Oral ketamine for depression

Five uncontrolled, open-label studies were found that investigated the antidepressant properties of oral (including sublingual) ketamine. ^{Reference Paslakis, Gilles, Meyer-Lindenberg and Deuschle24–Reference De Gioannis and De Leo28} A small study (n = 4) found depression relief in patients with treatment-resistant unipolar or bipolar depression who were given up to 1.25 mg/kg oral (S)-ketamine for 2 weeks. ^{Reference Paslakis, Gilles, Meyer-Lindenberg and Deuschle24} In one study on palliative healthcare, ^{Reference McNulty and Hahn25} the effects of ketamine on pain, anxiety and depression were assessed. This case report described a hospice patient who was treated daily with 40 mg oral ketamine, which relieved all three complaints. Another hospice-based study described two severely ill and depressed patients who showed significant improvements lasting 1 or 2 weeks after a single oral dose of 0.5 mg/kg ketamine. ^{Reference Irwin and Iglewicz26} A more recent hospice-based study administered daily oral ketamine (0.5 mg/kg) over a 28-day period to patients in hospice care who had depressive symptoms. Eight out of 14 patients completed the trial and showed significant improvement in pain and depression with few side-effects. ^{Reference Irwin, Iglewicz, Nelesen, Lo, Carr and Romero27} De Gioannis & De Leo treated two patients with chronic suicidal ideation (and at least two significant past suicide attempts) with a solution of ketamine ingested with a flavoured drink. The maximum dose used was 3 mg/kg of ketamine. Both patients achieved sustained remission from suicidal ideation. ^{Reference De Gioannis and De Leo28}

Lara et al reported on 10 mg sublingual ketamine, administered once, or every 2, 3 or 7 days for a total of up to 20 doses. They observed improved mood in 20 out of 26 patients with treatment-resistant unipolar or bipolar depression. The antidepressant effects outlasted the acute side-effects, which primarily concerned light-headedness, and which did not include euphoria or dissociation. ^{Reference Lara, Bisol and Munari29}

Clearly, these are only first indications of possible antidepressant effects of oral ketamine, as all of these studies were very small and uncontrolled, and the quality of the evidence was low.

Dosing regimen and treatment duration of ketamine in chronic pain

Figures 1 and 2 show that both for depression and pain most studies used the i.v. route of application. Expressed in daily oral racemate equivalent dose, the doses for depression are in the lower range compared with studies that investigated analgesic use. Also, the graphs show that ketamine as an antidepressant is generally given for shorter durations (1–32 days) than ketamine as an analgesic. Finally, it shows that on average i.v. ketamine is given for a shorter duration than oral ketamine. Studies with oral ketamine, where pain was the primary indication, administered ketamine once ^{Reference Kaviani, Khademi, Ebtehaj and Mohammadi30} or for as long as 660 days, ^{Reference Villanueva-Perez, Cerdá-Olmedo, Samper, Mínguez, Monsalve and Bayona31} with most studies in the range of 20–80 days.

The doses used in the pain studies we analysed differed from the 0.1 daily oral racemate equivalent dose via oral administration ^{Reference Kaviani, Khademi, Ebtehaj and Mohammadi30} to 62.5 mg/kg/day intravenously. ^{Reference Klepstad, Borchgrevink, Hval, Flaat and Kaasa32} It is not possible to establish a dose–response association, but the majority of the pain studies we analysed describe ketamine as effective in reducing pain, even with low oral doses. The exceptions are six studies that used i.v. ketamine, ^{Reference Kapural, Kapural, Bensitel and Sessler33–Reference Barreveld, Correll, Liu, Max, McGowan and Shovel38} which did not lead to any reduction in the pain scores. Although the study conducted by Kapural et al used a high dose (daily oral racemate equivalent dose of 21.5 mg/kg/day), it did not achieve an improvement in long-term pain scores in patients with high opioid requirements. ^{Reference Kapural, Kapural, Bensitel and Sessler33}

Some studies in patients with chronic pain (that could be progressive or related to terminal illness) showed that patients required higher doses over time. For instance, Villanueva-Perez et al administered 30 mg of oral ketamine every 8 hours to a patient with complex regional pain syndrome type 1, increasing this dose weekly by 5 mg until a maximum dose of 60 mg/6 h was reached. This patient kept this last dose for more than 2 years with significant improvement mainly in the first 17 months. ^{Reference Villanueva-Perez, Cerdá-Olmedo, Samper, Mínguez, Monsalve and Bayona31} Vick & Lamer achieved significant improvement in pain, allodynia and hyperalgesia in one patient with central post-stroke pain at a dose of 50 mg oral ketamine three times per day. This treatment lasted 3 months. ^{Reference Vick and Lamer39} This is in line with preclinical and clinical studies on anaesthesia and studies on ketamine misuse, that suggest that tolerance may develop. ^{Reference Pouget, Wattiez, Rivaud-Péchoux and Gaymard40–Reference Cumming45}

Clearly, the dosage is directly related to the bioavailability of ketamine. With oral administration the bioavailability is generally low, because of extensive first-pass metabolism. ^{Reference Clements, Nimmo and Grant21} Reported values of oral ketamine in adults are in the range of 17–24%. ^{Reference Clements, Nimmo and Grant21–Reference Yanagihara, Ohtani, Kariya, Uchino, Hiraishi and Ashizawa23,Reference Chong, Schug, Page-Sharp, Jenkins and Ilett46} A study by Brunette et al in children showed the highest bioavailability (45%), and used a nasogastric tube and a 10 mL water flush, ^{Reference Brunette, Anderson, Thomas, Wiesner, Herd and Schulein47} but Yanagihara et al also used a water flush (100 mL) and found a bioavailability of only 20% in adults. ^{Reference Yanagihara, Ohtani, Kariya, Uchino, Hiraishi and Ashizawa23} Other factors underlying the variability after oral dosing may include the formulation (tablet or solution, ketamine concentration), state of the stomach, dietary enzyme induction, and individual differences in cytochrome phenotype. It should be noted that interindividual pharmacokinetic variability is common to oral administration in general ^{Reference Zimm, Collins, Riccardi, O'Neill, Narang and Chabner48–Reference Di, Kadva, Johnston and Silman50} and has also been described for currently prescribed antidepressants. ^{Reference Lund, Thayssen, Mengel, Pedersen, Kristensen and Gram51} Intranasal and sublingual ketamine administration have been reported to yield 45% and 30% bioavailability, respectively, ^{Reference Yanagihara, Ohtani, Kariya, Uchino, Hiraishi and Ashizawa23} but interindividual variability has been described for these routes of ketamine administration as well. ^{Reference Weber, Wulf, Gruber and Biallas52,Reference Rolan, Lim, Sunderland, Liu and Molnar53} Ketamine absorption after intramuscular injection has been described as more rapid, with a bioavailability of 93%. ^{Reference Clements, Nimmo and Grant21}

Safety and abuse potential

The most common side-effects of i.v. ketamine are psychotomimetic effects and dissociative symptoms, ^{Reference Morgan, Muetzelfeldt and Curran54} which correlate with high initial plasma levels and may thus be less pronounced in oral administration. ^{Reference Bowdle, Radant, Cowley, Kharasch, Strassman and Roy-Byrne55} Feeling ‘high’ after ketamine is also dependent on plasma levels. ^{Reference Bowdle, Radant, Cowley, Kharasch, Strassman and Roy-Byrne55} Other known side-effects are confusion, dizziness, euphoria, elevated blood pressure and increased libido, although all of these usually dissipate within 2 h of i.v. infusion. ^{Reference Liebrenz, Borgeat, Leisinger and Stohler56}

Ketamine neurotoxicity has been described in preclinical studies, ^{Reference Malinovsky, Cozian, Lepage, Mussini, Pinaud and Souron57} but this was suggested to be due to the presence of the preservative chlorobutanol rather than to the ketamine itself. ^{Reference Malinovsky, Lepage, Cozian, Mussini, Pinaudt and Souron58} Without preservative, ketamine can induce neurotoxicity when injected in very high doses into the subarachnoid space. ^{Reference Gomes, Garcia, Ribamar and Nascimento59} The study by Sun et al showed that i.v. ketamine given to adolescent cynomolgus monkeys at a dose of 1 mg/kg in saline for 6 months might also produce permanent and irreversible deficits in brain function through the neurotoxic effect caused by the activation of the apoptotic pathway in the prefrontal cortex. ^{Reference Sun, Li, Li, Zhang, Liu and Jiang60} This appears to be in contrast with studies in humans where ketamine was given in similar or higher doses with few mentions of cognitive problems. ^{Reference Diazgranados, Ibrahim, Brutsche, Newberg, Kronstein and Khalife10,Reference Zarate, Brutsche, Ibrahim, Franco-Chaves, Diazgranados and Cravchik11} It should be noted that currently available clinical studies with i.v. ketamine used only one or few applications. In the studies involving pain, patients were given ketamine more often but mostly did not have the ‘peak effect’ of i.v. application. Prolonged ketamine misuse has been associated with white matter changes, ^{Reference Edward Roberts, Curran, Friston and Morgan61} memory changes, ^{Reference Freeman, Morgan, Pepper, Howes, Stone and Curran62} neurocognitive impairment ^{Reference Morgan, Muetzelfeldt and Curran54,Reference Morgan and Curran63} and reduced well-being. ^{Reference Morgan, Muetzelfeldt and Curran54} Finally, inflammation and damage to the ureter and bladder are well documented in very heavy ketamine users who consume daily amounts of 1 g by inhalation and for prolonged periods of months or even years. ^{Reference Shahani, Streutker, Dickson and Stewart64,Reference Tsai, Cha, Lin, Tsao, Tang and Chuang65} Notably, in these studies daily doses were substantially higher than those used in clinical studies. Calculated in daily oral racemate equivalent dose, these users had approximately 80 mg/kg/day, which is 2.2 times higher than the highest daily oral racemate equivalent dose found in a study where ketamine was used to treat depression. ^{Reference Correll and Futter66}

The majority of the pain and depression studies retrieved by our search did not report the side-effects of oral ketamine as a major burden in treatment maintenance. Side-effects commonly mentioned were: dizziness, hallucinations, nausea, vomiting, drowsiness, confusion, light-headedness, headache, somnolence and anxiety. An exception to this is the study by Kannan et al involving nine patients with neuropathic pain, which stated that the beneficial effects in the management of intractable neuropathic pain were limited in some patients by adverse events such as nausea, vomiting, loss of appetite, drowsiness, sedation and feeling of unreality. ^{Reference Kannan, Saxena, Bhatnagar and Barry67} Haines & Gaines found that ketamine caused an analgesic response in only 14% of individuals and described that the adverse events (light-headedness, dizziness, tiredness, headache, nervous floating feeling and bad dreams) limited the use of ketamine in almost half of their patients. ^{Reference Haines and Gaines68} Side-effects commonly mentioned in studies using oral ketamine were light-headedness or dizziness, nausea, vomiting, drowsiness, confusion, headache, somnolence, and having bad dreams. Hallucinations and paranoid feelings were reported in only one patient, ^{Reference Villanueva-Perez, Cerdá-Olmedo, Samper, Mínguez, Monsalve and Bayona31} and memory impairment and dysuria were reported in one study on 12 patients. ^{Reference Bredlau, McDermott, Adams, Dworkin, Venuto and Fisher69}

Very-low-dose sublingual administration of 10 mg (approximately equivalent to 0.036 mg/kg i.v.) was not associated with euphoria, or psychotic and dissociative symptoms. ^{Reference Lara, Bisol and Munari29} In some studies, increased blood pressure was recorded when a benzodiazepine was administered concomitantly. ^{Reference Mercadante, Arcuri, Tirelli and Casuccio70,Reference Schwartzman, Alexander, Grothusen, Paylor, Reichenberger and Perreault71} The reported adverse events were usually limited to the ketamine treatment phase and did not persist after ketamine discontinuation (see online Tables DS1 and DS2 for more details on these side-effects).

Another concern with ketamine is its misuse potential, which has been demonstrated in both animals and humans. ^{Reference Beardsley and Balster72,Reference Klein, Calderon and Hayes73} Ketamine has been used as a street drug since the 1960s, probably because of its rapid effects, its low cost and its specific psychotropic effects, such as hallucinatory and dissociative experiences (e.g. ‘melting into the surrounding’, ‘out-of-body experiences’) as well as ‘giggliness’. ^{Reference Corazza, Assi and Schifano74,Reference Muetzelfeldt, Kamboj, Rees, Taylor, Morgan and Curran75} Multi-drug users who have used ketamine in large doses recreationally have also expressed concerns about its addictive properties. ^{Reference Muetzelfeldt, Kamboj, Rees, Taylor, Morgan and Curran75} No studies compared different routes of ketamine administration directly, but the misuse potential is generally found to be higher with i.v. administration or inhalation that produces much more rapid and intensive effects compared to oral administration. ^{Reference Argoff, Stanos and Wieman76} In line with this, the psychedelic effects of ketamine are directly related to plasma concentrations. ^{Reference Bowdle, Radant, Cowley, Kharasch, Strassman and Roy-Byrne55} Importantly, in the pain studies mentioned earlier, addiction or misuse were not described as side-effects. Still, it is clear that these unwanted effects should be balanced against the possible beneficial properties of ketamine.