied in animal models and suggest a coordinated down-regulation of cellular responses that can occur through altered trafficking, selective apoptosis, or functional skewing of antigen presenting cells and T cells away from T helper type 1 or Th17 response patterns . Similar results have been observed when purified human T cells are stimulated in vitro in the presence of Δ9-tetrahydrocannabinol . However, the extent to which the effects are observed in humans in vivo is unclear. Daily administration of marijuana or oral THC to research subjects in a prospective and randomized study had no obvious effect on T cell proliferation or cytokine production when blood cells were subsequently isolated and stimulated in vitro . Sipe et al. examined the distribution and function of a common polymorphism in the human CB2 gene associated with the replacement of a glutamine by an arginine at amino acid position. Functionally, lymphocytes from subjects with either of these genotypes proliferated normally when stimulated with anti-CD3 antibody. However, when stimulated in the presence of an endocannabinoid, lymphocytes expressing the glutamine residue at position 63 were markedly inhibited while those expressing the arginine were only modestly suppressed. The arginine substitution also correlated with the prevalence of autoimmune disease in the subjects tested. Collectively, this body of work suggests that cannabinoids are biologically active immune regulators in humans. Expanding upon this hypothesis, we examined the expression of cannabinoid receptors by human monocytes and the impact of THC on their differentiation into monocyte-derived dendritic cells . Exposing monocytes to THC blocked many of the features normally associated with their differentiation into functional DC and impaired their capacity for T cell activation. Furthermore, the T cell activation that did occur was associated with a change in T cell phenotype and cytokine secretion. However, the impact of THC was partially overcome when DC and T cells were exposed to a combination of activation signals and exogenous cytokines. Our findings suggest that cannabinoids are capable of altering the differentiation and activation of cells involved in human cell-mediated immunity. As an initial step in understanding the potential interaction between cannabinoids and human monocyte-derived DC, monocytes were evaluated for the expression of the CB1 and CB2 receptor sub-types by RT-PCR and flow cytometry . RT-PCR studies were carried out on monocytes that had been purified to >90% purity by either negative depletion or fluorescent cell sorting. mRNA encoding for both CB1 and CB2 were detected, although expression of CB2 predominated whether analyzed by standard RT-PCR or by an automated quantitative RT-PCR using cells from 4 different donors.