Increased encoding of aversive stimuli by lateral habenula neurons during Δ9-tetrahydrocannabinol withdrawal

Hot Off the Press – October 1, 2026

Published in Nature Communications by Eun-Kyung Hwang and Carl Lupica, et al. of the NIDA IRP Electrophysiology Research Section.

Summary

Withdrawal from many abused drugs results in negative emotional states such as anxiety, depression, and increased aversion to some environmental stimuli. Also, avoiding these negative emotional states through continued drug use represents an obstacle to drug abstinence. Although withdrawal-associated negative states are well-understood for drugs like cocaine, nicotine, and opiates, much less is known about changes in brain function during withdrawal from cannabis. Here, NIDA researchers investigated how withdrawal from repeated exposure to the main psychoactive component of cannabis, known as delta-9-tetrahydrocannabinol (THC), changes brain activity and behavior when unpleasant experiences are encountered. In rats withdrawn from THC, neurons in the lateral habenula (LHb)—a brain region involved in processing negative experiences—responded more strongly to mild foot shock and developed a stronger learned fear response, known as freezing, to a tone that was paired with the shock.

To explain the increased LHb response that was observed during THC withdrawal, NIDA researchers measured synaptic inhibition of LHb neurons and found that it was impaired for up to 30 days after THC withdrawal. This loss of inhibition shifted the balance of LHb neuron activity toward increased excitability.

The findings suggest that repeated use of cannabis can produce lasting changes in a brain circuit that processes unpleasant experiences, potentially contributing to heightened negative emotional states during withdrawal. Additionally, the study identifies a synaptic mechanism through which this occurs. Because the study was conducted in rats, it does not conclusively establish that the same mechanism is involved in cannabis withdrawal symptoms in people. Thus, further research is needed to determine whether this brain region could eventually be a target for treating cannabis withdrawal and cannabis use disorder in humans.

Publication Information

@article{cite-keyi,

title = {Increased encoding of aversive stimuli by lateral habenula neurons during Δ9-tetrahydrocannabinol withdrawal},

author = {Eun-Kyung Hwang and Deborah Daphne and Charlie J. Maddox and Agustin Zapata and Alexander F. Hoffman and Carl R. Lupica},

url = {https://doi.org/10.1038/s41467-026-77429-9},

doi = {10.1038/s41467-026-77429-9},

isbn = {2041-1723},

year  = {2026},

date = {2026-09-03},

journal = {Nature Communications},

abstract = {The lateral habenula (LHb) integrates cortical and basal forebrain (BF) input and is implicated in negative affective states, but its involvement in negative affect associated with cannabis withdrawal is unknown. Here, effects of withdrawal from the psychoactive cannabis constituent, Δ9-tetrahydrocannabinol (Δ9-THC), on fear conditioning (FC) and LHb function were measured in rats using calcium photometry and electrophysiology. FC-associated LHb calcium signals, freezing behavior, and LHb excitatory-inhibitory (E-I) ratios were increased during Δ9-THC withdrawal, and local GABA release was impaired, indicating disinhibition of LHb output neurons. GABA release was also impaired at optogenetically activated BF-LHb axons, and not from ventral tegmental area-LHb inputs. The results indicate that Δ9-THC withdrawal increases LHb excitability through disinhibition, contributing to increased fear of primary and conditioned aversive stimuli. Our findings implicate the LHb in cannabis withdrawal-associated negative affect and offer insight into the neural mechanisms of cannabis use disorder.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}