Contents

1 Abuse of Stimulant Drugs

Methylphenidate (MPH) and amphetamine (AMPH) increase extracellular dopamine (DA) in the brain, as do cocaine and methamphetamine, the most commonly abused stimulant drugs. MPH increases DA by blocking dopamine transporters (DATs) [40], and AMPHs (like methamphetamine) increases DA by releasing DA from the terminal [23]. Both increase DA in NAcc, which is thought to underlie the reinforcing effects of drugs of abuse [11]. This has raised legitimate concerns about the abuse liability of MPH and AMPH, although their abuse in the context of clinical use is thought to be quite limited [28], despite the magnitude of their clinical use. However, MPH and AMPH are self administered by animals [3, 22, 24], and MPH abuse has been increasing, especially on college campuses [36, 54], as both a cognitive enhancing drug, as well as a stimulant used recreationally [15, 24], so prevention of diversion and abuse is essential and is the rationale for MPH and AMPH being tightly controlled as Schedule II drugs.

1.1 Drug Metabolism

Differing routes of administration affect many pharmacokinetic properties, which in turn affect the reinforcing effects of stimulant drugs. Two primary pharmacokinetic properties are relevant for relating serum concentration of MPH to its therapeutic use and abuse [39]: the time to reach maximum concentration (T_max), which is related to the absorption and distribution of the drug, and the time required for the concentration to drop by 50 % from the peak level (T_1∕2), which is related to the metabolism and excretion of the drug. T_max (rise time) differs dramatically for i.v. and oral dosing, but T_1∕2 is about the same for these two routes [7]. The speed of drug delivery to the brain affects the reinforcing effects of drugs [2, 27]. Routes of administration that produce relatively fast brain uptake—injecting, smoking, or sniffing—are more reinforcing than oral administration, which produces relatively slow brain uptake [38].

1.2 Routes of Administration

The acute intravenous doses of MPH, which produce serum concentrations in excess of 10 ng/ml and 60 % DAT blockade, reliably elicit the reinforcing effects (‘high’), but oral doses that produce the same serum concentrations and DAT blockade do not reliably produce a ‘high’. In addition to exceeding a threshold, the speed of DAT blockade and the rate of DA accumulation are critical factors [35]. While recognizing that MPH has potential for drug abuse when administered intravenously or intranasally, the abuse potential of oral MPH is low [47], due primarily to the relatively slow onset and offset of the effects of MPH at its site of action in the human brain [40].

Functionally, MPH is remarkably similar to cocaine in both DAT blockade and subjective ‘high’ when administered by the same route [34, 39, 40]. Human studies using positron emission tomography (PET) imaging show that i.v. MPH increases DA transmission in the striatum [52], which is an earmark of addictive drugs [10]. The reinforcing and rewarding effects of many drugs of abuse are related to their ability to elevate DA in the nucleus accumbens (NAcc) of the ventral striatum [11]. When DA signaling from the ventral tegmental area (VTA) is prevented, the reinforcing effects of drugs decrease, as indicated by prevention or attenuation of both self-administration and conditioned place preference [6, 8, 21, 26, 33].

Chronic drug use, which markedly stimulates DA neurotransmission, results in attribution of excessive salience to drug taking and to drug-associated stimuli [30]. Studies in animal models show that high doses of MPH can produce reinforcement or reward, which are behavioral measures in animals that are used as surrogate measures for addiction in humans [3, 17, 20, 25, 26]. A number of studies suggest that rapid elevation of MPH levels in the blood and brain that occurs following intranasal or oral administration of supra-therapeutic doses is a key requirement for development of MPH-associated euphoria, reinforcement and addiction [12, 18, 35, 50].

2 Reinforcing Effects of MPH

The reinforcing effects of stimulant drugs have been shown to vary widely across subjects [53]. Imaging studies have consistently documented low levels of striatal DA D2 receptors in stimulant abusers [51], suggesting that differences in DA D2 receptors could underlie some of the differences in the sensitivity to the reinforcing effects of MPH. In Volkow et al. [46], approximately half of the subjects described the effects of MPH as pleasant and half as unpleasant and these differences were not accounted for by differences in the levels of MPH in plasma. Rather it was the subjects with low levels of DA D2 receptors that tended to describe MPH as pleasant, whereas the subjects with high DA D2 receptors tended to describe it as more unpleasant. Moreover, DA D2 receptor levels correlated negatively with MPH-induced pleasant effects and positively with its unpleasant effects (‘annoyed’ and ‘distrustful’). The differences in response to MPH between subjects with high and low DA D2 receptors could be explained if there is an optimal range for DA D2 receptor stimulation to be perceived as reinforcing; too little may not be sufficient but too much may be aversive [51].

On the basis of its potency for DAT blockade, oral MPH (at clinical doses used for ADHD) should not be considered a weak CNS stimulant compared with i.v. MPH or even cocaine (at doses typically seen with abuse). The peak levels of DAT blockade for a clinically relevant oral dose of MPH, although delayed by about 2 hours, was about the same (i.e., > 50%) as that seen with i.v. MPH doses that produce reinforcing effects [39]. Also, the magnitude of DA increases after oral MPH are comparable with those that were reported for i.v. MPH [45], and the level of DAT occupancy is similar to previously reported for oral MPH [43]. However, these oral doses did not reliably produce the subjective experience of being ‘high’ like the i.v. doses did [48]. Despite similar levels of DAT blockade and DA changes the self-reports of ‘high’, after subtracting for placebo, were lower after oral than after i.v. MPH [45, 48]. This indicates that the > 50% threshold for DAT blockade is necessary but not sufficient to produce reinforcing effects, so consideration of additional factors is required to understand why MPH is reinforcing under some circumstances and not in others [39].

Volkow and Swanson [39] hypothesizes that under certain circumstances MPH overactivates the DA system, making the experience of the drug ‘very salient’ (by i.v. or very large oral doses that produce fast and large increases in DA). Another major concern with the administration of oral MPH is that by blocking DAT and amplifying DA signals it may enhance the reinforcing properties of other drugs of abuse when taken in combination (e.g. with nicotine or alcohol) [49]. Moreover, by exceeding the usual threshold for salience, this can operate to decrease the salience of non-drug-related stimuli.

3 Abuse of MPH

The recent pharmaceutical approach of creating slow- or extended-release formulations of MPH has not reduced MPH abuse because most abuse (whether MPH or other stimulants) occurs via intranasal administration of crushed preparations [4]. Pulverization negates slow-release mechanisms and leads to rapid increases in brain MPH concentrations. Moreover, the immediate-release preparations continue to be in wide circulation, perhaps due to their lower cost [57]. Thus, we face today the unfortunate reality that MPH abuse continues and may even be on the rise [13, 31].

Abuse of MPH for stimulant reasons by oral administration is rare. When abused, MPH is usually administered intranasally or injected intravenously [28]. The typical intranasal dose of MPH in abuse have not been well described in the literature [39]. However, typical doses of cocaine are 0.3 mg/kg to 0.6 mg/kg for i.v. administration and 50 mg to 100 mg for intranasal administration [16]. The higher potency of MPH than cocaine [44] suggests that i.v. doses of 0.1 mg/kg to 0.3 mg/kg or intranasal doses of 25 mg to 50 mg would be ‘effective’ in MPH abuse [39]. While oral or nasal MPH abuse was associated with only minor to moderate sympathomimetic toxicity, which was mainly self-limited and was treated with sedatives in some cases [5], i.v. MPH abuse was associated with serious local ischaemic and inflammatory complications attributed to non-active ingredients in the pill formulations [5].

An early hypothesis for the limited abuse of MPH was that MPH was a weak stimulant compared to cocaine or methamphetamine. This has been adressed in PET studies showing that greater than 50 % DAT blockade was necessary for either MPH or cocaine to be reinforcing as assessed using self-reports of ‘high’, ‘craving’, and ‘drug liking’ [14, 42, 45]. Surprisingly, the potency of MPH for blocking DAT was found to be greater than for cocaine; the median effective dose (ED₅₀) dose for i.v. MPH was about half that for cocaine (0.075 mg/kg vs. 0.13 mg/kg i.v.) [44], and in studies with cocaine addicts, at the respective ED₅₀ doses, reinforcing effects (self-reports of ‘high’) of i.v. MPH were equivalent to those of i.v. cocaine [39].

While DAT blockade is relevant in the reinforcing effects of these two stimulant drugs it is the dynamic nature of this blockade that modulates their reinforcing effect [49]. The faster the DAT blockade the stronger the drug’s reinforcing effects, whereas their rate of clearance from the DAT may modulate the frequency at which these drugs are self-administered. Since the ‘high’ is linked to the fast DAT blockade that is achieved when MPH or cocaine are given intravenously, the slow clearance of MPH is thought to interfere with its frequent repeated administration since it will rapidly lead to DAT saturation [49], and on the other hand, the slow rate of MPH uptake into the brain when orally administered may interfere with its reinforcing effects.

4 Potency of MPH vs Cocaine

It was hypothesized that oral MPH at the doses used clinically would not achieve the threshold of DAT blockade considered necessary for reinforcement. The PET study used to address this question revealed that oral MPH at doses used therapeutically induced greater than 50 % DAT blockade with an estimated ED₅₀ dose of 0.25 mg/kg, and although the between subject variability was high, there was a strong correlation between plasma MPH levels and DAT blockade measured 2 hours after administration [43]. On the basis of this relationship, the 50 % DAT blockade ‘threshold’ would be reached in adults at a serum concentration of about 10 ng/mL [43]. In this study, even when higher oral doses of MPH were administered that induced greater levels of DAT blockade, they were rarely perceived as reinforcing [43]. Indeed, in PET studies that evaluated the relationship between MPH-induced DA increases and reinforcing effects, when equivalent levels of DA increases were established for i.v. and oral MPH, i.v. MPH induced a ‘high’ but oral MPH did not [32, 46]. This would suggest that the relevant variable for reinforcement is the magnitude of the DA changes per time unit [39].

Following i.v. dosing, uptake in the brain is very fast for both [¹¹C]cocaine (4–6 minutes) and [¹¹C]MPH (6–10 minutes), and for both drugs, the onset of the perceived ‘high’ parallels the fast uptake of the drugs in the striatum, with the peak for the ‘high’ reported at about the same time as the peak striatal concentration [40]. In contrast to these very similar and short values of T_max, the T_1∕2 for cocaine and MPH differed dramatically: for [¹¹C]MPH, T_1∕2 was much longer (90 minutes) than that seen with [¹¹C]cocaine (20 minutes). Despite this four- to five-fold difference, the duration of the ‘high’ was about the same for cocaine and MPH. For cocaine, the decline of the ‘high’ paralleled the clearance of [¹¹C]cocaine in the striatum and returned to baseline when most of the [¹¹C]cocaine had left the brain. For MPH, however, the ‘high’ returned to baseline even while the striatal levels of [¹¹C]MPH remained high (80 % of peak) [35, 40]. In the case of MPH, its slow clearance may limit self-administration because of the persistence of side effects, whose duration parallels the levels of MPH in the brain [41]. Drugs that block DAT but have very fast clearance, such as cocaine, are much more likely to promote frequent self-administration than drugs with relatively slow clearance such as MPH [40]. Likewise, fluctuating vs. steady-state drug concentrations in brain will affect the drug’s reinforcing effects [39]. This prediction is based on animal studies that show that the rate at which animals self-administer stimulant drugs is associated with the downward slope of DA that follows the drug-induced increases in the NAcc [29, 56].

These pharmacokinetic and behavioral properties of MPH suggest that acute tolerance occurs to the reinforcing effects of i.v. MPH , which is consistent with studies of cocaine that show that the ‘high’ from cocaine also dissipates rapidly even when high plasma levels are maintained by repeated i.v. administration [16] or by infusion [1]. This dissociation suggests that the initial fast DAT blockade (and rapid increases in synaptic DA) is associated with the ‘high’ and not the continuous blockade of the DAT (or consistant high levels of synaptic DA) [39]. Although much less investigated, the T_1∕2 and clearance of stimulant drugs from the brain is also likely to affect its reinforcing effects. If a drug blocks greater than 50% of DAT with a single administration but then has slow clearance, then DAT saturation will occur with repeated frequent administration [39]. However, prior DAT blockade with MPH was unable to block the ‘high’ associated with a second dose of i.v. MPH. It may take several repeated doses in order to saturate the DAT response, and alternatively, mechanisms other than DAT blockade may be involved in the subjective perception of the ‘high’. This is supported by the temporal dissociation observed between the short lasting high and the long lasting occupancy of the DAT [41]. Therefore, the use of long-lasting DAT blocker drugs as an interventional strategy to block cocaine’s reinforcing effects is unsupported [41]. This dissociation cannot be explained completely by acute tolerance, since the ‘high’ was elicited by a second dose given while DATs were still inhibited by the prior dose. This would suggest that action in other neurotransmitter pathways, in addition to DA, are very likely to be involved in the reinforcing properties of psychostimulant drugs in humans [41].

It should be noted that even though T_max is about the same for any oral dose of MPH, the time at which serum concentration would cross a threshold value is related to dose, with higher doses exceeding thresholds faster than lower doses. Thus, for very large oral doses, the time required to achieve a critical level for serum concentration and DAT blockade (e.g. 50 % to 80 %) may be similar to that for low i.v. doses, which could account for why large oral doses produce reinforcing effects in some subjects [24].

5 Opioid Receptors and Activation by MPH

Although the principal molecular targets of MPH in the central nervous system (CNS) are the DAT and norepinephrine transporter (NET), at sufficiently high-doses MPH can also activate the μ opioid receptor in the brain [9, 19, 55]. Blocking the μ opioid receptor using naltrexone mitigates the rewarding effects of MPH [57]. Opioid receptors in the brain fall into 3 types: Mu (μ), delta (δ), and kappa (κ). The caudate–putamen, NAcc, frontal cortex and ventral midbrain, all of which are intricately involved in the reward and addiction circuitry, are enriched in these receptors [37]. Each receptor is believed to facilitate different aspects of reward circuits via interactions with opioids and neurotransmitters including DA [37]. Activation of the μ opioid receptor is associated with euphoria and reward whereas activation of the κ opioid receptor is associated with dysphoria and aversion [37]. Upregulation of the μ opioid receptor is generally associated with rewarding effects — e.g. following cocaine exposure. High doses of MPH upregulate μ opioid receptor activity in caudate-putamen and NAcc, as does cocaine [57]. Prior exposure to opioid receptor antagonist attenuates high-dose MPH-induced CPP, therefore, blocking opioid receptors using naltrexone prior to MPH administration can significantly attenuate rewarding effects of MPH [57]. Naltrexone also blocked MPH-induced μ opioid receptor activity [57]. DA D1-type-receptor antagonist SCH 23390 also attenuates high-dose MPH-induced CPP, whereas D2-type-receptor antagonist raclopride does not attenuate MPH-induced CPP [57] D1-type-receptor antagonist also attenuates high-dose MPH-induced upregulation of μ opioid receptor [57]. This may be the mechanism that allows MPH and cocaine to be perceived as rewarding in the presence of previous DAT blockade [39, 41].

Acronyms

AMPH

amphetamine

CNS

central nervous system

DAT

dopamine transporter

DA

dopamine

ED₅₀

median effective dose

MPH

methylphenidate

NAcc

nucleus accumbens

NET

norepinephrine transporter

PET

positron emission tomography

VTA

ventral tegmental area

References