Lecture 15 - Inhalants and GHB Flashcards
1
Q
What are inhalants?
A
- Inhalants are ‘volatile’ liquids/gases (readily vaporize)
- They are a diverse range compounds with wide-ranging effects
- Volatile solvents: liquid at room temperature, give off fumes
- Aerosols: contain solvents/propellants
- Gases: can be sniffed/inhaled/sprayed into the mouth
- All euphoriants (can result in a ‘high’) – sedatives/’rush’
- Can buy/sell legally (household items) but not intended to be inhaled
2
Q
What are some commonly abused inhalants?
A
Picture in notes
3
Q
What are behavioural effects of inhalants?
A
- Snorted, sniffed, or gas mask so cross blood-barrier quickly, get to brain quickly and cause rapid highs and declines
- Acute: euphoria, disinhibition, stimulation then lightheadedness, drowsiness (like alcohol)
- Heavy exposure: slurred speech, ataxia, lethargy, hallucinations, sometimes delusions
- Very high doses: anesthesia, coma
4
Q
What are the origins of consumption of inhalants?
A
- Use of inhalants dates to early human history. Ancient inhalant use is known primarily because it related to mystical practices of which there is written record. Spiritual leaders inhaled fumes from incense, oils, or perfumes to alter consciousness
- Nitrous oxide was regarded as a cheap substitute for alcohol and was popularized by the British scientist Sir Humphry Davy. He held nitrous oxide parties and coined the word “laughing gas” in 1799
5
Q
How do inhalants work?
A
- Because they have only relatively recently been used for recreational purposes, less is known about the neurochemical activation of these drugs compared to other recreational drugs
- How are these effects mediated in the brain?
- Rapidly absorbed - fat soluble
- Distribute widely around the brain - especially striatum, thalamus, deep cerebellar nuclei
- Human and animal inhalation studies have shown high toluene concentrations in adipose tissue, bone marrow, adrenals, highly vascular tissues (for example, the kidney and liver), brain and blood (Environment Agency, 2009)
- Prolonged exposure can cause white matter lesions
- Often, neurological damage is irreversible
6
Q
Why are inhalants addictive?
A
- Dopamine is the substrate of normal reward systems and is common factor across a broad spectrum of addictive drugs
- Mesolimbic pathway is implicated in natural reward and drug abuse (The dopamine pathway responsible for rewards, motivation, and emotions)
- Is there evidence that this pathway is activated when consuming inhalants, such as toluene?
- Anaesthetized rats toluene and measured firing in ventral tegmental area (VTA; Riegel & French (1999)
7
Q
Describe evidence that inhalants are reinforcing
A
- Funada et al. (1992)
- Study conducted on mice where mice are placed in two connected chambers
- Toluene is distributed in one of the two chambers
- Mice show preference for toluene chambers than non-toluene chamber, where before administration of the substance they showed no preference of either chamber
- The same brain areas are activated in response to toluene as alcohol, opiates and cannabis
- Would dopamine antagonists stop toluene being rewarding?
8
Q
What are the theories of inhalant effects on CNS excitability?
A
- Inhalants enhance function of GABA & glycine inhibitory receptors
- Inhalants inhibit excitatory NMDA glutamate receptors (like ketamine)
- So similar to alcohol - reduce CNS excitability
9
Q
What happens with chronic use of inhalants?
A
- Short term – slurred speech, runny nose or nosebleeds, tiredness (fatigue), ulcers or irritation around their nose and mouth
- Long term – confusion, poor concentration, depression, irritability, hostility, paranoia
- Neurological damage: toluene can cause permanent damage to the nervous system, leading to conditions such as peripheral neuropathy and encephalopathy
- Respiratory issues: inhaling toluene can irritate the respiratory tract and lead to chronic respiratory problems
- Cardiovascular problems: toluene abuse can result in irregular heart rhythms and increase the risk of sudden cardiac arrest
10
Q
What are some adverse effects of inhalants?
A
- Sudden Sniffing Death Syndrome (SSDS) can be caused from use of inhalants leading to sudden rapid heart rhythms or irregular heart rhythms (typically fatal – medical aid ineffective because of how sudden the onset it)
- Deadly Blood Disorder (methemoglobinemia) can result from inhaling nitrates or poppers which is where the blood becomes physically changed so that it can’t deliver oxygen to the body
- Health care providers are reporting increases in deaths and hospitalizations related to intentional ingestion or inhalation of nitrite products for recreational use, including sexual experience enhancement
- Commonly referred to as “poppers,” these products contain chemical substances like the prescription medication, amyl nitrite, which is prescribed for the relief of chest pain. However, poppers have not been evaluated by the FDA for safe use. These products are not safe to ingest or inhale
11
Q
What are some legal issues with inhalants?
A
- Solvent misuse isn’t illegal - although it’s illegal in England and Wales for shopkeepers to sell intoxicating substances to those ‘likely’ to be inhaling them
- Under Scottish law you can be prosecuted for ‘recklessly’ selling substances to any age group if you suspect they’re going to inhale them
- Since October 1999, the law makes it an offence to supply gas lighter refills to anyone under the age of 18. This law applies to the whole of the UK
12
Q
What are some social issues with inhalants?
A
- In the US about 6% of children have tried inhalants by 4th grade, and usage peaks between 7th and 9th grades - for 12-year-olds more popular than marijuana (especially true in Alaska!)
- In Australia there is a long-standing problem with petrol sniffing in indigenous (aboriginal) communities; in some remote areas they have started using a non-sniffable fuel called Opal to combat this
- In South Africa a glue manufacturer greatly reduced the n-hexane content in their glue products to reduce danger for street children, after reports of some being left paralyzed
13
Q
Describe tolerance and withdrawal to inhalants
A
- Tolerance increased dose required for same effect
- Withdrawal – symptoms include nausea, tremors, irritability, sleep disturbance
14
Q
What is GHB?
A
- GHB = gamma hydroxybutyrate
- GHB is closely related to GABA – gamma-aminobutyric acid, an inhibitory neurotransmitter
- Chemists were trying to design GABA analogues, as a CNS depressant (new sedatives or anesthetics)
- They are used clinically to treat cataplexy (sudden loss of muscle control experienced by narcoleptics)
- Initially sold commercially in US health food shops as nutritional supplement for body builders – to reduce fat and increase muscle
- “Cherry meth”, “Georgia home boy”, “liquid X”
- But reported adverse effects then resulted in a ban
- One of the two most common date rape drugs alongside Rohypnol
- GHB (gamma-hydroxybutyrate) is not a newly-discovered designer drug
- It is a natural product of human metabolism. It is a carbohydrate found in abundance in our diet as animal meat contains GHB, as does wine and small citrus fruits
- It is also biologically synthesized from GABA (gamma-aminobutyric acid), an amino acid that is structurally similar to GHB
15
Q
What are some behavioural effects of GHB?
A
- Relaxation, drowsiness, sociability, euphoria, lack of inhibition, increased sex drive, heightened sensitivity to touch dizziness, vomiting, tremors, tunnel vision, loss of coordination (ataxia), confusion, irritation and agitation, hallucinations, blackouts and memory lapses, seizures, coma, respiratory arrest (stopping breathing) and death
- Generally, the effects of GHB are felt within 15 minutes and last for around 3 to 4 hours
- GHB comes in a few forms including:
- a colourless, odourless, bitter or salty-tasting liquid – sold in small bottles or vials
- a blue coloured liquid
- crystals or powder (this is less common)
- GHB and related substances have been used in horrific crimes, such as those committed by Reynard Sinaga, who was found guilty of 136 counts of rape in trials lasting until December 2019, and serial killer Stephen Port, both of whom used the substance to incapacitate their victims
16
Q
What neurotransmitters are involved with GHB?
A
- Dopamine associated with most drugs and leads to reinforcement. Targets the mesolimbic pathway, induced a sense of reward through dopamine release, thus becomes reinforcing
- GHB however is more associated with GABA. GABA is an inhibitory neurotransmitter, which explains some of the behaviour effects of GHB, e.g. sense of relaxation, drowsiness etc.
- Toluene binges in rats lead to increased GABA several days after exposure in key cortical areas such as hippocampus, prefrontal cortex and ventromedial striatum; regions with recognized roles in behavioural flexibility and decision-making (Furlong et al., 2016; Perine et al., 2011)
17
Q
What is one hypothesis for neural mechanisms of GHB?
A
- (1) GBH mediates pre and post-synaptic GABA release
- Evidence from animal studies show that some of the effects of GHB can me mitigated by GABA receptor antagonists (Carai et al., 2001)
- Some research also suggests GHB can act as a GABA receptor antagonist, but has a relatively low affinity for these receptor sites (Madden & Johnson, 1998)
18
Q
What is another hypothesis for neural mechanisms of GHB?
A
- (2) GHB effects are mediated by a specific GHB receptor
- There are specific GABA receptor sites for this substance (Benavides et al, 1992).
- Highest density of receptors tends to be found in the hippocampus and cerebral cortex (Castelli et al., 2000)
- These receptors would respond to both naturally produced GHB and chemically produced GHB, thus excess of this substance could cause a “high” and potentially reinforcing effects
- Both GABAs and GHB receptors affect dopamine release (inhibit and excite respectively)
19
Q
Why is GHB addictive?
A
- Dopamine is the substrate of normal reward systems, and is common factor across a broad spectrum of addictive drugs
- Mesolimbic pathway is implicated in natural reward and drug abuse (the dopamine pathway responsible for rewards, motivation, and emotions)
- Is there evidence that this pathway is activated when consuming inhalants, such as toluene?
- Anaesthetized rats toluene and measured firing in ventral tegmental area (VTA; Riegel & French (1999)
20
Q
Describe evidence that GHB is reinforcing
A
- Funada et al. (1992)
- Study conducted on mice where mice are placed in two connected chambers
- Toluene is distributed in one of the two chambers
- Mice show preference for toluene chambers than non-toluene chamber, where before administration of the substance they showed no preference of either chamber
21
Q
What happens with chronic use of GHB?
A
- The literature has relatively little information regarding the long-term impacts of GHB usage. Few surveys have been conducted
- Some evidence of long-term neurological damage
- Can lead to: severe memory problems, heart disease, hallucinations, extreme anxiety, breathing problems
- Some evidence from rats that long term exposure can lead neurological damage, affecting the ‘grasping’ reflex, as well as alteration in spatial and working memories (Pedraza et al., 2009)
22
Q
What are some adverse effects of GHB?
A
- Participants were significantly slower on behavioural tasks that other addicted groups and healthy controls (Zeng et al., 2022)
- Particularly bad at visuospatial, executive function, and memory tasks
- Showed significant decreases in activation of the frontal lobe (F3, F4, F7, and Fz), central area (C3/4 and Cz), temporal lobe (T4, T5, and T6), parietal lobe (P3/4 and Pz), and occipital lobe compared to healthy individuals
23
Q
What are some legal issues with GHB?
A
- Club drug – GHB used like ecstasy and ketamine; has gained notoriety for use as ‘date rape’ drug
- From the Telegraph, October 2015:
- ‘An alleged serial killer has appeared in court accused of drugging and murdering four young men he met on gay websites.’
- Stephen Port, 40, is alleged to have used the drug GHB to poison the men, who were all in their 20s, before dumping their bodies in and around a churchyard in east London.
- The case is the latest to feature GHB, which has become increasingly common on the clubbing scene over the past ten years, despite not attracting the same level of recognition as other substances such as cocaine and Ecstasy.’
24
Q
What are some social issues with GHB?
A
- In the US about 6% of children have tried inhalants by 4th grade, and usage peaks between 7th and 9th grades - for 12-year-olds more popular than marijuana (especially true in Alaska!)
- In Australia there is a long-standing problem with petrol sniffing in indigenous (aboriginal) communities; in some remote areas they have started using a non-sniffable fuel called Opal to combat this.
- In South Africa a glue manufacturer greatly reduced the n-hexane content in their glue products to reduce danger for street children, after reports of some being left paralyzed
25
Q
Describe tolerance and withdrawal to GHB
A
- Tolerance - informal reports from users suggest that they may increase the dosage, up to sometimes every 2-4 hours all day and night
- Withdrawal - symptoms reported as insomnia, anxiety and tremors, and at high doses even hallucinations, delirium, extreme agitation and psychosis… but actually little is known about this
- The withdrawal syndrome appears to be similar
- to those from other CNS depressants such as alcohol, sedatives and hypnotics. Symptoms include insomnia, anxiety and tremors which usually resolve themselves within two weeks (Galloway et al., 1997). There are indications that in frequent, heavy users these symptoms can progress to severe delirium (Dyer et al., 2001)
26
Q
Describe clinical applications of GHB
A
- GHB and narcolepsy
- EDS is the most common symptom seen in narcolepsy. It causes persistent sleepiness and sudden “sleep attacks” despite getting enough sleep at night
- Cataplexy describes extreme and sudden muscle weakness and loss of control while awake. In severe cases, a person may collapse
- A systematic review and meta-analysis found GHB was effective in treating EDS and cataplexy, though the medication was also not well tolerated (Xu et al., 2019)
