Risks of Combining GHB and Ketamine
The combination of GHB and ketamine is extremely dangerous and potentially lethal, with significantly increased risk of severe respiratory depression, coma, and death compared to either drug alone. 1
Critical Safety Data on Combined Use
Co-use of GHB with ketamine increases the risk of major adverse effects or death by 3.43 times (adjusted prevalence ratio = 3.43,95% CI: 1.57-7.46) compared to ketamine use alone. 1 This represents one of the highest risk combinations identified in poisoning surveillance data.
Mechanism of Dangerous Interaction
The combination creates a pharmacokinetic and pharmacodynamic interaction that amplifies toxicity through multiple pathways:
- Ketamine significantly decreases GHB's total and metabolic clearance, leading to higher and more prolonged GHB blood levels than expected. 2
- Ketamine prevents the compensatory respiratory response to GHB, specifically blocking the increase in tidal volume that normally occurs, resulting in severe minute ventilation decline. 2
- This respiratory interaction produces significantly worse respiratory depression than either drug alone. 2
Life-Threatening Effects of the Combination
Respiratory Complications
- Severe respiratory depression is the primary cause of death, as ketamine blocks GHB's normal compensatory breathing mechanisms. 2
- While ketamine alone typically causes only mild respiratory depression, and GHB causes dose-dependent respiratory depression progressing to coma, their combination creates synergistic respiratory suppression. 3
Cardiovascular Effects
The combination produces unpredictable cardiovascular effects:
- GHB causes hypotension and bradycardia at higher doses. 3
- Ketamine normally increases heart rate, blood pressure, and cardiac output through sympathetic stimulation. 4
- In the presence of GHB intoxication, ketamine's expected cardiovascular stimulation may be blunted or reversed, potentially leading to profound hypotension. 4
Neurological Complications
- Prolonged unconsciousness and coma with significantly increased sleep time compared to GHB alone. 2
- Amnesia for the entire period of drug effect, making self-rescue impossible. 3, 5
- Ketamine's emergence reactions (hallucinations, delirium, agitation) occur in 10-30% of cases and may be more severe or prolonged. 4, 5
- Seizures can occur with either drug and may be more likely in combination. 3, 6
Additional Risk Factors
Polydrug Use Context
- Polydrug use was present in 53% of ketamine-related deaths and 33.4% of poisoning cases. 7, 1
- The combination is frequently used in recreational "club drug" settings where additional substances (alcohol, benzodiazepines, opioids) may be present, further compounding risks. 8
Detection and Treatment Challenges
Critical timing issues complicate emergency care:
- GHB is undetectable in urine after only 12 hours or less, making diagnosis difficult. 3
- Ketamine is detectable for 24-72 hours but may not be included in standard toxicology screens. 3
- Effects occur rapidly: GHB within 15 minutes, ketamine within 20 minutes. 3
Use as Incapacitating Agents
Both drugs are used to facilitate sexual assault due to their sedative, amnestic, and incapacitating properties. 3, 5 The combination produces:
- Profound sedation and passivity. 3
- Complete amnesia for events. 3, 5
- Inability to resist or call for help. 3
Clinical Management Considerations
If this combination is suspected, immediate emergency care is required:
- MCT (monocarboxylate transporter) inhibition with L-lactate or AR-C155858 can increase GHB clearance and improve respiratory depression even in the presence of ketamine. 2
- GABAB receptor antagonism with SCH50911 improves GHB-induced respiratory depression when ketamine is co-ingested. 2
- Naloxone is not effective for this combination. 2
- Supportive care with airway management and ventilatory support is essential, as bag-valve-mask ventilation or intubation may be required. 3