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Report on the risk assessment of GHB in the framework of the joint action on new synthetic drugs PDF Print E-mail
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Reports - EMCDDA Report on the risk assessment of GHB
Written by Richard Dennis   

On 17 April 2000, the Portuguese Presidency of the European Council formally
notified gamma-hydroxybutyric acid (GHB) for risk assessment under
Article 4 of the joint action on new synthetic drugs of 16 June 1997.

A meeting of the Scientific Committee of the EMCDDA, extended with
experts nominated by the Member States and representatives of the
European Commission, Europol and the European Agency for the Evaluation
of Medicinal Products (EMEA), to assess the health and social risks — as well
as the possible consequences of prohibition — of GHB was held on 25 and
26 September 2000.

The meeting considered the following documents:

‘Review of the pharmacotoxicological data on gamma-hydroxybutyric
acid (GHB)’, report to the EMCDDA;

‘Public health risks of GHB: epidemiological evidence’, EMCDDA;

‘Sociological and criminological evidence on the risks of GHB’, EMCDDA;

Europol’s contribution to the risk assessment of GHB; and

EMEA’s contribution to the risk assessment of GHB.

These documents, in conjunction with further information and comments
from the expert participants, formed the basis of the risk assessment reported
below.

1. Chemical description

Gamma-hydroxybutyric acid refers to the protonated form whereas gammahydroxybutyrate
refers to the deprotonated form of the carboxylic acid
moiety. The abbreviation GHB refers to both of these chemical names. Other
chemical names include oxybate, 4-hydroxybutanoic acid, and 4-hydroxy-
butyric acid. GHB can also form various salts (for example, sodium and
potassium salts) which are soluble in water and methanol.

GHB was initially developed as an anaesthetic agent but was later found to
be a naturally occurring compound in mammalian brain and tissue, existing
as a by-product of GABA metabolism and putative neurotransmitter. Major
chemical and metabolic precursors include gamma-butyrolactone (GBL) and
1,4-butanediol which are both rapidly converted to GHB in the body.

Registered names for GHB are: Alcover, Somsanit, Gamma-OH.

GHB has various street names including ‘liquid ecstasy’, ‘liquid E’, ‘GBH’,
‘easy lay’, ‘scoop’, ‘liquid X’, ‘fantasy’ and ‘cherry meth’.

2. Pharmaceutical description

Pharmaceutically, GHB is available as sodium gamma-hydroxybutyrate in
liquid form. Recreationally, GHB is available as either a liquid formulation
or as a powder (either loose or in tablets or sometimes in a capsule).

GHB is used therapeutically in anaesthesia, in the treatment of alcohol withdrawal
and in long-term sedation, and is being investigated for the treatment
of narcolepsy-associated cataplexy. It is a licensed medicine for human use in
only four Member States. GHB is not authorised for veterinary use. There are
no known reported industrial uses of GHB, however, GBL and 1,4-butanediol
have many uses in various industrial processes.

3. Health risks

3.1. Individual health risks

(a) Acute effects: Evidence relating to the activity of GHB on neurotransmitter
systems is largely contradictory. However, it is believed that GHB binds to
GABA B and GHB-specific receptors. It blocks dopamine release at the
synapse and produces an increase in intracellular (neuronal) dopamine. This
is followed by a time-dependent or dose-dependent non-functional leakage
of dopamine from the neurone. In addition, GHB does not appear to be a
monoamine oxidase (MAO) inhibitor.

GHB has been reported to lengthen slow-wave/delta sleep without a
decrease in oxygen consumption while the respiratory centre remains sensi-
tive to carbon dioxide. It also induces anaesthesia but does not provide pain
relief. An increase in growth hormone and prolactin release has been reported
in one study of six human subjects.

GHB can cross the blood-brain barrier and is rapidly absorbed and
metabolised, possessing a plasma half-life of approximately 20 minutes. It
also has a steep dose-response curve, where a small increase in the dose can
cause sedation as opposed to just nausea. Following an oral dose, effects
usually occur after 15 minutes and can last up to 7 hours, depending on the
dose.

At present there are no animal or human data concerning reproductive toxicity,
neurotoxicity or the mutagenicity and carcinogenic potential of GHB.
However, animal and human studies indicate that GHB toxicity is dosedependent
and can result in nausea, vomiting, hypotonia, bradycardia,
hypothermia, random clonic movements, coma, respiratory depression and
apnoea.

Other depressant or sedative drugs (e.g. opiates, benzodiazepines, alcohol
and barbiturates) and possibly other psychoactive compounds (e.g. amphetamine)
can exacerbate the toxic effects of GHB ingestion.

Reported subjective effects of GHB use include: euphoria, hallucinations,
relaxation and disinhibition.

(b) Clinical effects: GHB has been associated with 11 deaths in the EU
between September 1995 and January 2000: four in the United Kingdom,
four in Sweden, two in Finland and one in Denmark. Two deaths have been
reported in Norway. Deaths involving solely GHB appear to be rare. The
majority of these cases have involved the ‘recreational’ abuse of GHB for its
subjective euphoric (‘high’) effects, primarily by young adults. The mode of
GHB abuse frequently involves the use of other drugs such as alcohol or
MDMA.

Non-fatal hospital admissions associated with GHB are difficult to assess as
GHB analysis is not routinely performed by hospital toxicology laboratories.
However, there have been at least 200 reported GHB overdose cases in
Europe (in particular in Sweden, the United Kingdom, the Netherlands,
Denmark, Belgium, Finland, Spain and Norway). Clinical management of
such patients can be quite difficult, posing risks to both patients and staff.

(c) Dependence: There have been few studies regarding the dependence
potential of GHB. However, during studies involving administration of GHB
to patients at varying concentrations, no dependence has been observed at
low doses of GHB. At prolonged high doses, however, physical dependence
as evidenced by a withdrawal syndrome has been noted in some cases and
included symptoms of insomnia, muscular cramping, tremor and anxiety.

(d) Psychological effects: There is limited published data concerning specific
psychological effects of GHB either acutely or chronically, therefore the
exact effect of GHB on cognition, mood and psychomotor ability is unclear.
However, the effects of GHB on the central nervous system have implications
for the ability to drive and to operate machinery.

3.2. Public health risks

(a) Availability and quality: Preparations containing GHB have marketing
authorisation (4) in four countries: in Austria and Italy for alcoholic craving
and in France and Germany as an anaesthetic. Growing concern about nonmedical
use of GHB in Europe as well as in the United States and in Australia
has prompted a number of these countries to introduce new and more stringent
controls on GHB. The disruption of overt supply has lead to distribution
patterns similar to illicit drug networks.

More discreet methods have therefore been adopted by suppliers of GHB
alongside the appearance of substitutes for GHB in name or content as well
as the development of a home-made ‘kitchen-sink’ GHB industry due to the
fact that it is easily manufactured and no special equipment is required for
this process. However, there have been some reports of burns to mouths due
to high caustic soda content in home-made preparations.

In dance settings, GHB is frequently sold in liquid form in small 3 ml plastic
bottles containing approximately 3 g of GHB, where it is used socially for
relaxation, mild euphoria or post-party for sleep. Pharmaceutical-grade GHB
is also available through the Internet, catalogue sales and specialist shops in
some countries. This market has recently been curtailed by legislation and
bad publicity.

On the basis of the available information, it is generally suggested that a
0.5 g dose be taken for relaxation and disinhibition, a 1g dose for euphoric
effect, and a 2–3 g dose for deep sleep.

(b) Knowledge and perception of GHB among users: Although media reporting
of GHB is limited, information is available to the populations who use
recreational drugs, smart drugs or body-building drugs, via associated social
networks. A vast number of Internet sites and newsgroups promote the use
of GHB for a wide rage of purposes which include: inducing sleep, mood
enhancement, treatment of drug and alcohol withdrawal, sexual enhancement,
body-building and anti-ageing.

(c) Prevalence and patterns of use: There are no data specifically on prevalence
or patterns of the use of GHB and at present there is little evidence that
GHB is used on a wide scale in any Member State.

Anecdotal and Internet reports suggest that use of GHB may not be confined
to recreational party drug settings. Some sub-populations appear to use GHB
for desired specific effects. Internet postings and outreach workers suggest
that GHB can also be used as a substitute for alcohol or drugs to achieve inebriation
whilst avoiding detection tests in treatment, the workplace, and for
driving. Some police sources and media cover have expressed concern
about the ease with which GHB may be used to facilitate sexual assault, but
the extent of this is unclear. In this regard, it should be noted that GHB dissolves
easily and is colourless, odourless and may be difficult to taste. It can
therefore be taken unobtrusively in social settings where drinks are served.

(d) Characteristics and behaviour of users: There is limited information available
concerning the characteristics and behaviour of users. Within recreational
drug settings, anecdotal reports from youth media and drug workers
suggest that the negative effects of GHB may lead to a negative image for the
drug. However, it should be noted that the comparatively low price of GHB
provides a cheap alternative to alcohol and when used for illicit purposes the
effects of GHB are much closer to those produced by alcohol, cannabis and
benzodiazepines, than they are to MDMA and other stimulant drugs. The
physical incapacity and unconsciousness resulting from a relatively small
increase in GHB doses demonstrates that health risks in relation to road traffic
or operating machinery are high.

(e) Indicators of health consequences: There is no information on the health
consequences for the general population. GHB has been associated with 11
deaths in the EU between September 1995 and January 2000: four in the
United Kingdom, four in Sweden, two in Finland, and one in Denmark. In
addition, two deaths have been reported in Norway.

Non-fatal hospital admissions associated with GHB are difficult to assess as
GHB analysis is not routinely performed by hospital toxicology laboratories.

However, there have been at least 200 reported GHB overdose cases in
Europe (in particular in Sweden, the United Kingdom, the Netherlands,
Denmark, Belgium, Finland, Spain and Norway).

(f) Context of use: An important factor with regard to context of use is the
lack of reliable indications of dose accompanying sales of GHB at ‘street
level’. However, the steep dose response curve of GHB makes it risky for
recreational use even where dose is both accurately measured and known.
The combination of GHB with other drugs, particularly alcohol and other
sedative drugs, also substantially increases the risks related to taking GHB.

4. Social risks: sociological/criminological aspects

4.1. Sociological aspects

(a) Social consequences: The social consequences for the user are mainly
related to the steep dose-response curve and unpredictable dose resulting in
loss of physical control and consciousness, and to the ingestion of caustic
soda.

(b) Consequences for the social behaviour of the user: There is anecdotal evidence
of clumsy behaviour, vomiting and loss of consciousness in dance settings
which is regarded unfavourably by music promoters, club owners and
youth media journalists.

(c) Other social consequences: The ease with which GHB can be acquired
or manufactured allows more consumer power than that usually found in
illicit drug markets in the EU. The use of GHB to induce relaxation and sleep
promotes the concept of illicit drug use for self-medication purposes rather
than hedonism.

The similarity to alcohol regarding effects and route of administration may
facilitate diffusion, i.e. in the absence of major value conflicts about use. In
view of the pharmacological effects and known health risks, there are implications
for a number of social institutions: the media, drug outreach workers,
research institutes, hospital emergency departments, community drug
and rape services, and the police.

A range of factors such as low price, ease of availability and administration,
lack of information, the need for sedation following heavy stimulant use, and
careless media coverage, increase the probability of GHB diffusion and consequent
harm. Other factors, such as antisocial effects, relatively short dura-
tion, and its low-status image, mitigate against widespread diffusion and so
decrease the probability of harm.

4.2. Criminological aspects

No Member State has information on large-scale production, trafficking and
distribution of GHB. Seizures of GHB in the EU are very small when compared
to seizures of ‘regular’ types of synthetic drugs such as amphetamine,
MDMA and MDA.

Three Member States — France, the Netherlands and the United Kingdom —
have information on illicit production of GHB in their country. Production in
France seems to be incidental and limited to one ‘kitchen’-type facility.

Two Member States — the Netherlands and the United Kingdom — report
on the role of organised crime in the production, trafficking and distribution
of GHB. In both countries producers of GHB are thought to also be involved
in the production of controlled drugs, with dealers possibly having links to
ecstasy producers. They are individuals with a criminal background or members
of small groups, rather than criminal networks.

A particular consequence that has been linked with GHB by some media
and police reports is the potential for GHB to be used surreptitiously for sexual
purposes, possibly including rape.

5. Possible consequences of prohibition

5.1. Legal status

An analysis of the legal status of GHB in the 15 Member States shows that
the drug is controlled under the misuse of drugs legislation in six of them:
Belgium, Denmark, France, Ireland, Italy and Sweden. It is similarly controlled
in Norway. GHB is controlled by the Medicines Act in Austria,
Finland, Germany and the Netherlands. In the United Kingdom where its
manufacture and supply fall within the scope of the Medicines Act, consideration
is being given to controlling GHB under the misuse of drugs legislation.
In Greece and in the Netherlands, it is subject to monitoring.

The precursor GBL (gamma-butyrolactone) is currently on the voluntary
monitoring list of the Drug Precursors Committee of the European
Commission. The other precursor of GHB — 1,4-butanediol — is not on this
list. The list is circulated to the chemical industry, members of which are
asked to notify any suspicious enquiries and transactions in the chemicals to
the competent authorities. There are no formal controls on the chemical.

5.2. Possible consequences of prohibition

The possible consequences of prohibition were discussed at the meeting and
included the points listed below.

The EMEA drew attention to the existence on the market of authorised
medicines containing GHB in four Member States and the possibility of an
application for Orphan Drug Designation for GHB being submitted in light
of the submission to the US-FDA (US-Food and Federal Administration).
The EMEA also highlighted the fact that changes in the conditions of marketing
authorisations for GHB containing medicinal products proposed by
the meeting should be dealt with at national level.

The meeting was informed of the results of a critical review of GHB by the
32nd WHO Expert Committee on Drug Dependence which recommended
to the Commission on Narcotic Drugs (CND) that GHB be listed in
Schedule IV of the 1971 United Nations Convention on Psychotropic
Substances. It was pointed out that it was for the CND to decide whether
or not to accept this recommendation.

It was reported by a number of participants that Member States who had
subjected GHB to control had noted a reduction in intoxications involving
GHB. It was pointed out that following a decision not to control GHB in
one Member State, a reduction in non-fatal emergencies was also
observed. Systematic data, however, was unavailable in both instances.

Concern was expressed about the possible impact of prohibition on the
licit production of GBL and 1,4-butanediol because of the high level of
production and the wide range of industrial applications for both compounds.

Concern was also expressed about the negative effects of prohibition on
black market conditions.

Considerable debate took place about the possible methods of control.
One opinion was that medicines legislation (5) was sufficient because it
could permit seizure of products and prevent both advertising and sale of
such products. Other participants were of the view that medicines legislation
was insufficient and that stronger measures of control were necessary.
It was pointed out that such strong measures of control did not mean that
the consumer should be punished. Doubt was expressed as to whether
medicines legislation would be effective where no marketing authorisations
were in place and it was recommended that this point should be further
investigated.

6. Conclusions

The Scientific Committee of the EMCDDA, extended with experts from the
Member States, and representatives of the Commission, Europol and the
EMEA, have considered the health and social risks as well as the possible
consequences of prohibition of GHB and in accordance with Article 4 of the
joint action, submit the following conclusions:

6.1. GHB is not a new synthetic drug. It has therapeutic potential and preparations
containing it are registered medicines in four Member States. It
is also used in recreational settings.

6.2. GHB has anaesthetic and sedative properties. In recreational use, the dose
margin between the desired and the serious adverse effects is narrow.
Because of the effects of the drug, the levels of fatal and non-fatal emergencies
and reports of dependency, GHB is considered to pose significant
risks to health. The possible involvement of GHB in drug-assisted
sexual assaults was of concern even though the extent of this involvement
is unclear.

6.3. An opinion which received significant support at the meeting was that
this substance should be subjected to more stringent control measures
than the medicines legislation.

6.4. Another opinion was that control through medicines legislation is sufficient.

6.5. The meeting noted that the precursor GBL was rapidly converted to GHB
both within and outside the body whereas the precursor 1,4-butanediol
was rapidly converted within the body. Noting that GBL is included in
the monitoring programme under the Precursor Regulations, the meeting
recommended that the Drug Precursors Committee set up under
Article 10 of Regulation 3677/90/EEC and Directive 92/109/EEC should
strongly consider the inclusion of 1,4-butanediol within the monitoring
system.

6.6. The Committee recommended that Member States should consider convening
an expert group to consider the role of GHB and other drugs in
cases of sexual assault.

6.7. The meeting noted that biological samples could contain levels of GHB
in circumstances where there was no evidence of GHB consumption
and recommended that this phenomenon should be the subject of further
study with a view to establishing guidance for best practice in the
handling and analysis of biological samples containing GHB.

6.8. The meeting highlighted the need to target objective information on
GHB to existing and potential users as well as to key professional
groups.

Lisbon, 26 September 2000

(4) Classification for the supply of medicinal products for human use is regulated by Directive
92/26/EEC of 31 March 1992, and Article 12 of Directive 75/319/EEC of 20 May 1975 regulates
through the Committee for Proprietary Medicinal Products (CPMP) the suspensions,
withdrawal or variations to the terms of the marketing authorisation, in particular to take
account of the information collected in accordance with Pharmacovigilance.

(5) That is to say EU Regulation based upon Council Directive 65/65/EEC of 26 January 1965,
as amended by Directives 83/570/EEC, 87/21/EEC, 89/341/EEC and 93/39/EEC, as well as
Decisions of the Court of Justice of the European Communities, especially Case C-112/89.

 

Our valuable member Richard Dennis has been with us since Monday, 20 February 2012.

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