Anyone who inhaled in the 1960s can recall the effects of cannabis—euphoria, paranoia, changes in perception, an inability to concentrate and short-term memory failures. A laboratory-controlled study by Yale scientists published in the journal Neuropsychopharmacology last summer has found that delta-9-tetrahydrocannabinol (THC), the active ingredient of cannabis, transiently induced a range of schizophrenia-like effects in healthy people. And in the past year, three large epidemiological studies have supported the long-suggested link between cannabis use and a risk of schizophrenia.

“No one really knew how cannabis worked until about 10 years ago,” said D. Cyril D’Souza, M.D., associate professor of psychiatry and lead author of the study. “The discovery of cannabinoid receptors and several other advances in the basic pharmacology of the cannabinoid receptor system have renewed interest in that association between cannabis and psychosis.”

Because animal models of psychosis have significant limitations, scientists have used drugs to induce transient psychosis in humans. “Perhaps by studying drug-induced psychosis, that might lead us to a better understanding of psychoses in general and schizophrenia in particular,” D’Souza said, adding that this is the first study, to his knowledge, that has applied measures for schizophrenia to study the effects of THC in healthy people screened for any vulnerability to schizophrenia.

In the study, THC induced temporary responses similar to the three domains of schizophrenia: positive symptoms such as paranoia and disorganization of thinking, negative symptoms such as blunted affect and reduced spontaneity, and cognitive deficits such as memory lapses. On three test days at least a week apart, the researchers administered THC to 22 test subjects—including Yale medical students and undergraduates and other volunteers. All had used cannabis previously but none had ever been diagnosed with cannabis abuse disorder or a major psychiatric disorder. On each test day the subjects received one of three injections, a placebo or a low or medium dose of THC, before taking a series of behavioral and cognitive tests.

The subjects reported how they felt, using a scale of feeling states associated with cannabis effects—high, calm, relaxed, tired, anxious and panicked. Some subjects experienced schizophrenia-like symptoms lasting between half an hour and an hour. In addition, THC induced euphoria and raised levels of cortisol and prolactin, biological markers for activity of cannabinoid receptors.

The tests relied on self-reporting and the observations of trained researchers, which at times differed from those of the subjects. “We had a subject who refused to complete some of the cognitive testing because she was convinced we were trying to trick her,” said D’Souza. “But when we asked if she felt paranoid, she said ‘no.’ ”

Follow-up months after the study revealed no side effects among participants.

Ultimately, D’Souza said, the research may provide clues about the pathophysiology of psychotic disorders. “By understanding how cannabis produces psychosis, that may help us understand what goes wrong in schizophrenia,” he said.