Failure to extinguish fear can lead to persevering anxiety and has been postulated as an important mechanism in the pathogenesis of human anxiety disorders. In animals, it is well documented that the endogenous cannabinoid system has a pivotal role in the successful extinction of fear, most importantly through the cannabinoid receptor 1. However, no human studies have reported a translation of this preclinical evidence yet. Healthy medication-free human subjects (N=150) underwent a fear conditioning and extinction procedure in a virtual reality environment. Fear potentiation of the eyeblink startle reflex was measured to assess fear-conditioned responding, and subjective fear ratings were collected. Participants were genotyped for two polymorphisms located within the promoter region (rs2180619) and the coding region (rs1049353) of cannabinoid receptor 1. As predicted from the preclinical literature, acquisition and expression of conditioned fear did not differ between genotypes. Crucially, whereas both homozygote (G/G, N=23) and heterozygote (A/G, N=68) G-allele carriers of rs2180619 displayed robust extinction of fear, extinction of fear-potentiated startle was absent in A/A homozygotes (N=51). Additionally, this resistance to extinguish fear left A/A carriers of rs2180619 with significantly higher levels of fear-potentiated startle at the end of the extinction training. No effects of rs1049353 genotype were observed regarding fear acquisition and extinction. These results suggest for the first time involvement of the human endocannabinoid system in fear extinction. Implications are that genetic variability in this system may underlie individual differences in anxiety, rendering cannabinoid receptor 1 a potential target for novel pharmacological treatments of anxiety disorders.

According to Susan Wolf's hybrid view about meaning in life, a life is meaningful in virtue of subjective attraction to objectively valuable pursuits. Recently, several philosophers have presented counterexamples to the subjective element in Wolf's view. We argue that these examples are not clearly successful and present a modified version which is even stronger in the face of them. Finally, we offer some positive reasons for accepting a subjective condition on a meaningful life.

In his recent book Slaves of the Passions, Mark Schroeder defends a Humean account of practical reasons (hypotheticalism). He argues that it is compatible with 'genuinely agent-neutral reasons'. These are reasons that any agent whatsoever has. According to Schroeder, they may well include moral reasons. Furthermore, he proposes a novel account of a reason's weight, which is supposed to vindicate the claim that agentneutral reasons (if they exist), would be weighty irrespective of anyone's desires. If the argument is successful, it could help avoid an error-theory of moral language. I argue that it isn't, and that we should reject a Humean approach to reasons.

Stephen Finlay analyses 'ought' in terms of probability. According to him, normative 'ought's are statements about the likelihood that an act will realize some (contextually supplied) end. I raise a problem for this theory. It concerns the relation between 'ought' and the balance of reasons. 'A ought to F' seems to entail that the balance of reasons favours that A F-es, and vice versa. Given Finlay's semantics for 'ought', it also makes sense to think of reasons and their weight in terms of probability. In this paper, I develop such a theory of weight. It turns out, however, that it cannot explain the entailments. This leaves Finlay with a challenge: to explain these entailments in some other way consistent with his theory, or to show why the appearances deceive and there are no such entailments.

Sharon Street (Can J Philos Suppl Vol 35: 213-248, 2009) argues that realism about epistemic normativity is false. Realists believe there are truths about epistemic reasons that hold independently of the agent's (or anyone else's) attitudes. Street argues by dilemma. Either the realist accepts a certain account of the nature of belief, or she does not. If she does, then she cannot consistently accept realism. If she does not, then she has no scientifically credible explanation of the fact that our epistemic behaviours or beliefs about epistemic reasons align with independent normative truths. I argue that neither horn is very sharp for realists about epistemic normativity.