Recreational Ketamine trials

 Recreational ketamine use has increased in recent years, but remains rare

Recreational ketamine use and availability of the drug have increased in recent years, but it remains an uncommon drug used by less than 1 percent of people in the US, according to a new study published in the American Journal of Public Health.

Ketamine has long been used as an anesthetic in veterinary and health care settings, but ketamine is also a party drug that produces hallucinations and feelings of dissociation. In 2019, the Food and Drug Administration (FDA) approved the use of a nasal spray version of the drug as a fast-acting option for treatment-resistant depression.

"Since the approval of ketamine for psychiatric use, we've seen substantial attention and media coverage about the drug. As such, we wanted to determine whether there have been shifts in recreational ketamine use and availability," said study author Joseph Palamar, Ph .D., MPH, an associate professor of population health at NYU Grossman School of Medicine and an affiliated researcher with the Center for Drug Use and HIV / HCV Research at NYU School of Global Public Health.

Palamar and his colleagues examined past-year recreational use of ketamine between 2006 and 2019 using the National Survey on Drug Use and Health, a nationally representative survey of US teens and adults. They also looked at trends in ketamine-related poisonings between 1991 and 2019 as reported to poison control centers across the country. Finally, they examined trends in law enforcement seizures of ketamine, tracked by the Drug Enforcement Administration's National Forensic Laboratory Information System from 2000 to 2019.

Their results suggest an increase in recreational use and availability of ketamine in recent years — particularly in 2019, coinciding with the drug's FDA approval for depression. However, despite these increases, its use has remained relatively rare, with less than 1 percent of teens and adults using the drug. The highest prevalence of recreational ketamine use — 0.9 percent — was reported in late 2019.

Poisonings were highest in 2000-2001, which was also the peak in use of other club drugs such as MDMA (also known as ecstasy or Molly). "As a 'club drug,' ketamine use has always been closely linked with ecstasy use, which is also most likely to take place in nightlife settings," said Palamar. After a decline in poisonings, there was an increase again through 2014 to 1.1 poisonings per 1,000,000 people; this measure has remained relatively consistent since.

Rates of ketamine seizures by law enforcement have increased exponentially since 2012, although seizures are still uncommon relative to other drugs. The proliferation of seizures suggests an increase in the drug 's availability.

"Increases in ketamine use in nightclub and non-hospital settings indicate the need for additional public health measures so that individuals who use non-medically are aware of risks and side effects," said Katherine Keyes, Ph.D., associate professor of epidemiology at Columbia University Mailman School of Public Health, and co-author.

"While ketamine is used medically throughout the world, it is important for surveillance efforts to focus on recreational use in an effort to inform prevention and harm reduction programs," added Palamar.

No adverse cognitive effects of ketamine or esketamine for treatment-resistant depression

Used for the treatment of depression that does not respond to standard antidepressant medications, the anesthesia drug ketamine — and the related drug esketamine, recently approved for depression treatment — has no important adverse effects on memory, attention, or other cognitive processes, concludes a systematic review of medical research in the September / October issue of Harvard Review of Psychiatry .

"Current evidence suggests that ketamine and esketamine do not appear to exert significant deleterious neurocognitive effects in treatment-resistant depression ," according to the new research, led by Breno Souza-Marques, BA, and Lucas C. Quarantini, MD, Ph.D., of Federal University of Bahia, Salvador, Brazil. In fact, some cognitive functions improved 7 to 13 days after repeated ketamine infusions.

Evidence supports cognitive safety of ketamine and esketamine for depression treatment

Ketamine is a widely used surgical anesthetic that produces a detached, dreamlike state. Multiple studies have shown that at low doses, ketamine can have rapid antidepressant effects — typically improving mood within 24 hours to 7 days. Similar benefits have been reported with esketamine, a version of the drug recently approved for use in patients with treatment-resistant  depression . Although ketamine is not yet approved for treatment of depression, some physicians prescribe it for that purpose on an "off-label" basis.

However, there are potential safety concerns with ketamine, which is "a highly sought-after recreational drug," according to the authors. Studies have reported  memory impairment  after long-term recreational use of ketamine, as well as in  medical studies  in which healthy volunteers received just one infusion. That's particularly worrisome because memory problems and other cognitive symptoms — such as difficulties with thinking and concentrating — are a key aspect of major depressive disorder. Cognitive symptoms may continue even after mood improves.

To investigate the cognitive safety of ketamine and esketamine, Mr. Souza-Marques, Dr. Quarantini, and colleagues searched the medical literature for studies in which one of these drugs was given to patients who had treatment-resistant depression. Definitions vary, but most experts consider depression "treatment-resistant" if it persists after the patient has tried at least two different antidepressants.

The team identified 14 studies that collectively involved 1,019 patients: One study of esketamine nasal spray for 44 weeks, seven studies of a single ketamine intravenous infusion, and six studies in which patients received six ketamine infusions over two or three weeks. Neuropsychological performance assessment was variable for the ketamine studies (1 study at 40 minutes, 1 study at 24 hours, 1 study at 3 days, and 1 study at 7 days), while the esketamine study performed repeated assessments at 28 days, 20 weeks, 32 weeks, and 44 weeks.

The esketamine study showed no changes in cognitive performance. Five studies of ketamine actually reported improvements in memory, processing speed (the time it takes to complete a mental task), or cognitive flexibility (the ability to switch between mental tasks or thoughts).

Only one of the 14 studies reported cognitive impairment after ketamine treatment. Memory was worse 24 hours after six ketamine infusions, and processing speed was worse 24 hours after a single infusion, but these deficits were no longer present seven days after treatment. Moreover, the group that received multiple infusions showed improved processing speed, cognitive flexibility, and memory. Despite this encouraging evidence, further studies are needed to assess the longer-term neurocognitive effects of these drugs.

Some studies showed that individuals who had certain cognitive attributes before treatment — poorer attention, slower processing speed, or better memory — were more likely to respond to ketamine. The researchers conclude, "Results suggest possible neuropsychological profiles predictive of antidepressant response to ketamine, such as lower attention, slower processing speed, or higher working  memory , that should be further assessed in future studies, as these results could provide time-saving evidence to clinicians and mental health practitioners. "

Comparing the impacts of propofol and ketamine on the brain

A team of researchers at Indiana University has tested the effects of propofol and ketamine on the brains of macaques as a means to better understand what happens when humans ingest the drugs. In their paper published in the journal  Royal Society Open Science , the group describes electrophysiological activity they recorded from the cerebral cortex of two macaques after they were given propofol and ketamine.

The  drug  ketamine  has been in the news in recent years due to its increasing use as an illicit drug — people who take it dissociative experience, dreamlike states and hallucinations. Prior to its current popularity as a party drug, ketamine was used as an anesthetic for both human and animal patients. Its use in such a way was mostly discontinued, however, as propofol was found to be a better option.

Prior research has shown that ketamine produces sensory detachment because it blocks glutamate receptors in the  brain . This leads to increased levels of glutamate, which results in feelings of disassociation. But ketamine can also lead to unconsciousness, which is why it was used as an anesthetic. In this new effort, the researchers wanted to know more about the different ways that ketamine and propofol impact the brain, so they compared the two using macaques.

The work by the team involved giving two adult macaques ketamine and propofol on different occasions and then studying their brain waves. They also obtained electrocorticographical recordings of macaques made by other researchers working on prior research efforts, to use as a benchmark.

In looking at their data, the researchers found that ketamine induced a dual state in the brain — one was of normal consciousness and the other a form of anesthetic sleep. This led to a sort of liminal space where aspects of both states were present — one of them looked a lot like the state a brain was in when under the influence of  propofol , while the other was similar to a sleeping, non-drug influenced state . They found that plotting the data on a graph showed roughly the same thing — that the brain existed in both an unconscious and semi-conscious state at the same time. They suggest it is the dual state nature in the brain that produces the feelings of disassociation.