Natural Highs: The Oldest Drugs

Question 1

From Reefer Madness
to High Economy:
Cannabis

Question 2

What IS
cannabis,
anyway?

Answer 2

 One of the world’s oldest crops (hemp harvested in China 8500 years ago).
 However, cannabis is very mysterious.
 Current broad use of the term ‘cannabis’ is often vague, unscientific, and confusing.
 Unsure if the genus Cannabis is monotypic (one species) or polytypic (three or more
species?)
 Why so weird?
 ancient origin.
 extremely long evolutionary and domestication history (including artificial
selection) – may have wiped out other variants.
 widespread geographic dispersal.
 prohibition made it hard to investigate scientifically.

Question 2

By the end of this lecture, you will be
able to…

Answer 2

 Describe the botanical profile of cannabis.
 Describe key events in the cultivation and use of cannabis
in the US and Australia.
 Describe the basic pharmacodynamics and
pharmacokinetics of cannabis.
 Describe the benefits and limitations of cannabis as a
medical treatment, based on current evidence.

Question 2

A ‘third strain’
– ruderalis?

Answer 2

 Molecular genetics is providing increasing evidence that cannabis
is a polytypic genus.
 Some classify cannabis as three sub-species:
 Indica
 Sativa
 Ruderalis
 Ruderalis plants are small and yield relatively little medicine with
low potency?
 Seems to have a different flowering and life cycle.
 Ruderalis strains are typically avoided by breeders and cultivators.
 Medical cannabis is usually indica or sativa strains (whatever they
may be!)

Question 3

Cannabis in
the US

Answer 3

 Hemp grown in North American colonies from early seventeenth
century (by slaves).
 American hemp industry peaked before 1860 - declined after
Civil War (loss of slaves; rise of industrialisation).
 Medicinal cannabis included in the American pharmacopoeia by
1851.
 Imported from India via Britain.
 Medical uses were sporadic and ill-defined.
 By the early 1900s, US government began experimenting with
domestic production of drugs, including cannabis.

Answer 3

Question 4

Recreational
uses

Answer 4

 Early reports of recreational cannabis use in the US - Southwest
and the port of New Orleans, c.1900.
 New term - ‘marijuana’ - smoked version of cannabis indica.
 Racist fears about Mexican immigrants and drug trade.
 In 1915, El Paso, Texas was first US municipality to ban the nonmedical cannabis trade (fears of Mexican drug trade).
 Street name was ‘muggles’!
 Recreational marijuana smoking spread rapidly during the 1920s:
 industrial hubs like Kansas City and Chicago – working class, youth,
Black associations.
 jazz musicians like Louis Armstrong brought ‘reefers’ to various gigs
across the country

Question 4

The 1950s and 1960s

Answer 4

1950s Beatnik movement – cannabis use.
 1960s – growing counterculture.
 American soldiers sampled Thai and Vietnamese varieties while
serving in Vietnam.
 Mostly imported cannabis – wild cannabis has little THC.
 By the 1970s, harvesting of wild cannabis was common in the US.
 Led to chemical pesticide spraying by local governments.

Answer 5

Question 6

1980s and the USWar on Drugs –
dope goes indoors

Answer 6

 Greater US state and federal law enforcement campaigns.
 After 1989, growers moved largely indoors – labs, hydroponics.
 1996 - California became the first state to re-legalise marijuana for
medicinal use.
 Indoor growing became the norm.
 2012: Colorado and Washington state re-legalise adult use of
marijuana.
 Both states focused on regulating - and privileging - energyguzzling indoor cultivation!

Question 7

Australia’s cannabis history

Answer 7

 As with the US, medicinal cannabis available in colonial Australia.
 No data on extent of use.
 Opium was seen as a much more dangerous drug of abuse and
traffic (racist associations with Chinese).
 1938: the term ‘marihuana’ appears in Australia in connection with
the ‘reefer madness’ moral panic in the US.
 Medical cannabis finally phased out in the 1960s in Australia.
 Destruction of wild crops in 1970s.
 Similar VietnamWar and counterculture influences in Australia.

Question 8

Current
cannabis law in
Australia

Answer 8

Question 8

ACT, 1977 –
Australian
Marijuana
Party

Answer 8

Answer 9

Question 9

Legalisation – the high economy

Answer 9

Impact of legalisation of recreational and medicinal use in the US:
 23 US states allow adult recreational use, 38 allow medical sales.
 2020: legal sales = $17.5 billion, a 46% increase from 2019.
 By comparison, craft beer industry in the US = $41 billion in annual sales.
 Estimated creation of just over 6,000 new full-time jobs in retail and
production.
 Also marketing, data analysts, lawyers, health professionals.
 Reduction of cannabis-related criminal convictions – similar use rates,
but black people are 3.6 times more likely to be arrested for marijuana
possession compared to whites.

Question 9

Legalise
Cannabis Party
- bill

Answer 9

 20 June 2023 - bill introduced in state parliaments in Victoria, New
South Wales andWestern Australia.
 Legalise Cannabis Party has representation in all three states’
upper houses.
 Bill would allow adults to possess and grow small quantities of
cannabis at home.
 Similar toACT model.
 The bill is NOT currently supported by WA’s ALP government
(Roger Cook).

Question 10

Legalisation – the high economy

Answer 10

Impact of legalisation of recreational and medicinal use in the US:
 State and federal taxes, fair wages, infrastructure and regulation all cost
small business owners.
 They can’t always make a profit.
 California – very complex state laws: selling 500g for $3000 illegally, or
selling 500g for $600 legally?
 Most cannabis trade still illegal.
 Illicit cannabis sales estimated at $100 billion each year.
 Both legal and illegal sellers use a mix of bricks-and-mortar, e-commerce
and ‘rideshare’ type delivery systems.
 Legal traders rely on government to shut down illegal traders.

Question 11

How it gets into the body

Answer 11

 Inhaled as smoke: cannabinoids travel rapidly from the
lungs to the blood and brain.
 This leads to higher levels of THC in blood plasma.
 Ingested: absorbed from the intestines => liver where it is
metabolised (first-pass metabolism)
 This leads to lower levels of THC in blood plasma.

Question 11

Cannabinoid receptors

Answer 11

 The two major identified cannabinoid receptors in the body are CB1 and
CB2
 G-protein-coupled receptors (see eTute 1).
 CB1
receptors: mostly CNS and peripheral NS.
 CB2
receptors: mostly immune cells and spleen; also GI tract, skeletal
muscle, skin, cardiovascular system, reproductive system, liver.
 CB2
receptor agonists [stimulate a response] are targets of emerging
research due to their potential analgesic, anti-inflammatory, and
immune-modulating properties.
 https://www.azolifesciences.com/article/Comparison-of-ReceptorPharmacology-in-Cannabinoids.aspx

Question 12

How is it
turned into
product?

Answer 12

 Most cannabis produced and consumed in the world is herbal:
dried flowers and smallest leaves and stems of the female
cannabis plant.
 sinsemilla (‘seedless’) crops: remove all male plants from field.
 hashish (‘grass’) or resin: paste-like substance obtained by
compressing the resin glands (trichomes) of the female cannabis
plant.
 bhang: edible paste-like cannabis, used in foods and drinks during
some Hindu and/or Sikh religious occasions.
 butane hash oil (BHO): a solvent-extracted, cannabis
resin concentrate made with liquid butane.
 rosin: solvent-less extract - heat and pressure with heating
hydraulic press.
 edibles: gummies, tea, powders, butter/oil, brownies.

Question 13

Pharmacodynamics

Answer 13

 Cannabis is a polypharmaceutical substance (comprised of many
compounds, including cannabinoids).
 Those of primary interest are:
 Cannabidiol (CBD)
 Tetra-hydro-cannabinol (THC)
 Cannabinoid receptors are located throughout the body: brain,
major organs, connective tissues, glands, immune cells.
 The human body has cannabinoid receptors …
 … which means the human body has endocannabinoids!
 anandamide - discovered and named in 1992
 responsible for biological effects such as increasing appetite,
decreasing nausea, decreasing pain sensitivity, and providing
anti-inflammatory activity.

Question 14

What goes
where?

Answer 14

 All cannabinoids are not equal!
 THC has equal affinity to both CB1 and CB2 (partial agonist).
 Synthetic cannabinoids are “fussy” - highly selective agonists or
antagonists to one of the receptor types.
 CBD does not directly affect either CB receptor (antagonist):
 It modifies the receptors’ ability to bind endocannabinoids.
 For example, CBD enhances the activity of anandamide.
 CBD is thought to interact with several other receptors like the μreceptor and serotonin (5-HT) receptors.

Question 15

How does THC
get you high?

Answer 15

 Good question …
 May cause short-term dopamine flooding (and long-term blunting of
dopamine effects).
 THC seems to unplug the brain’s ‘default mode’ network (how we daydream
and think about past and future).
 Psychedelics such as LSD and psilocybin seem to have a similar effect on the
brain’s ‘default mode’ network.
 Difficulties in studying this phenomenon: illegality, subjective experience of
‘high’.

Question 16

Pharmacokinetics -
smoking

Answer 16

 This depends on:
 The route of administration.
 The cannabinoid involved.
 The physical characteristics of the user.
 Both THC and CBD are highly lipophilic -> they like to snuggle in your fat cells.
 THC produces the ‘high’.
 CBD acts without euphoric effects.
 Bioavailability of inhaled THC is highly variable: between 10% and 35%.
 The THC content also varies depending on how inhaled:
 Doobs: less THC content partially due to pyrolysis at higher temperatures and
loss due to side smoke; more tar and impurities.
 Vaping: highest content of THC and cleaner vapour.
 Smoking effect can occur within seconds; can be fully apparent within minutes; lasts up
to 3 hours.

Question 17

Pharmacokinetics -
edibles

Answer 17

 The amount of THC absorbed from edibles depends on your body
mass index, metabolism, gender, and eating habits.
 bioavailability of THC and CBD from edibles also widely variable -
4% to 12%.
 Edibles can have a longer effect compared to inhaled THC – 6-12
hours.
 But: higher risk of toxicity!
 THC and CBD content labelling may be inconsistent: as high as
23% for under-labelling and 60% for over-labelling

Question 18

THC -
Evidence from
meta-analyses

Answer 18

 Human brain has considerable neuronal plasticity = potentially
vulnerable to ongoing THC use due to effects on cannabinoid
receptors.
 Literature overall supports causal and correlational relationships with
ongoing THC use:
 reduced cognitive and motivational abilities - verbal memory and
attention (reversible with abstinence?Variables like use, age, THC
content can moderate risk?)
 associated psychosis, depression, anxiety, addiction, violence.
 Robust relationship between chronic marijuana use and increased risk
of suicide.
 Paediatric exposure is highly risky.
 Risks to adolescent brain: brain connectivity, CNS grey matter, altered
CB1R signaling, potential short-term memory dysfunction via
hippocampal changes = increased risk of neurodevelopmental
conditions, psychosis.
 https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2782160

Question 19

THC -
Evidence
from metaanalyses

Answer 19

 Cannabis smoke inhalation increases risks of
pneumonia, bronchiolitis, pneumothorax,
emphysema, and pulmonary
haemorrhage.
 Evidence suggests cannabis smoke is
carcinogenic.
 Cardiovascular system:
 increased myocardial oxygen
demand.
 pro-oxidative stress.
 decreased myocardial contractility.
 promotion of atrial and ventricular
arrhythmia.
 Arrhythmia.
 Stroke.
 Arteritis.
 arterial dissection.
 myocardial infarction, and
 sudden cardiac death.

Question 20

Medicinal uses
of CBD – the
most recent
evidence

Answer 20

Presently available data do not allow any firm recommendations
for the use of cannabinoids (usually CBD) in pain management or
opioid use disorders.
Three examples:
1) Adult cancer-related pain – the addition of cannabinoids to
opioids did not reduce cancer pain.
2) Acute pain management - low-quality evidence that
cannabinoids may be a safe alternative for a small but
significant reduction in subjective pain score – only with
intramuscular injection.
3) Movement disorders – not enough good quality data to
determine that any forms of cannabis are effective.

Question 20

Medicinal uses
of CBD – the
evidence

Answer 20

There IS some evidence for other areas (these are just some examples):
1) Treatment resistant epilepsies – some evidence that CBD oil is a good
adjunct therapy.
2) Multiple sclerosis - potential therapeutic symptomatic effects, including
alleviation of pain, spasticity, and bladder dysfunction.
3) Nausea from cancer treatment – good evidence for relief.
Two principal objections to medicinal CBD use:
1) We have better medicines already available for these conditions.
2) There are known and unknown interactions between CBD and other
standard treatments, some of which are potentially harmful.
Cannabis in Medicine: An evidence-based approach (Springer, 2020) - UWA
Library online

Answer 21

Question 22

Legalisation – the high economy

Answer 22

The historical push for legalisation has always been
about recreational use.
 But legalisation came first for medicinal cannabis – based
on tenuous medical evidence.
 Bonus question: Is legalising medicinal use a way of
smoothing the path to increased legal recreational use?

Question 22

Summing up

Answer 22

 Cannabis is tricky and elusive, botanically and chemically.
 Although a very old drug, it’s still misunderstood because of the
legal/illegal divide.
 It has a recent modern history that has made this more complicated.
 It’s still hard to develop a global picture of its growth, trade, and uses.
 It has different ways of preparation and use for extraction and ingestion.
 Its two main interesting cannabinoids behave differently in the body:
 THC is fun - but tends to be mostly harmful to the body.
 CBD is less fun, and can be therapeutic, but the evidence base is
still very much in development.
 There are both risks and benefits associated with the legalisation of
recreational and medicinal cannabis.

Question 22

Therapeutic
Goods
Administration
(TGA)
Australia

Answer 22

 Category 1: CBD medicinal cannabis product (CBD ≥ 98%) - Prescription only
(Schedule 4).
 Category 2: CBD dominant medicinal cannabis product (CBD ≥ 60% and < 98%) -
Controlled drug (Schedule 8).
 Category 3: Balanced medicinal cannabis product (CBD <60% and ≥ 40%) -
Controlled drug (Schedule 8).
 Category 4: THC dominant medicinal cannabis product (THC 60% - 98%) -
Controlled drug (Schedule 8).
 Category 5:THC medicinal cannabis product (THC >98%) -
Controlled drug (Schedule 8).
 Want to know more? Try the Medicinal Cannabis Hub -
https://www.tga.gov.au/products/unapproved-therapeutic-goods/medicinalcannabis-hub