Psychedelics are being studied again as treatments for depression, anxiety, PTSD, and substance use disorders. Their beneficial effects are mostly due to activating the serotonin 2A (5-HT2A) receptor, but they differ greatly in chemical structure, how they bind to receptors, how they are broken down, and how long they last. Short-acting psychedelics like DMT and 5-methoxy-DMT may be better for brief therapy sessions, while long-acting ones like LSD and mescaline might be more effective for some outcomes. This review covers the chemistry, structure-activity relationships, and pharmacology of both types, and discusses how small chemical changes affect receptor binding and duration. It aims to guide development of next-generation treatments with controlled effects.
Combining the sigma1 receptor antagonist CM304 with delta9-tetrahydrocannabinol (THC) enhances pain relief without worsening THC's side effects. In mice, CM304 increased the pain-blocking effect of THC and caused greater body temperature drops when combined. A high dose of CM304 alone reduced movement. In rats, CM304 made THC's pain relief more potent. CM304 did not produce THC-like effects in rats trained to recognize THC, nor did it amplify THC's subjective effects. The findings suggest sigma1 receptor antagonists could be safer adjuncts to cannabinoid-based pain treatments, offering pain relief without increasing adverse effects like sedation or abuse potential.
Cannabis and its psychoactive component Δ9-tetrahydrocannabinol (THC) can improve working memory in aged rats, depending on sex and route of administration. Acute cannabis smoke enhanced working memory accuracy in aged male rats but impaired it in aged females, with no effect on young adults. Chronic oral THC improved working memory in aged rats of both sexes, again with no effect on young adults. Neither cannabis smoke nor oral THC affected hippocampus-dependent memory tasks in any age group. The findings suggest that cannabis may attenuate some age-related working memory deficits without worsening other cognitive impairments, though effects vary by sex and administration route.