While ketamine may not have been available for clinical use until 1970, its origins begin two decades earlier. In the 1950’s the pharmaceutical company Parke-Davis was trying to develop a new anesthetic that could reduce pain. The company ended up developing CI-395, otherwise known as PCP. While PCP was an effective pain reliever, it also induced severe mind-altering effects and production was eventually stopped in 1978 after it started to be used recreationally as “angel dust”. To create a version of PCP without the severe mind-altering effects, ketamine was developed in the 1960s, and while the analgesic effects were less effective than PCP, so were the psychogenic effects (9). Ketamine’s effects were tested on prisoners in 1964, where the term “dissociative anesthesia” was coined to describe its psychoactive effects (10).

The recreational use and abuse of ketamine started during the Vietnam war and increased in 1978 following the publication of two books which highlighted the psychedelic effects that ketamine had on the author. The books ‘Journeys Into The Bright World’ by Marcia Moore and ‘The Scientist’ by John Lily played a large role in introducing recreational ketamine use to the public. The increase in ketamine abuse led to it being deemed a class III substance in 1999 under the US Controlled Substances Act (11).

While recreational use of ketamine in the 1970s was in line with the psychedelic movement, during the 1980s, it was more popular as a party drug (often snorted) and was often seen as a cheaper alternative toMDMA. Ketamine gained a reputation for inducing the “k-hole” experience, which describes the feelings of strong dissociation one experiences with a large enough ketamine dose.

More recently, research has demonstrated ketamine’s therapeutic potential as a treatment for depression. Discussions around ketamine’s use have changed from that of an anesthetic or party drug to a potential treatment for sufferers of major depression.

In recent years, there has been more focus on the therapeutic potential of ketamine, specifically its ability to decrease pain, inflammation, and help with addiction. Considerable clinical evidence shows that ketamine can induce rapid antidepressant effects in severely depressed individuals, especially those that have not responded to conventional therapies, and those that are on the brink of suicide.

Ketamine’s potential to treat depressive episodes and suicidality, in particular, is incredibly promising. Ketamine can cause a rapid antidepressant-like effect that has even been shown to be successful in patients with depressive disorders that are resistant to conventional treatments. These antidepressant effects can last from a week to months, with a rapid onset within hours of treatment, with higher doses of ketamine alleviating depressive symptoms for a longer time span.

• A meta-analysis of 21 studies examined the effects of ketamine infusion on depressive symptoms over time in major depressive disorder (MDD) and bipolar disorder (BD) (12).  A significant antidepressant effect from a single ketamine infusion  was observed from 4 h to 7 days, there was no significant difference at 12–14 days post infusion. The peak response for MDD occurred at 24 hr post infusion, whereas the peak response for BD occurred at 7 days.
  
  
• In one study 24 participants with treatment resistant depression (TRD) had six intravenous (IV) infusions of ketamine (0.5 mg/kg) administered open-label three times weekly over the course of 12 days, and monitored for relapse for up to 83 days from the last infusion (13). The overall response rate at study end was 70.8%. There was a large mean decrease in depressive scores at two hours following the first ketamine infusion that was largely sustained for the duration of the infusion period. Among responders, relapse time following the last ketamine infusion ranged widely from 4 to 83 days, with the median time being 18 days.
  
  
• In one double-blind, placebo-controlled study, researchers set out to examine the effect of ketamine on patients ages 18-70 with treatment-resistant depression (14). These patients were selected based on achieving less than 50% improvements in their depression symptoms after at least two depression treatment courses during their current depressive episodes. The patients were randomly assigned different doses of ketamine that were given as a single dose and then were assessed at days zero, one, three, five, six, 14, and 30. The results showed that the standard and high doses of ketamine were significantly more effective than placebo for reducing depressive symptoms. Ketamine treatment was well tolerated when compared to the placebo, except for increased transient blood pressure levels and dissociative symptoms with higher ketamine doses. Overall the study demonstrated that the most effective ketamine doses for depression treatment were 0.5 mg/kg and 1.0 mg/kg, while lower doses were ineffective.
  
  
• A review of clinical trials involving ketamine treatment for depression and suicidal ideation found that ketamine was associated with reduced scores over four separate depression and suicidal ideation rating scales (15). Overall repeated suicidal assessments over minutes and days indicated that ketamine treatment reduced suicidal thoughts compared to placebo.

Ketamine has similar pain-relieving effects to fentanyl, an opioid prescribed for pain.  Recently, however, there has been much interest in the role of ketamine as a treatment for chronic pain management, and doctors have begun to prescribe low doses of this medication to patients with chronic pain conditions such as complex regional pain syndrome (CRPS).

• A double-blind, randomized, controlled trial compared the effects of fentanyl (1.5 μg/kg) and ketamine (1 mg/kg) on pain levels of children aged three to 13 with isolated limb injury (16). Fentanyl and ketamine both caused similar reductions in pain, although ketamine was associated with more minor side effects.
  
  
• A review of 11 studies investigating low dose ketamine treatment for pain when compared to opioids found that ketamine was effective for pain conditions and has minimal side effects when administered at lower levels that do not induce dissociative states of mind (17). Ketamine’s pain-relieving effects were also shown to be comparable to opioids, which are known to have a high risk for abuse and other adverse effects.
  
  
• A meta-analysis of IV ketamine to treat patients suffering from chronic pain found that it provides significant short-term analgesic benefit (18).
  
  
• Complex regional pain syndrome (CRPS) is a painful, debilitating neurological condition. A meta-analysis was conducted to evaluate the efficacy of ketamine infusion in the treatment of CRPS. The study suggested that ketamine infusion provided clinically effective pain relief in short term for less than 3 months. More research is need to the long-term effectiveness of ketamine treatment for CRPS (19).

Despite ketamine itself having a potential for abuse, research has shown that ketamine treatment may help prolong drug abstinence and reduce cravings.

• A review of the research into ketamine’s ability to treat addiction found that ketamine treatment can prolong abstinence from alcohol, heroin and reduce cravings in cocaine users (20).
  
  
• Maladaptive reward memories (MRM), which are associations between environmental stimuli (ex. smell of beer) and drug reward, play an important role in overconsumption disorders to harmful drugs and alcohol. A recent study found that ketamine disrupted MRMs in hazardous drinkers, and reduced the reinforcing effects of alcohol and long-term drinking levels. Ketamine, when given in a specific window may “rewrite” these memories providing a novel approach to treating substance abuse disorders (21)

Ketamine also has anti-inflammatory properties which may help quell the chronic inflammation associated with depression and help relieve depressive symptoms (22), and may aid in healing after surgery.  

• One study found that ketamine managed to significantly reduce the production of proinflammatory cytokines in the blood, such as TNF-alpha, IL-6, and IL-8 (23).
• A review found ketamine demonstrated the ability to significantly reduce inflammation without affecting local healing processes. The anti-inflammatory effects of ketamine may occur through blocking the NMDA receptor (24).
• In one study, researchers examined the effects of giving patients ketamine before abdominal surgery. The results showed that patients had significantly lower levels of the inflammatory cytokines IL-6 and TNF-alpha when compared to controls (25).

While ketamine holds potential as a treatment for a range of symptoms, it can still induce side effects that need to be considered before use. While most of the side effects of ketamine are temporary and dose-dependent, there is always the risk of permanent damage with long term abuse.

Recreational use of ketamine is particularly dangerous due to the risk of the drug being cut with other substances. Ketamine should only be used for therapeutic purposes under the supervision of a qualified medical professional.

It is important to carefully choose your ketamine treatment provider , as not all providers provide a high quality of care.  Be sure your ketamine provider works collaboratively with mental health practitioners (26), as this combination (ketamine treatment + psychotherapy) provides the highest likelihood of successful treatment.

Ketamine can have serious side effects (27) which include (but are not limited to):

• Seizures, coma, death- it is extremely dangerous to combine ketamine with central nervous system (CNS) depressants like alcohol, benzodiazepines or GHB
• Respiratory blockage
• Loss of motor coordination which may lead to accidents
• Psychological dependency
• Neuroses or other mental disorders from frequent use
• Severe urinary tract, kidney, and bladder damage with chronic or high dose use
• Neurotoxicity can occur from ketamine use in the form of Olney lesions. These lesions typically do not last longer than 24 hours, although high doses of ketamine could cause long-term complications (28).
• Serious side effects may result from unknown compounds used to cut street ketamine

Click here for additional info on ketamine side effects.

Contraindications

People with the following conditions should avoid using ketamine:

• High blood pressure (ketamine use may increase the risk of uncontrolled hypertension, myocardial infarction, aneurysms)
• Hypersensitivity
• Pregnant or breastfeeding women
• Persons with raised intraocular pressure (ketamine can further increase IOP)
• Chronic alcoholics and the acutely-intoxicated (may cause death)
• Acute porphyria
• Patients with schizophrenia or other psychiatric disorders (may exacerbate symptoms) (29)

You can read more about potential adverse drug interactions here.

Addiction Potential

Ketamine can lead to substance abuse (30). Frequent use of ketamine can impair learning, memory, and cause addiction due to its modulation of dopamine release. While there is evidence to suggest that ketamine could help to treat addiction, ketamine treatments must be administered under the guidance of qualified psychotherapists.

The ‘out-of-body’ effects of ketamine are short-lived, and tolerance develops

quickly, forcing users to seek larger and more frequent doses to experience the same effects. (31)  Withdrawal symptoms such as anxiety, shaking, and palpitations can occur after frequent use stops (32). 

Long-Term Effects

Research has shown that long-term ketamine use is associated with an impairment of spatial memory and altered hippocampal activation. These results were based on the observation of 11 frequent ketamine users (33). There is no current evidence showing that single doses of ketamine have long-lasting adverse effects on users. With that being said, frequent and chronic abuse of ketamine is associated with negative structural changes to the brain.

Chronic ketamine use can result in irreversible damage to the urinary tract, bladder, and kidneys (34).  The clinical symptoms of ketamine bladder syndrome include: painful bladder, increased frequency of urination, incontinence, blood in the urine, a blocked upper tract and death of the cells in the kidney. There is no treatment available for ketamine-associated lower urinary tract destruction.  In the late stages, reconstructive surgery of the urinary system is the only option to relieve symptoms. Stopping ketamine use upon the first signs of is the best chance to resolve symptoms.

Harm Reduction Measures

• Know why you are using it
• Avoid taking other substances while using ketamine
• If you have been taking ketamine and have symptoms of a urinary tract infection, stop use and seek medical care
  
  
• Illicit ketamine can be cut with other substances – testing kits can give you a better idea about what is in the batch but does not guarantee safety
  
  
• Always take under the care of medical professionals
  
  
• Monitor vital signs (blood pressure, pulse, breathing, oxygen saturation) and cardiac function when using ketamine
  
  
• Do not drive or use heavy machinery for 24 hours after ketamine use (35)

For more information on Ketamine safety and harm reduction