Comparisons with Known Addictive Compounds and Interactions between Caffeine and Addictive Drugs
- Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use

XI. Comparisons with Known Addictive Compounds and Interactions between Caffeine and Addictive Drugs

A. General Considerations

It is generally admitted that even though important variations in individual sensitivity to the effects of caffeine exist, abuse of caffeine represents a minimal risk, particularly when compared with other stimulant drugs (Griffiths et al., 1986a

B. Interactions between Caffeine and Cocaine or Amphetamine

To compare caffeine with other substances, effects on mood (POMS scale) and euphoric and dysphoric effects (using several different scales) of placebo, caffeine base (50-800 mg) and amphetamine (25 mg) were measured (Chait and Griffiths, 1983

Caffeine is able to sensitize rats to the reinforcing effects of cocaine (Horger et al., 1991) in that self-administration was acquired more rapidly and the cocaine-induced increases in dopamine release were stronger. Caffeine also enhanced cocaine-induced conditioned place preference (Tuazon et al., 1992), but it is unclear whether we are dealing with true synergy or only with additivity (Bedingfield et al., 1998). In some rhesus monkeys trained to self-administer smoked cocaine base, pretreatment with oral caffeine increased the number of smoke deliveries using a high dose (1.0 mg/kg per delivery) but not a low dose (0.25 mg/kg per delivery) of cocaine. The authors concluded that caffeine pretreatment can produce small, but statistically significant increases in smoked cocaine self-administration in rhesus monkeys, but the interpretation of this finding is not straightforward. Essentially similar results were obtained in a rat study where rats self-administering cocaine were treated with caffeine either as an i.p. injection (20.0 mg/kg) before each self-administration test or the caffeine was coadministered with cocaine in the infusion syringe (0.25 mg/kg per infusion). Both of these routes of administration of caffeine increased the intake of low doses of cocaine (Schenk et al., 1994). An increased self-administration of cocaine could easily be construed as evidence of a blockade of the action of cocaine.

In drug discrimination studies, cocaine substituted for the caffeine-discriminative stimulus in rats trained to discriminate caffeine from saline (Holtzman, 1986), whereas caffeine only partially substituted for the cocaine-discriminative stimulus in rats trained to discriminate cocaine from saline (Gauvin et al., 1989, 1990; Harland et al., 1989). Similarly, the potentiation by caffeine of the effects of low doses of dopaminergic agonists has been observed in the tests of the discriminative stimulus properties of both amphetamine (Schechter, 1977) and apomorphine (Schechter, 1980).

These studies have thus shown caffeine effects on acquisition of cocaine-related behavior, interaction with the maintenance of such behavior, and a partial overlap in drug discrimination. It was also demonstrated that caffeine dose-dependently reinstated extinguished cocaine-taking behavior in rats, indicating that nondopaminergic agonists can also provide an effective prime to reinstate responding (Worley et al., 1994). Although caffeine was an effective cue for reinstatement of extinguished cocaine taking, the effect was reduced when repeated exposures occurred in the test environment (Schenk et al., 1996). In rats trained to press a lever to self-administer cocaine, substitution of saline for cocaine leads to a progressive decline in lever pressing. In such animals a priming dose of 10 mg/kg caffeine, given s.c., reinstated the lever pressing to an extent resembling that achieved by the dopamine D2/3 agonist 7-OH-dopamine (Self et al., 1996). By contrast, a dopamine D1 agonist reduced the priming effect of cocaine in this paradigm.

It has been suggested that caffeine may be capable of priming reward-relevant circuitry that is used by cocaine. In an unpublished study, Kuzmin, Johansson, Zvartau, and Fredholm used a mouse model that tests whether drug-seeking behavior can be reinstated by noncontingent drug primes. Naive DBA/2 mice were trained to self-administer cocaine i.v. (bolus dose 0.04 mg/kg) in a single initiation session. Cocaine exhibited a distinct reinforcing effect, which manifested itself as a higher level of nose-poke responding in "active" mice (response-contingent injections) when compared with "passive" mice (yoked control). Forty-eight hours later the mice were placed again in the operant boxes but without i.v. infusions. Groups of mice were treated i.p. with saline, low or high doses of cocaine (5 and 20 mg/kg) or caffeine (3 and 30 mg/kg). In saline-treated animals a time-dependent extinguishing of the drug-related behavior was found. Administration of both caffeine and cocaine in the high doses produced immediate elimination of the cocaine reward-associated behavior. Conversely, noncontingent priming injections of the low doses of cocaine and caffeine were found to have a priming effect, i.e., they reinstated the extinguished cocaine-seeking pattern despite the absence of contingent infusions of cocaine. This effect of caffeine could be partly mimicked by DPCPX, an adenosine A1 receptor antagonist, but not by the A2A receptor antagonist SCH 58261. This is surprising because evidence was recently presented that acute disruption of cAMP generation in the nucleus accumbens might provide a stimulus for drug relapse (Self et al., 1998). The adenosine A2A receptor antagonist would be expected to do this directly, but the A1 antagonist only indirectly.

These findings may be taken as evidence that caffeine use is a risk factor for individuals who have been cocaine abusers. This conclusion is, however, not necessarily warranted. Normal caffeine use in humans is long-term, oral use, whereas the experiments in rodents used single parenteral administrations. As noted elsewhere in this review, there can be major differences between acute and long-term caffeine use. As yet unpublished data from our groups suggest that this may be true in this context.

It has been found that caffeine use is less prevalent among cocaine users than among age-matched controls, and that the amount of cocaine is reduced among the cocaine users who do consume caffeine (Budney et al., 1993). However, much more research on humans is needed. Recently, it was found that, in a small group (11 subjects) of former cocaine users, caffeine did not produce cocaine-like effects and it did not increase the desire for cocaine (Liguori et al., 1997). Nonetheless, the majority of the subjects preferred caffeine-containing coffee over decaffeinated. This suggests that there may be major differences between current cocaine users (Rush et al., 1995) and ex-cocaine users (Liguori et al., 1997).

C. Interactions between Caffeine and Ethanol

There is a weak association between caffeine and alcohol consumption, which is stronger if the drugs are used heavily (Istvan and Matarazzo, 1984

There is some evidence for a causal link between caffeine and ethanol use from animal studies, and this relates to effects of ethanol on adenosine. Thus, there is evidence that ethanol can increase adenosine levels by decreasing adenosine uptake (Diamond and Gordon, 1994) or secondarily to acetate metabolism (Carmichael et al., 1991). Indeed, there is good evidence that the increase in portal blood flow that is observed following a meal with ethanol is due to acetate-induced formation of adenosine, which dilates the portal vessels (Carmichael et al., 1988). Therefore, caffeine can reduce this vasodilatation and redirect blood flow to other areas, including the brain. This may be one physiological basis for the marked alerting effect of a cup of coffee after a meal with ethanol intake.

The magnitude of the ethanol-induced increase in adenosine may be smaller in brain than in liver (Brundege and Dunwiddie, 1995; Fredholm and Wallman-Johansson, 1996). Nonetheless, there is some evidence that adenosine may contribute to the behavioral effects of ethanol (Dar, 1990). It has also been shown that mice bred for increased ethanol sensitivity also exhibit increased sensitivity to behavioral effects of adenosine analogues (Proctor et al., 1985), and this is related to the number of adenosine A1, but not A2, receptors (Fredholm et al., 1985). Furthermore, ethanol-tolerant rats have been shown to be tolerant also to behavioral effects of adenosine (Dar and Clark, 1992). Some of the motor-incapacitating effects of ethanol have been suggested to depend on adenosine-related mechanisms in the basal ganglia (Meng and Dar, 1995). Part of this might be explained by an adenosine A1 receptor-mediated modulation of ethanol-induced changes in striatal chloride ion flux (Meng et al., 1997). Based on studies using an antisense approach, it was suggested that adenosine A1 receptors in this region are not important (Biggs and Myers, 1997). However, it was not shown that the antisense oligonucleotide altered A1 receptor expression in this region and furthermore, as discussed above, many of the A1 receptors in this region are present on nerve terminals and thus cannot be modified by local antisense injection. Acute administration of ethanol may also cause an increase in the number of adenosine A1 receptors (Clark and Dar, 1991), but it is not known if long-term exposure has similar effects. A recent study using a rat model of alcoholism showed that life-long ethanol intake does not significantly affect the age-dependent changes in A1 or A2A receptors (Fredholm et al., 1998).

It is obvious that ethanol has a large number of effects that are unrelated to adenosine and that the interactions with caffeine will be complex. This is further underscored by the fact that the behavioral effects of both ethanol and caffeine are strongly dose- and time-dependent. Consequently, it is not surprising that a complex picture arises from the numerous animal studies (see White, 1994).

The literature on alcohol-caffeine interactions in humans is relatively modest despite the importance of the issue: we are dealing here with interactions between the two most widely used psychoactive compounds. One review (Fudin and Nicastro, 1988) mentioned among 20 studies a single study (Franks et al., 1975) that documented a significant antagonism between the two substances. All other considered studies differed widely in their methods and compared mostly the effect of alcohol alone versus the combination with caffeine, without ensuring that caffeine alone was able to affect the experimental variables in a direction opposite to that of alcohol. Thus, the fundamental question---if caffeine specifically antagonizes ethanol effects or if one is considering the joint effects of a stimulant and a depressant drug---has often not been addressed. Several newer studies that included this necessary control condition were successful in demonstrating a significant antagonism in several test models, including compensatory tracking of a moving target with a joystick (Kerr et al., 1991), a digit-symbol substitution task (Rush et al., 1993), and a subject-paced rapid information processing task (Hasenfratz et al., 1993). In these three experiments caffeine was given not after alcohol, as was done in most earlier studies, but rather some time before or at the latest together with alcohol. One investigation of this dimension even suggested that it may be more helpful to drink a few cups of coffee before rather than after a party (Hasenfratz et al., 1994). There thus appears to be a negative interaction between caffeine and alcohol in humans. It appears to be at least as complex as in animals, and to depend on the doses, the considered variables, and the order and time interval between the intake of the two substances, to mention but a few aspects.

D. Interactions between Caffeine and Nicotine

There is a positive correlation between drinking coffee and smoking (Istvan and Matarazzo, 1984

There is ample evidence that smokers metabolize caffeine by approximately 50% more rapidly than nonsmokers (Benowitz et al., 1989). Exsmokers consume somewhat less caffeine than smokers (although more than nonsmokers), but they also metabolize the drug more slowly (Swanson et al., 1994). Thus, the levels of caffeine may be at least as high. As we noted above, the effects of caffeine are probably due to a mixture of caffeine, theophylline, and paraxanthine, and the changes in the total amount of active drug are not known. Therefore, the speculation (Swanson et al., 1994) that lowered metabolism of caffeine in exsmokers may lead to increased toxicity remains unsubstantiated.

Both nicotine and caffeine are minor stimulants and one might expect that these effects would be additive. This appears to be the case for the cardiovascular actions and the effects on plasma catecholamines (Smits et al., 1993; Perkins et al., 1994) and EEG (Hasenfratz and Bättig, 1992). There appear to be no additive effects on subjective arousal and mental performance. There was no additive effect for the beneficial actions of the two substances on rapid information processing (Hasenfratz et al., 1991) or on the Stroop task (Hasenfratz and Bättig, 1992). Interestingly, an increase of subjective arousal with either caffeine or nicotine alone but an antagonistic effect with the two in combination has been reported (Rose, 1987).

It has also been reported (Rush et al., 1995) that, among stimulant abusers, those who do not smoke report a higher reinforcing effect of caffeine than do the smokers. If such results were confirmed, they would suggest that the coconsumption of the two substances might not be pharmacologically based.

; Puccio et al., 1990; Swanson et al., 1994), which is stronger and more consistent than that between drinking coffee and alcohol. In addition, it is well known that smokers are particularly liable to smoke when drinking coffee, whereas, on the other hand, coffee is consumed more in the morning and alcohol in the evening. In twin studies, a heritability for caffeine consumption (36%) was detected, but this was lower than for smoking (56%) or alcohol consumption (50%) (Swan et al., 1996). Furthermore, multivariate analysis showed that about 10% of the total variance in caffeine consumption could be related to a common factor related to drug use, but in the case of nicotine the contribution of this factor was more than one third of the total variance (Swan et al., 1996). According to an extensive review by Swanson et al. (1994), all considered studies reported smokers to drink more coffee, on an average of about 50% more. There is also a larger proportion who do not consume caffeine among nonsmokers than among smokers. The review also cites several studies showing that the typical desire of smokers to smoke while drinking coffee is independent of the caffeine dose. There is, however, no evidence that caffeine intake increases the number of cigarettes smoked or the amount of smoke inhaled (Chait and Griffiths, 1983; Rose, 1987). In this respect, caffeine differed from amphetamine, which did increase both parameters. The amounts of nicotine and its metabolites in blood are also unchanged by caffeine intake at several dose levels for several days (Brown and Benowitz, 1989). In another study (Lane, 1996) it was found that the rate of smoking was higher during such periods of the day when caffeine-containing beverages were consumed than during other parts of the day. However, only a minimal part of the total number of cigarettes consumed were associated with caffeine intake, and at least half of the caffeine intake occurred without smoking. This suggests that other variables than caffeine are of overriding importance.). At least part of the association may be related to a factor denoted polysubstance use (Swan et al., 1996).). Caffeine and amphetamine produced markedly different subjective and behavioral effects. Amphetamine produced a prominent increase in the MBG scale (euphoria), whereas caffeine gave only very modest dose-related increase in euphoria in the range of 200 to 800 mg.). Recently, the effects of an i.v. administration of caffeine were tested in 10 subjects with histories of stimulant drug abuse. In that study, caffeine dose-dependently increased ratings of positive mood, and the higher doses of caffeine were more frequently identified with other stimulant drugs like amphetamine and cocaine. While the effects of i.v. administration of caffeine on mood were similar to those previously reported for cocaine in the same subjects, the physiological effects were different (Rush et al., 1995). In other respects as well, caffeine differs from drugs that are typically abused (Heishman and Henningfield, 1994). Thus, there is little evidence for compulsive use of caffeine. Hence, the great majority of consumers drink caffeinated beverages in a controlled manner, although a small minority use caffeine compulsively, such that they have difficulties in reducing or stopping intake.

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