Previous psychophysical studies have revealed inconsistent results regarding the effects of THC on pain and hyperalgesia [1,35,56,62]
. Such studies employed psychophysical indices that focused on the sensory aspects of pain, and consistent with these studies, we report no significant effect of THC on the perceived pain intensity (sensory aspect) of capsaicin-induced pain or hyperalgesia. Instead, we found that THC relieved specifically the perceived unpleasantness of pain and hyperalgesia induced by capsaicin. The divergent effect of THC on sensory and affective aspects of somatosensation has also been reported by Libman and Stern, who observed that THC can lower sensory thresholds to innocuous stimuli whilst increasing pain tolerance 
. THC does have sedative effects 
, which was evidenced by a generalised increase in visual-motor reaction times in our study. Importantly, the analgesic effect of THC was evident only when pain and hyperalgesia were induced by capsaicin. Thus, general sedation does not account for the analgesic effect of THC that was reported by our subjects.
The dissociative analgesic effects of THC on experimentally induced pain in this study were further corroborated by fMRI data. We found that THC specifically decreased BOLD activation related to hyperalgesia within the ACC but did not significantly reduce activation in the posterior thalami (). Only a subset of all regions known to be involved in punctate hyperalgesia was significantly activated in this study when compared to 2 of our previous studies [38,69]
. This may relate to the presence of ongoing pain induced by highly concentrated capsaicin (1%) that was maintained throughout scanning and was not present in those previous studies. Ongoing pain induced by capsaicin itself is associated with increased cerebral blood flow and hence, elevates baseline BOLD signal in brain regions associated with punctate hyperalgesia 
. Experimental data have revealed that the absolute increase in BOLD signal evoked by a stimulus is constant regardless of the baseline signal [26,57]
. Increases in the baseline BOLD signal can be associated with a relative decrease of stimulus-evoked response compared to the baseline. This implies that areas where the increase in activity related to punctate hyperalgesia is less marked to begin with may not exhibit significant responses when the baseline signal is increased in the presence of ongoing pain. Hence, BOLD-fMRI assay sensitivity in our study may be reduced for the detection of responses related to hyperalgesia with strong ongoing pain. The robustness of BOLD responses in the anterior cingulate and thalami to punctate stimulation in the presence of ongoing pain suggests their significant involvement during capsaicin-induced hyperalgesia, which is supported by previous data of capsaicin-induced hyperalgesia (refer to Supplementary Table in 
Preclinical studies consistently demonstrate that ACC lesions reduce conditioned place avoidance but not withdrawal behaviour in inflammatory and neuropathic [10,19,33,37]
pain models, supporting a role for that region in higher-order pain behaviour. Patients who have undergone anterior cingulotomy for the treatment of intractable pain [25,63,68]
have relatively intact sensory perception of noxious stimuli, but their affective responses to the stimulus are markedly attenuated 
. In further support of the role of the ACC for the affective-motivational aspects of pain, Rainville and colleagues have shown that the limbic structure is more active when the unpleasantness of pain is aggravated by hypnotic suggestion 
. Notably, the ACC region activated in their study is precisely where THC suppressed activation related to hyperalgesia in our study.
Based on recent cytoarchitectural studies, Vogt suggests that the ACC may be subdivided into the anterior and mid cingulate cortices 
. Under his proposed anatomical classification, the cingulate region in our study is identified as the anterior mid cingulate cortex, which crucially, is a region that communicates anatomically with the amygdala [3,20,61]
. Preclinical studies clearly demonstrate that ablation or inactivation of the amygdalae attenuate analgesia afforded by systemic CB-1 agonists [42,43]
. These data led us to specifically explore whether amygdala activity plays a key role during cannabinoid analgesia in humans. In contrast to the decreased ACC response during cannabinoid analgesia, the main effect of THC was to increase amygdala response during noxious stimulation. Importantly, the increase in capsaicin-induced amygdala response and the analgesic effect of THC was positively correlated, which indicates that amygdala activity contributes to interindividual variation in analgesic drug response. Evidence from rodent studies suggests that cannabinoid analgesia involves activation of the brainstem circuitry for the descending inhibition of nociception via the amygdala [42,44]
. However, our Fc analyses did not reveal significantly altered Fc between the amygdala and brainstem during cannabinoid analgesia with this study design.
Instead, we found that THC significantly reduced Fc between the amygdala and a large portion of the primary sensorimotor area. Specifically, the reduction of Fc between the amygdala and the left S1 region was positively correlated with the dissociative effects of the drug on the reported intensity and unpleasantness of pain in the right lower leg. For an unbiased analysis, the S1 ROI was centred on the peak coordinates within the left postcentral gyrus, even though they are unlikely to fall within the representation area of the right leg. Direct anatomical connections between S1 and amygdalae are sparse 
. In contrast, ample clinical [15,48]
and physiological [18,24,36,49]
evidence in humans supports the concept that nociceptive information ascends in divergent parallel ascending pathways to sensory and limbic regions. A selective action of THC on CB-1 receptor dense limbic pathway could explain parsimoniously the findings of reduced sensory-limbic Fc in the face of drug-induced dissociative analgesia. However, the parallel model does not account for how the separable dimensions of pain are normally united in human consciousness 
, and THC might well disrupt the integration of neural information between sensory and limbic regions from which the experience we recognise as pain arises.
We found involvement of the right rather than the left amygdala during cannabinoid analgesia. There are previous data that can account for the lateralisation of cannabinoid effects on pain-related amygdala activity. Several investigators have recently demonstrated that inflammation-induced activation or plasticity of the right amygdala is independent of the laterality of peripheral inflammation, which attests to the right-hemispheric lateralisation of amygdala function during pain [11,32]
. The male gender in our study may also contribute to the hemispheric lateralisation of drug effect: highly salient stimuli are preferentially processed by the right amygdala in men 
THC was administered systemically in our study. Consequently, peripheral mechanisms for the observed effect of the cannabinoid on capsaicin-induced hyperalgesia cannot be excluded 
. However, peripheral or spinal mechanisms do not account adequately for the divergent effects of THC on the sensory and affective aspects of pain that we observed in this study. Instead, our data demonstrate that the effects of THC in the brain, characterised by altered functional activities of the right amygdala, account for the interindividual variation in analgesic efficacy.
Cannabis has been reported to be remarkably effective for the relief of otherwise intractable pain in patients 
. However, the bases of such pain relief afforded by this psychotropic agent are debatable [51,54]
. Our data reveal that specific effects of THC, the psychotropic component of cannabis, on the amygdala contribute to the analgesic effects of the drug reported by healthy volunteers. Identifying patients who rely on similar central effects from cannabis-based medicines for pain relief remains challenging, but our study indicates that the use of functional brain imaging for that purpose merits further investigation.