Depression V: Background For Ketamine, a Psychedelic Antidepressant


Ketamine is thought by some to be the biggest breakthrough in the treatment of depression in the last 50 years.  However to provide broader perspective on ketamine’s use as an antidepressant, this post looks at its original role as an anesthetic and why it can also be a recreational drug of abuse.  In addition, this post looks at ketamine’s mechanism of anesthetic action, the 2 different ketamine variants, and the various ways ketamine can be administered.  The next post will look at ketamine’s role as an antidepressant.

Ketamine as an anesthetic.

Ketamine is a relatively short-acting synthetic drug, FDA-approved as an anesthetic in 1970.  Ketamine’s action is terminated by liver enzymes that degrade it into metabolites that are excreted, mainly in the urine.  At the appropriate dosage, ketamine has the anesthetic properties of rendering a patient both unconscious and amnestic to events while anesthetized.  At the same time, ketamine has some other desirable characteristics that distinguish it from most other anesthetics.  These include an unusually good safety profile; little respiratory or circulatory depression; and analgesia, reducing the need for pain medication.

At the same time, ketamine has its downsides.  When fully anesthetized, the patient strangely appears as if they might be awake, with their eyes open and with noticeable muscle tone.  Since some body movement is possible, ketamine is less desirable when movement is detrimental to medical procedures.  In addition, ketamine has the same mode of action as phencyclidine, an anesthetic drug removed from the market in 1955 because it can produce a temporary, dissociative, trance-like, catatonic psychosis indistinguishable for schizophrenia.  Ketamine can also produce these symptoms but, because it is less potent and shorter acting, the effects are typically less severe.  Around 10-20% of patients experience hallucinations and delusions upon emerging from ketamine anesthesia, although the effects usually wear off quickly without lasting effects.  However, ketamine can cause more prolonged psychiatric symptoms in psychiatrically predisposed individuals. Interestingly, this psychotomimetic effect is more pronounced in adults than children and becomes more likely to occur after early-adulthood, the time when schizophrenic symptoms are typically first noticed.  (In fact, the phencyclidine/ketamine “psychosis” has contributed to our understanding of the neurological underpinnings of schizophrenia).  Ketamine’s potential psychiatric side effect certainly provides a caution for its use.

An additional downside is that at the subanesthetic doses used for treating depression, ketamine is rewarding and potentially addictive.  This effect, in part, underlies its illicit recreational use as a club drug (some street names: K, Special K, Super K, Vitamin K, Donkey Dust, Cat Valium, Ket, and Wonk).  However, ketamine is also used recreationally for its hallucinogenic and dissociative properties.  Unfortunately, chronic abuse can lead to liver and kidney toxicity.  Ketamine can also be used as a date rape drug.  Historically, ketamine’s illicit uses have been diverted mainly from veterinary supplies.

Nonetheless, because ketamine’s desirable properties sometimes outweigh its downsides, it remains a valuable anesthetic.  For example, because of its safety and reduced need for accompanying analgesia, ketamine was used extensively as an emergency field anesthetic during the Vietnam war.   Nowadays ketamine is used as a pediatric anesthetic since children are unlikely to experience psychiatric side-effects.  Because ketamine doesn’t depress breathing, it is also used with asthmatics, individuals suffering from obstructive airway issues, or if ventilation equipment is not available.  Ketamine is also sometimes used as a preanesthetic to prepare patients for surgery which allows its psychoactive effects to wear off by the time the patient awakens, and also sometimes for its analgesic properties.  Ketamine is used even more extensively as a first-line veterinary anesthetic.

Ketamine anesthesia works by binding the NMDA receptor.

Ketamine is a pharmacologically “messy” drug that binds numerous receptors in the brain. However, ketamine’s highest affinity is for the N-methyl-D-Aspartate (NMDA) receptor, a type of glutamic acid (i.e glutamate) receptor, which mediates its anesthetic, analgesic, and amnestic effects.  As seen in figure 1, The NMDA receptor is an ionotropic receptor in which 4 proteins join together in the cell membrane to provide both an extracellular glutamate binding site as well as an ion channel through the membrane.  The 4 proteins are of 2 types: R1 and R2.  In addition, several different genes code for the different subtypes of the R2 protein resulting in a variety of ways of assembling the NMDA receptor.  The interchangeable R2 subtypes, at least in part, provide redundancy so that if one gene is defective, functional receptors can still be formed.  In addition, differential R2 gene expression in different parts of the brain might also serve to optimize local NMDA functioning.  It is worth noting that biological systems possessing redundant “backup systems” are generally those most crucial to survival.

Figure 1: Schematic representation of an NMDA receptor showing the binding sites for glutamate and ketamine as well as other molecules that can modulate the ability of glutamate to open the ion channel. Double click on graphic to enlarge.

In the receptor’s resting state, the relatively nonselective ion channel (seen in blue) is closed and requires glutamate binding to open. However, several preconditions must first be met including that the membrane be depolarized and that glycine be attached to its binding site.  The ability of glutamate to open the ion channel can also be modulated by other molecules such as magnesium, zinc, and ethanol attaching to their respective binding sites as seen in Figure 1.

Once preconditions are met, glutamate binding opens the ion channel and 4 of the small ions in biological fluids (Ca++, Na+, K+, and Cl)  are free to move down their concentration gradients, through the ion channel, and across the membrane.  Ca++ and Na+ are more prevalent in the extracellular fluid, so they move to the inside of the cell, while K+ and Cl, more prevalent in the cytoplasm, do the opposite.  The  electrical charges of the ions crossing the membrane come close to cancelling each other out and make only a negligible contribution to neuron excitability.  However the entry of  Ca++ is critical for activating intracellular enzymes underlying the brain’s capacity to form new glutamate synapses as well as strengthening existing ones.  This “neuroplasticity” is incredibly important as it provides the physical basis for our capacities for learning, memory, and ultimately cognition!  As a result, the NMDA receptor is among the most studied receptors in the brain.

Ketamine exerts its effects by attaching to its binding site inside the ion channel (seen in Figure 1), physically blocking the channel and preventing glutamate’s ability to initiate ion flow.  The immediate effects are very disruptive to brain functioning and cause ketamine’s anesthetic, analgesic, amnestic, and psychotomimetic effects.  However, after these immediate effects have subsided, ketamine’s longer term effects somehow reduce depression symptoms even more effectively than the first-line SSRI antidepressants!  More about that in the next post.

Different ketamine enantiomers.

Figure 2: The two mirror-image enantiomers of ketamine.

Ketamine is synthesized in pharmaceutical laboratories as a “racemic” mixture consisting of equal amounts of two chemically identical, but spatially different molecules (called “enantiomers”), termed R-ketamine and S-ketamine.  The binding of these mirror-image molecules to brain receptors is analogous to putting your hands into a glove.  Although either hand can be put into either glove, the right hand fits best in the right glove and the left in the left.  The same is true for these 2 enantiomers, each fits certain brain binding sites better than the other.

Once the racemic mixture is synthesized, it is possible to chemically separate the two enantiomers, although the process is both difficult and expensive.  The S-enantiomer (also called esketamine) is the more potent anesthetic and analgesic because it more effectively blocks ion flow through the NMDA ion channel.  Other differences from R-ketamine are that the S-ketamine is cleared from the body quicker, produces less impairment of cognition, less loss of concentration, fewer psychotic reactions and less agitated behavior.

The S-version recently recently received FDA approval as an antidepressant under certain conditions (more about that in the next post).  However, the racemic mixture containing both enantiomers remains the most common formulation for both anesthetic and antidepressant use.

How is ketamine is administered?

Ketamine is available as a white powder or as an aqueous solution and can be administered intravenously, intramuscularly, subcutaneously, orally, rectally or intranasally.  These methods differ significantly in first-pass metabolism and in percentage absorption into the blood.  First-pass metabolism (from enzymes in the digestive system and liver) intervenes between drug administration and entry into general circulation and contributes to differences in bioavailability (percentage of administered drug that actually gets into the blood).  First-pass metabolism also introduces ketamine metabolites into general circulation, some of which also have anesthetic and antidepressant properties.  This contribution has not been well studied in humans and could have implications for dosage.

For depression, ketamine is most often administered as an aqueous solution via intravenous (IV) infusion over a period of around 40 minutes.  Unlike the other methods, IV administration results in 100% bioavailability and no first-pass metabolism which allows for precise dosage control.  The slow rate of IV infusion is also thought to minimize some of ketamine’s acute side effects. An additional advantage is that the dosage can be adjusted during the course of administration.  The other methods can also be effective, but do not allow for such dosage adjustments and are also less predictable because of individual variability in first-pass metabolism and absorption.  There is no antidote for ketamine toxicity, however, all methods are generally considered safe in the dosages used for treating depression.

Next Post.

The next post looks at ketamine’s role as an antidepressant












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