Gamma-hydroxybutyrate abuse: pharmacology and poisoning and withdrawal management

GHB shows good absorption after oral administration. In a study with eight male healthy volunteers receiving 12.5, 25, and 50 mg/kg of GHB (29) its time to reach maximum blood concentration (T_max) ranged between 20 and 60 min and correlated with the dose (25, 30, and 45 min in average, respectively). On the other hand, the maximum blood concentration achieved (C_max) did not vary considering the received doses (23, 23, and 20 μg/mL respectively), which suggests that GHB absorption is limited.

In another study with 12 healthy volunteers (six men and six women) (30) who received a single 25 mg/kg dose of GHB mean urine T_max was 1 h and C_max 67.6 μg/mL, whereas blood T_max was 24.6 min and C_max 48.0 mg/L.

The mean volume of distribution varies from 192 to 741 mL/kg in healthy volunteers and from 225.9 to 307 mL/ kg in patients with narcolepsy and liver failure (37, 38, 39). No significant variations have been observed between the sexes or associated with concomitant food intake. GHB can cross the placental barrier. Its capacity of binding plasma proteins is reduced.

Over 90 % of the administered dose of GHB undergoes hepatic metabolism by several enzymatic pathways and is closely related to GABA metabolism. The main route is oxidation by GHB dehydrogenase to produce succinic semialdehyde, which is further oxidised into succinic acid. Further metabolism via the Krebs cycle transforms it into carbon dioxide and water (Figure 2) (37, 38, 39).

Figure 2

According to many animal studies, GHB excretion is non-linear. The same was observed in the eight volunteers after oral administration of a therapeutic GHB dose (29).

In the study with 12 healthy volunteers referred to above (30), urinary GHB concentration dropped below the endogenous cut-off of 5 mg/L in eleven of them six hours after administration, which suggests that only a small percentage (from 0.6 to 2.5%) is excreted in urine (35, 36, 37).

Acute GHB poisoning can pose a medical challenge because it starts with unspecific symptoms shared by other acute poisonings with depressants.

In a retrospective study of 88 patients (61 men and 27 women, mean age 28 years) treated for acute GHB poisoning 59 ingested other substances as well, mainly alcohol (34 patients) and amphetamines (25 patients). In 53 patients the Glasgow Coma Scale (GCS) score was below 9. Of them, 25 patients had the GCS score 3 and 28 from 4 to 8 (39). The most common clinical signs were bradycardia (present in almost all patients with the GCS score under 8), frequently accompanied by hypotension, then hypothermia (21 patients), and acute respiratory acidosis. Tachycardia and hypertension were early clinical manifestations, usually occurring 15–30 min after ingestion (39).Almost all patients regained consciousness spontaneously within five hours of GHB ingestion.

There where GHB is taken with other substances, clinical presentation and management require more attention, because these other substances can “mask” some of the symptoms (2, 40).

Considering that GHB is a depressant acting on the central nervous system, the effects of acute poisoning can range from sleepiness to deep coma. They usually occur 15–50 minutes after ingestion and are short lived, which mainly depends on the dose. In most cases, neurological effects resolve within six hours. As a rule, management is supportive (29).

Table 1 shows neurological symptoms of acute GHB poisoning.

The most common respiratory manifestation is bradypnoea, which is often accompanied by type 2 respiratory failure.

The most common gastrointestinal symptoms are vomiting (present in 20–55 % of cases, as reports vary in this respect), abdominal pain, and sialorrhoea (40, 41, 42, 43).

To distinguish between exogenous and endogenous GHB, a threshold commonly used for samples taken from living patients is 10 mg/L in urine, and 5 mg/mL in blood. GHB is not stable in either and its concentration increases with time after sampling. In post-mortem blood, endogenous GHB concentrations can be much higher (see above) (44, 45, 46, 47).

There are many methods for GHB detection in urine and blood. The most common is gas chromatography (GC) coupled with mass spectrometry (MS) or flame ionisation detection (FID). In addition, a number of liquid chromatography tandem mass spectrometric (LC-MS/MS) methods have recently been developed, which detect GHB after solid phase extraction (SPE) (48, 49, 50).

Therapy is essentially supportive and based on continuous monitoring of vital signs. Particular attention is paid to the cardiovascular and respiratory symptoms described earlier in the text.

Intubation is indicated in unconscious patients who are vomiting to prevent aspiration and choking.

Many substances such as (naloxone, flumazemil, or GABA_B antagonists have been tried as potential antidotes, but there is no sufficient scientific evidence to support their routine application (51, 52, 53, 54, 55).

The clinical presentation of GHB withdrawal syndrome is similar to other withdrawal syndromes, alcohol and benzodiazepine in particular. This is the reason why it can sometimes be very difficult to distinguish between them, especially if GHB tests are negative or could not be run (4, 60, 61, 62, 63).

Considering the limited time of GHB action and its rapid elimination, signs and symptoms of GHB withdrawal syndrome soon become apparent, usually within 1–6 h after the last administration.

The withdrawal symptoms, however, can last for quite a while, 14 days or even more. They include anxiety, different degrees of depression, cognitive deficits, persistent insomnia (56, 57), tremor, and tachycardia, which is often accompanied by hypertension. Other common clinical manifestations include confusion, disorientation, and paranoia. They usually last between three and 21 days (58).

Most people with dependency have been taking GHB and/or its analogues/precursors for less than two years, and the first manifestations appear as soon as 8–13 weeks into the use.

In a retrospective study (59) of eight patients with chronic GHB use, the first clinical manifestations of withdrawal appeared as quickly as 1–6 h after the administration of the last dose, and symptoms lasted between 5 and 15 days. Within 24 h from the last dose manifestations included severe anxiety and insomnia, moderate nausea, and vomiting. In the following five days, anxiety and insomnia continued, accompanied by delirium, confusion, and visual hallucinations. Seven to 15 days after the last dose, moderate anxiety, confusion, insomnia, and visual hallucinations persisted only episodically. Delirium was more frequent in patients who had been taking GHB every 30 min to 8 h than in those taking it every 1–24 h.

Case studies presented in medical literature provide general guidelines based on experience and common symptoms with other withdrawal syndromes, but there are no formal detoxification protocols for GHB or its analogues. Withdrawal therapy is based on benzodiazepine and when benzodiazepine alone is not effective against severe symptoms, it can be combined with barbiturates, baclofen, and antipsychotics (4, 60, 61, 62, 63).

McDonough et al. (63) have come up with an algorithm (Figure 3) which takes into account the number of GHB/ analogue consumption in terms of amount and frequency per day. If a patient has been taking three or more doses or more than 30 g of GHB a day, the therapy should include diazepam (80–150 mg) for the first seven days. If the patient is in delirium, diazepam doses should be upped, and if the symptoms persists over 24 hours, adjuvant pentobarbital is recommended. If a patient has been taking less than three doses or 30 g of GHB/analogue a day, administration of lower doses of diazepam (20–40 mg) should suffice (63).

Figure 3