Ketamine is not only used to anesthetize horses or as a party drug in nightlife, but also as a medicine against depression. However, a placebo of this horse remedy also appears to be suitable for this.
The effect of ketamine on people with severe depression has been regularly studied. It is known that the drug can provide profound and rapid relief to people with very serious depression. But it is not entirely clear how exactly the substance alleviates depression symptoms. Something seems to change in receptors in the brain where the neurotransmitter dopamine is involved, but much is still unclear.
In addition, the studies have a crucial shortcoming, according to scientists Stanford Medicine University. Participants in these studies usually know whether they have received ketamine or a placebo. Even in blinded studies where participants are not told what they have received. The hallucinatory effects of ketamine quickly reveal which group you are in.
Placebo-effect
This makes it difficult to investigate whether a medicine works because of the active substances it contains, or whether it is due to the expectation that a medicine will work: the so-called placebo effect. People who respond to the placebo effect feel better when they think they have received an effective treatment or taken an effective drug. This effect exists not only in medicine, but also in everyday life – although the effects differ per person (see box). For example, you perform better in sports if you believe that you follow a personal schedule and you don’t really wake up from a cup of coffee. But because ketamine has very clear side effects in the form of hallucinations, participants in a control group are less likely to think that they have received the active substance.
Why the placebo effect does not apply to everyone
Research shows that not everyone is susceptible to the placebo effect. Initially, researchers explained this by looking at people’s personalities. But in recent years, researchers have increasingly turned to brain scans. Genetic variations have also been found that would determine the extent to which someone is sensitive to placebos. The placebo effect is therefore not merely something psychological and, according to the researchers, must also be viewed in a ‘serious, biological manner’.
Operation
In a new study, researchers from… Stanford Medicine a smart solution to circumvent those hallucinogenic side effects, so that the effect of ketamine on depression can be investigated more reliably. They selected forty participants with moderate to severe depression who underwent routine surgery – unrelated to their depression. During the operation, the participants – who were completely anesthetized and therefore unconscious – were administered a dose of ketamine or placebo. Both the participants and the researchers and doctors directly involved did not know who received which treatment. This was only revealed two weeks later, after the results were announced.
“They said they had never felt so good, even though these people were in the placebo group.”
Improvement
To the researchers’ surprise, it turned out that depression symptoms decreased in both groups. Just one day into treatment, the scores of both the ketamine and placebo groups dropped by half on the Montgomery-Åsberg depression scale (a measure used to indicate the severity of depression) on average. Those scores remained approximately the same during the following two weeks. “I was very surprised by this result,” says involved physician-researcher Boris Heifets. Not necessarily because of the rapid effect – that had already been demonstrated in previous studies – but because of those who reported feeling better. “I spoke to participants who told me that their lives had changed and they had never felt better, even though these people were in the placebo group.”
Guess which group
During this study, the participants had no idea which group they were in. At their final visit, participants were asked to guess whether they were in the control group (and therefore had received a placebo) or not. About a quarter really wouldn’t know. Of those who did dare to take a chance, more than 60% thought they had been given ketamine. This mainly concerned people whose depression symptoms had decreased the most, even if they were in the control group. While that sounds promising, the depression was not completely resolved. “To put the drop in depression symptoms into perspective, it took participants from the most intense levels of depression, to a category of mild depression,” explains lead author Theresa Lii.
“By saying it’s just a placebo, you’re discounting the placebo effect.”
Cause
The study – after it took an unexpected turn – raises more questions than it answers, the researchers admit. It is unlikely that the surgeries and general anesthesia themselves would explain the improvements, the researchers say, because previous research has shown that depression generally does not change after surgery. If it makes any difference, it makes the symptoms worse. A more likely cause is that the positive expectations of the participants played an important role. “Somehow, none of this is new,” Heifets said. “The placebo effect is probably the most effective, consistent intervention in medicine and is seen in every study.”
‘Between your ears’ is real
This does not mean that ketamine is “just a placebo,” Heifets emphasizes. “By saying it’s just a placebo, you’re discounting the placebo effect.” He means that saying something is a placebo, or that symptoms will go away if you believe hard enough, implies that there was nothing wrong with the patient in the first place. That if something is ‘between your ears’, it is not really something. “While there is definitely a physiological mechanism that kicks in – what happens between your ears – when you get hope,” Heifets said. This also means that it is possible that the placebo effect and ketamine work together.
To distinguish the pharmacological effects of ketamine and other psychedelics from the psychological effects, smarter experiments will have to be devised. But it seems clear that psychological effects have an influence. “Call it an expectation bias, call it a placebo effect or call it hope. Whatever the label, the psychological factors that play a role in treatment can be powerful,” the researchers conclude in their publication.
2023-10-24 11:20:34
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