LSD persistently disrupts affective pain processing

The study used male Sprague-Dawley rats. Behavioural experiments were conducted under institutional animal care approval, with animals acclimated after arrival and maintained on a standard light-dark cycle with food and water available ad libitum. The main behavioural assay was conditioned place aversion (CPA), which measures avoidance of a chamber paired with noxious stimulation. Rats underwent a preconditioning phase, conditioning with a pin-prick stimulus to the hind paw paired with one chamber, and a testing phase in which chamber preference or avoidance was reassessed. Animals with strong initial chamber bias or insufficient movement during testing were excluded. CPA scores were calculated as the difference in time spent in the pain-paired chamber between preconditioning and testing. To test systemic effects, rats received intraperitoneal LSD or saline at 85 µg/kg, and were tested 15 minutes later and again 14 days later without further drug exposure. To test regional specificity, the researchers implanted guide cannulas and infused LSD or saline directly into the ACC or, for comparison, into S1. In a separate manipulation, the 5-HT2A antagonist MDL 100,907 was infused into the ACC to assess receptor involvement. Doses and volumes are described in the extracted text as 1 µL per hemisphere for intracranial injections. To examine neural encoding, chronically implanted Neuropixels 2.0 probes were used to record spiking activity from the ACC in freely behaving rats after intraperitoneal LSD or saline. Rats received hind-paw pin-prick stimuli during recordings, independent of the CPA paradigm, and the experiment was repeated 14 days later. Spike sorting was performed with Kilosort4 and manual curation in Phy2, with two independent sorts used to reduce bias. The researchers also carried out ex vivo whole-cell current-clamp recordings from layer V pyramidal neurons in ACC slices taken from naïve rats. After baseline measurements, they bath-applied LSD at 700 nM and reassessed firing properties using repeated 1 s depolarising current steps to construct firing rate-current curves. Across behavioural and neural datasets, the authors used parametric or non-parametric tests depending on normality, with paired tests for within-group CPA comparisons and unpaired tests for between-group comparisons.

In the CPA assay, systemic LSD markedly reduced pain-related aversion. Saline-treated rats spent significantly less time in the pin-prick-paired chamber during testing than during preconditioning, whereas rats given LSD no longer showed this avoidance. The CPA score was much smaller in the LSD group than in the saline group. These effects were reported as persistent: when the CPA assay was repeated 14 days after a single dose, the saline group again showed strong avoidance, while the group previously given LSD still showed an attenuated aversive response, with the CPA score remaining significantly lower than in controls. Local infusion experiments suggested that the ACC was sufficient for this effect. Saline infusion into the ACC preserved normal avoidance of the pin-prick-paired chamber, but ACC infusion of LSD blocked the aversive response. The CPA score remained significantly different between saline and LSD conditions, including in the 14-day follow-up. By contrast, LSD infusion into S1 did not differ from saline infusion in CPA score, and both groups still showed aversion to the noxious-paired chamber. When the 5-HT2A receptor antagonist MDL 100,907 was infused into the ACC before systemic LSD testing, it significantly attenuated the anti-aversive effect, with rats again avoiding the pain-paired chamber. Neuropixels recordings showed that LSD reduced nociceptive firing in the ACC. Although the proportion of neurons classified as pain responsive was not significantly changed, peak firing rates in response to pin-prick were lower in LSD-treated rats than in saline-treated rats. This reduction was still present 14 days later. The same pattern held when analysis was restricted to pain-responsive neurons, indicating reduced stimulus-evoked responses rather than a global loss of recorded activity. In ex vivo slice recordings, LSD produced a more complex effect on intrinsic excitability. Layer V ACC pyramidal neurons exposed to LSD fired more readily at low current injections, but at higher currents their firing rates dropped below those seen in control conditions. When aligned to rheobase, this reduction in maximal firing was more pronounced. The authors present this as a dissociation between increased intrinsic excitability and reduced maximal firing output. The figures and legends also report sample sizes for several analyses, including 515 neurons in the saline in vivo group and 486 in the LSD group on day 1, and 569 versus 372 neurons on day 14; for pain-responsive neurons, the figure legend indicates 120 saline neurons versus 90 LSD neurons on day 1. The extracted text does not clearly provide every corresponding p value in the main narrative, but the direction of effects is consistent across the reported comparisons.

Plotkin and colleagues interpret their findings as showing that a single exposure to LSD produces a durable reduction in the affective, rather than sensory, component of pain. They argue that the ACC is a key site for this effect because local ACC administration reproduced the behavioural phenotype, whereas S1 infusion did not. They further suggest that the relevant mechanism is not simply a broad reduction in cortical activity, but a selective suppression of stimulus-evoked nociceptive encoding in the ACC. The authors place these findings in the context of earlier studies showing that psilocybin and ketamine can normalise elevated ACC activity and improve pain-related behaviours. In their view, the new results extend this literature by showing that LSD also alters pain processing, and that psychedelics may more generally disrupt the transformation of sensory input into aversive cortical representations. They emphasise that their data point to changes in affective pain processing rather than a general analgesic effect on sensory nociception. The discussion also highlights a mechanistic dissociation at the cellular level. LSD increased intrinsic excitability in ACC pyramidal neurons in slice preparations, yet in vivo it reduced the maximum firing response to pin-prick stimulation. The authors propose that this can reconcile earlier observations that psychedelics may enhance excitability or excitatory neurotransmission in slices while reducing firing in intact circuits. The main limitations acknowledged in the extracted text are that the study was conducted in rats, so translation to humans remains uncertain, and that future work is needed to identify the contributions of specific neuronal subtypes and local microcircuit dynamics within the ACC. The authors also imply that further studies should determine whether the mechanism generalises across psychedelics and pain models.