With frequent consumption, substantial tolerance develops to the anxiogenic effect of caffeine, even in genetically susceptible individuals, but no net benefit for alertness is gained, as caffeine abstinence reduces alertness and consumption merely returns it to baseline.The data showed that after a night of abstinence - participants were instructed to consume no caffeine after 7pm the previous evening - heavy caffeine consumers (on average ~350mg per day) showed no benefit to alertness from caffeine, but rather a precipitous decline in alertness when given placebo, compared to light- or non-consumers. They also reported a large increase in headaches when deprived of caffeine. How bad were they? Almost 4% of the group withdrew from the study due to headaches and feeling sick. This all suggests that rather than actually improving alertness in heavy consumers, the morning coffee ritual merely mitigates withdrawal effects, returning them to 'baseline'.
Surprisingly, in low- or non-consumers caffeine showed no difference in alertness, compared to placebo, but did result in increased anxiety and slight increase in headaches. The authors suggest this is due to discrepancies between this and earlier studies. Previous research on the effects of caffeine on alertness seems to have relied mostly on self-reported caffeine consumption. In this case, reporting was validated and compliance enforced based on saliva levels of caffeine and its metabolites.
The authors also identified a genetic component involved in modulating the anxiety effects of caffeine. A SNP in the adenosine A2a gene (ADORA2A) "showed greater susceptibility to caffeine-induced anxiety", and while people of that particular genotype habitually consumed more caffeine on average, the effects on anxiety were only observed in the low end consumers. Moderate to high consumers seemed to be tolerized to the effects.
It's also worth pointing out that 90% of the population from which participants were drawn (adults living in Bristol, UK) fall into the moderate to high caffeine consumption category (>40mg/day). If that's representative of western society, then most of us are sub-optimal without our morning hit. It also explains the widespread notion that coffee improves alertness: it does, but only because we're suffering without it.