Ketamine use linked to liver and other problems in HIV-positive people

Ketamine is a drug used as an anaesthetic in emergency departments of hospitals and by veterinarians. It can cause hallucinations, feelings of euphoria and floating, being in a dream-like state, out-of-body and other experiences. As a result, it is also used as a club or party drug. In such settings, ketamine has acquired the nickname “Special K.” Depending on the dose and how it is taken, ketamine can have a relatively swift onset of action, occurring within one to 30 minutes after ingestion. Ketamine’s effect can last for up to three hours.

Ketamine can also cause paranoia, confusion, dizziness and feeling disconnected from the body. Some of these effects may be responsible for accidents and subsequent injuries reported among ketamine users.

Exposure to ketamine can become addictive, as users strive to repeat their initial experience with the drug. This can lead to more frequent usage and the consumption of larger doses over time. There have been growing reports of ketamine toxicity when used recreationally, affecting the bladder and causing pain, difficulty urinating, frequent urination, infections, blood in the urine and urinary incontinence. Kidney injury from ketamine has also been reported.

Reports from the UK suggest that the use of ketamine as a party drug is increasing. As networks of substance users are connected, trends seen in the UK may also be occurring in Canada and other high-income countries.

Doctors in Brighton, UK, have reported two cases of injury to the liver and bile ducts that have been linked to ketamine use. In both cases the affected men were HIV positive and it appeared that the concentration of ketamine in their bodies may have been affected by their HIV treatment.

Case 1

The first case was a 38-year-old man with what doctors described as “a nine-year history of well-controlled HIV infection.” His CD4+ count was nearly 800 cells and his viral load less than 40 copies/ml for the past nine years. His HIV medications were as follows:

abacavir + lamivudine (a fixed-dose combination called Kivexa)

darunavir (Prezista) + ritonavir (Norvir)

He was taking these additional medicines:

salbutamol for asthma

perindopril for managing blood pressure

He sought medical care because of the onset of these symptoms:

nausea

vomiting

chronic abdominal pain

He told doctors that he had episodes of these symptoms four times in the past year.

His intake of alcohol was modest and he did not inject or use other substances.

Ketamine

The man disclosed that he had initially been taking ketamine orally at relatively low doses two years ago. However, in the past year, he had increased his intake to between 1 and 2 grams per day (self-prescribed), he said, to help deal with the abdominal pain he experienced.

Laboratory and other testing

Analyses of his blood found elevated levels of the following liver enzymes:

ALT (alanine aminotransferase) – three times the upper limit of normal

ALP (alkaline phosphatase) – nearly two times the upper limit of normal

Technicians conducted tests for viral hepatitis, autoimmune or inherited liver conditions but did not find anything remarkable.

Magnetic resonance imaging (MRI) scans of his abdomen did not find any tumours, though it appeared that his common bile duct was inflamed. Doctors inserted a small tube with a camera to assess his digestive tract but did not find any lesions or gallstones. However, they did notice that the muscle tissue (sphincter) controlling the opening and closing of his common bile duct was swollen, so they removed the sphincter.

Quitting ketamine

After this surgery, doctors advised the man to quit ketamine. He did and within four weeks his symptoms and abnormal laboratory tests resolved. Repeated medical investigation for 18 months after he stopped using ketamine has not found any return of his symptoms or abnormalities in his digestive tract.

Case 2

Another HIV-positive man, 25 years old, sought care three times in eight weeks because of recurring abdominal pain and nausea. He had been HIV positive for three years, with a CD4+ count of 154 cells and a viral load of 6,356 copies/ml. These results occurred despite the prescription of his HIV treatment, as follows:

tenofovir + FTC (a fixed-dose combination called Truvada)

lopinavir-ritonavir (Kaletra)

Bactrim/Septra (trimethoprim-sulfamethoxazole)

Doctors reported that this man’s ability to take his medicines exactly as directed was “poor.” In reviewing his medical records, they noticed that he had disclosed “occasional ketamine use” three years ago. However, in the past year the man told doctors that he had increased his intake to between 1 and 2 grams, taken two to three times weekly. He did not inject ketamine or other street drugs. However, his intake of alcohol was very high.

Lab tests of his blood revealed elevated levels of liver enzymes as follows:

ALT – 10 times the upper limit of normal

ALP – three times the upper limit of normal

GGT (gamma-glutamyl transpeptidase) – 15 times the upper limit of normal

Based on these results and his disclosed alcohol intake, doctors advised him to reduce his alcohol consumption.

He followed their advice but his symptoms persisted. Additionally, he was also experiencing recurring bacterial infections of his urinary tract (caused by E. coli).

As with the first case, investigation did not reveal viral hepatitis, autoimmune or inherited liver disease.

Analysis of his urine found blood and ketamine.

Scans and procedures

Ultrasound and MRI scans of the man’s abdomen detected a swollen common bile duct. Visual inspection of his digestive tract and his liver and gall bladder did not find any tumours or gallstones or any conventional cause of his problems. Doctors removed the sphincter at the end of his common bile duct. Liver biopsy did not reveal any scarring or tissue damage from alcohol.

Doctors changed his HIV treatment to this combination:

Truvada + darunavir-ritonavir (all drugs taken once daily to help his adherence)

A month after his scans and procedures, the man returned for medical care because of abdominal pain. Doctors then advised him to stop using ketamine. Two months after stopping ketamine, the pain and elevated liver enzymes resolved. Subsequent blood tests and MRI scans have not detected any abnormalities.

Noteworthy

Putting together the data collected from interviews—focusing on periods when ketamine was used as well as the development of symptoms—doctors noted that “regular ketamine use” was linked to abdominal pain.

Other doctors have reported liver injury and swollen common bile ducts in HIV-negative patients who have used ketamine recreationally. In such cases, on average, the onset of abdominal symptoms took about four years to appear.

However, in the case of the two HIV-positive men, regular use of ketamine occurred for one year before the appearance of symptoms.

The faster onset of symptoms in HIV-positive men may have happened because they were taking ritonavir. This medicine can slow down the activity of enzymes in the liver that process and break down drugs and substances. This property of ritonavir is useful and is used by doctors because a small dose of ritonavir is often prescribed with another HIV protease inhibitor in these combinations commonly used today in Canada and other high-income countries:

atazanavir (Reyataz) + ritonavir

darunavir + ritonavir

lopinavir + ritonavir

The effect of ritonavir in such cases is to raise (or boost) and maintain the concentration of the other protease inhibitor in the blood. Using ritonavir in this way often allows for once-daily dosing of protease inhibitors.

The Brighton doctors suggest that ritonavir may have elevated the amount of ketamine in the blood of their HIV-positive patients, resulting in a faster onset of toxicity compared to HIV-negative people. The increased levels of liver enzymes detected in blood tests may have occurred because ketamine can cause liver injury.

Withdrawal management

The two men in this report were apparently able to overcome their addiction to ketamine without difficulty fairly quickly. However, other long-term ketamine users may require assistance such as: temporary prescription of medicines for managing pain in their bladder and other places; gradually reduced doses of anti-anxiety medicines to cope with ketamine withdrawal; counselling about breaking free from addiction to help support mental and emotional healing.

Caution needed

Many medicines prescribed as part of HIV treatment—including but not limited to protease inhibitors and non-nukes (NNRTIs)—and many other prescription and non-prescription medicines have the potential to influence the concentration of other drugs in the body by affecting the activity of enzymes in the liver. This effect is called a drug-drug interaction. This is particularly the case with street drugs.

Since the release of potent anti-HIV therapy (commonly called ART or HAART) in the late 1990s, doctors have documented cases of serious, sometimes fatal, toxicity caused by substances interacting with ritonavir and possibly other protease inhibitors.

By building a trusting relationship with their healthcare team, HIV-positive patients should, whenever possible, disclose all the drugs that they are taking—both prescribed and non-prescribed (including street or club drugs), as well as supplements and herbs so that their doctor, nurse and pharmacist can advise them about possible interactions and ways to stay healthy.

“Special M”

Other researchers in the UK have reported that a street drug related to ketamine, called MXE (methoxetamine) or “Special M” by users, has appeared. This new drug has similar effects to ketamine but takes longer to exert its effects when inhaled or swallowed. This carries the risk that some users may inadvertently overdose. There are claims associated with MXE that this analogue of ketamine is “bladder friendly.” However, researchers in the UK who study substance use warn that it is too early to be certain about the effects of MXE on the urinary tract. As MXE has not been formally tested in people, its safety on the brain and other parts of the body are unknown.

—Sean R. Hosein

REFERENCES: