Jooyeun Lee, Knowing Neurons
Source: Jooyeun Lee, Knowing Neurons

Note: Ketamine is a controlled substance in the United States and many other countries. Do not use ketamine illicitly.

Imagine an injection that briefly gives you schizophrenia. Now imagine that this injection is all at once the same drug once abused by Steve-O of MTV’s Jackass, the same drug popped in karaoke bars in East Asia, the same drug given as anesthesia to animals and children, and the same drug that holds promise as an emergency antidote to suicidal thoughts.

Welcome to ketamine. First synthesized in 1962, ketamine is the little brother of a more notorious drug, PCP (phencyclidine). Both substances fit the same keyholes in the brain, pulling on the strings of sanity. In the process, they create a state of detachment from reality, known as dissociation. At higher doses, both drugs induce the deep “sleep” of anesthesia. Indeed, ketamine was the Parke-Davis pharmaceutical company’s would-be solution to PCP’s insufferable side effects as a general anesthetic, insidious hallucinations, and delusions that greet the patient upon waking after surgery. Yet ketamine packs most of the poison of PCP with a milder punch. Today, it is a back-of-the-shelf anesthetic used mostly on sick pets—and young children.

Confused? Perhaps you should be. After all, those whom we protect the most against questionable medications are children. But children, in the case of the ketamine, have a certain perplexing immunity—not against the drug’s anesthetic properties, but rather against its dissociative spell. Upon awakening from ketamine's anesthetic slumber, adverse reactions are rarely reported in children younger than 16.

And what else is rarely reported in children under 16? Schizophrenia. Whatever Achilles' heel the adult brain possesses is well-covered in children. Laid bare in adults, ketamine and schizophrenia target this weakness like a mythical arrow from Paris’ bow.

Adults injected with ketamine hear illusory sounds, feel detached from their bodies, and even perceive nonexistent messages from extraterrestrials. What does it feel like to be placed inside a brain scanner after being infused with ketamine?

“The mechanical clangor of the scanner became melodic,” said a graduate student who volunteered for a ketamine study at the UC Davis Imaging Research Center in Sacramento, California. The study was approved by an ethics committee and used ketamine to simulate schizophrenia, giving researchers deeper insight into the processes behind the disorder. “My body felt undeniably curved to the left from my head down, like a loosely curled ribbon,” the student said, whose name is withheld here for privacy reasons. “Even when I'd tap my fingers or wiggle my toes to try to re-establish normal body space, the floating ribbon continued to hang leftward, unperturbed.”

To safeguard against effects created by prior expectations, participants did not know in advance whether they would receive a saline solution or real ketamine. “When the infusion began, and I felt the cold fluid creep up my arm from the IV site in my hand, I first thought 'Oh, I guess I got the saline then.' No sooner did I breathe a sigh of relief than my vision and hearing abruptly warped into unfamiliar territory.”

Strange disturbances of perception conjured by ketamine are often consistent with the positive symptoms of schizophrenia, such as hallucinations and delusions. But schizophrenia is also characterized by negative symptoms, such as an inability to feel pleasure or produce normal speech, as well as cognitive symptoms like deficits in short-term memory. Does ketamine recapitulate these symptoms, too?

It does. In fact, the realization that ketamine simulates nearly all the symptoms of schizophrenia in adults—while having relatively little effect on children—allowed researchers to see past a long-held theory for how schizophrenia works. Antipsychotic drugs that treat the positive symptoms of schizophrenia work by blocking receptors for dopamine, a neurotransmitter involved in reward and attention. Naturally, psychiatrists formulated a “dopamine hypothesis,” which states that schizophrenia is caused by excessive levels of dopamine.

Recently, ketamine research has sent psychiatrists back to the drawing board. The medical community has long realized that dopamine-blocking antipsychotics cannot treat negative and cognitive symptoms of schizophrenia. Does the ability of ketamine to simulate all three categories of schizophrenia symptoms offer a patch for the flawed dopamine hypothesis?

Ketamine’s main targets in the brain are not dopamine receptors, but rather receptors for glutamate, the brain’s chemical messenger for excitatory impulses. Naturally, this finding has inspired a “glutamate hypothesis” of schizophrenia: Rather than being caused by excess dopamine levels, schizophrenia might be caused by deficient glutamate levels.

If only the story was so simple. Alas, the plot thickens as we consider ketamine’s promiscuous nature. Rather than acting only as a blocker of glutamate receptors, ketamine also flirts shamelessly with receptors for brain chemicals such as acetylcholine and endorphins. At least one study has even purported to show that ketamine binds to the same dopamine receptors as antipsychotic drugs like haloperidol. Yet the absence of similar reports by other scientists has cast doubt over such a ketamine-dopamine liaison. Instead, the new relationship can be summarized with two words: “It’s complicated.”

This doesn’t mean ketamine won’t offer the sorts of insights into schizophrenia that researchers have hoped for. The road ahead is foggy and narrow. To forge ahead, we need more experiments, more research, and more data. One thing appears clear: both ketamine and schizophrenia exploit a weakness in the adult brain that children have protected. As a child’s brain develops, many synaptic connections between neurons are pruned each day like bad flowers on a rose bush. If too many connections are pruned, the network becomes unstable in early adulthood; the slightest nudge threatens to knock it into the depths of psychosis. A fully pruned network is the apex from which the young adult brain may tumble. Ketamine is that little nudge that shows how the brain falls.

A powerful drug is emerging from its obscure past, ready to show us the true nature of one of psychiatry’s most debilitating mental illnesses. Ostracized by the careful anesthesiologist, ignored by the tripping counterculture, ketamine’s relevance is at last imminent. And an independent discovery has hastened this turn of the tide: ketamine offers promise as an antidepressant that acts not within weeks (like Prozac) but mere hours. The potential to treat suicidal patients is immense, beckoning more research and more data.

Looking closer, we realize ketamine is not schizophrenia in a vial. Ketamine is neither a potion nor a poison, but a lens into the opaquest corners of the brain. Only its careful use by scientists will yield the secrets of the mind’s most troubling disorders.

References

Frohlich, J, Van Horn, J.D. (2016) Chapter 60: Ketamine and the Dissociatives: Comparisons with Schizophrenia. In Preedy VR (Ed.) Neuropathology of Drug Addictions and Substance Misuse, Volume 2: Stimulants, Cub and Dissociative Drugs, Hallucinogens, Steroids, Inhalants and International Aspects. Part III: Dissociative Drugs, Section C: Structural and Functional Aspects. Pages 649-660. Academic Press.

Frohlich, J., & Van Horn, J. D. (2014). Reviewing the ketamine model for schizophrenia. Journal of psychopharmacology, 28(4), 287-302.

Kapur, S., & Seeman, P. (2002). NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D2 and serotonin 5-HT2receptors--implications for models of schizophrenia. Molecular psychiatry, 7(8), 837.

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