A Beneficial Psychedelic That Does Not Cause Hallucinations

Current drug therapies for treating depression, anxiety, and other major psychiatric disorders provide limited benefits for most patients and are associated with significant side effects that limit their usefulness.

Recently, psychotherapists have begun testing psychedelic drugs, such as psilocybin, N, N-dimethyltryptamine (DMT), and lysergic acid diethylamide (LSD), to treat a variety of psychiatric disorders. These drugs induce profound alterations of consciousness that are principally mediated by the ability of these drugs to activate a specific serotonin receptor called 5-HT2A. Multiple excellent placebo-controlled trials have shown that these psychedelics produce long-lasting reductions in depression and anxiety after only one or two doses. However, these drugs are not easily tolerated by many patients due to their intense hallucinogenic effects.

Scientists do not know whether the behavioral and emotional benefits of these drugs are linked to their bizarre subjective effects. A recent study investigated whether it was possible to decouple the hallucinogenic effects of psychedelic drugs from their therapeutic effects. Preliminary research suggests that psychedelics produce emotional benefits by rapidly inducing long-lasting structural and function changes in the brain's frontal lobes. In addition, psychedelics improve neurogenesis, the birth of new neurons that underlies the anti-depressant effects of most drugs.

In 1938, Dr. Albert Hofmann synthesized a series of compounds, LSD, a potent hallucinogen, and 2-bromo-lysergic acid diethylamide (Br-LSD), which has no hallucinogenic effects in humans. A recent study investigated whether Br-LSD possessed some of LSD’s antidepressant and anxiolytic effects. The studies demonstrated that Br-LSD promotes neuroplasticity and reduces the loss of synaptic connections in the cortex associated with depression. Increased neural plasticity is thought to underlie the therapeutic response to antidepressant drugs. Treatment with Br-LSD also promoted the exploration of novel environments that usually induce stress, as well as improved coping behaviors.

Br-LSD has less potential for side effects than other drugs that act on serotonergic neurons. The benefits and safety profile of Br-LSD may depend on the fact that it is a weaker stimulant at the 5-HT2A receptor. Five patients who received 30 mg/kg Br-LSD on three occasions experienced only minor side effects. Higher oral doses (64–256 mg/kg) induced mild subjective responses, including restlessness, anxiety, drowsiness, impaired concentration, and euphoria. None of the subjects who received 2-Br-LSD orally or intravenously experienced visual hallucinations or profound cognitive alterations similar to those induced by LSD.

These results suggest that Br-LSD has the potential to be an effective treatment for major depressive disorders and anxiety, possibly through its effects on neuroplasticity. Compounds modifying synaptic plasticity are considered promising therapies for these disorders. Indeed, a central hypothesis for the mechanism of action for the therapeutic antidepressant effects of psychedelics involves rapid induction of structural and functional neural plasticity and reversal of neuronal atrophy. The lack of Br-LSD tolerance may permit frequent dosing for mood disorders and other indications.

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