Testing the effects of Δ9-THC and D-cycloserine on extinction of conditioned fear in humans

Abstract

Preclinical evidence implicates several neurotransmitter systems in the extinction of conditioned fear. These results are of great interest, because the reduction of acquired fear associations is critical in therapies for anxiety disorders. We tested whether findings with respect to the N-methyl-D-aspartate (NMDA) and cannabinoid receptor (CB) systems in animals carry over to healthy human subjects. To that end, we administered selected doses of D-cycloserine (partial NMDA receptor agonist, 250 mg), delta-9-tetrahydrocannabinol (THC, CB(1) receptor agonist, 10 mg), or placebo prior to the extinction session of a 3-day conditioning protocol. D-cycloserine did not affect within-session extinction, or the retention of extinction in healthy human participants, in contrast with patient data but in line with previous reports in healthy volunteers. During extinction training, Δ9-THC reduced conditioned skin conductance responses, but not fear-potentiated startle. This effect was not retained at the retention test 2 days later, suggesting it was dependent on acute effects of the drug. Our findings implicate that facilitation of the CB(1) or NMDA system with the substances used in this study does not affect conditioned fear extinction lastingly in healthy humans. The apparent discrepancy between these findings and the results from (pre-)clinical trials is discussed in terms of room for improvement in these systems in healthy volunteers, and the lack of specificity of THC as a CB(1) agonist.

Figure 1

Illustration of the study set up. The top row illustrates the different study sessions, the middle row gives an example of one experimental block, and the bottom row exemplifies how a trial was construed. The flash of lightning represents administration of a shock (between brackets as shocks were only delivered during trials in the acquisition phase). The sound icon represents administration of a noise to elicit a startle reflex (startle probe).

Figure 2

Mean subjective ratings of drug effects scored with visual analogue scales (VAS). Anchors were ‘not at all’ (0) and ‘very much’ (10). Error bars are standard error of the mean (SEM).

Figure 3

Mean startle magnitudes relative to inter-trial interval (ITI) in the three drug groups during the different phases of conditioning. The difference between CS+ and CS− constitutes fear-potentiated startle (FPS). Error bars are SEM.

Figure 4

Mean skin conductance responses in the three drug groups during the different phases of conditioning. Skin conductance responses (SCRs) are divided into (a) early responses reflecting an orienting response to the CS (first interval responses) and (b) late responses reflecting anticipation of the US (second interval responses, panel B). Error bars are SEM. Acq, Acquisition; Ext, Extinction; Ret, Retention; CS, conditioned stimulus