Panacea Nostrum – The Forensic Toxicology of Cannabis

Artwork for Cannabis Panacea allegory, depicting the goddess Panacea seeding cannabis plants. Image: NaturPhilosophieWhat is Your Poison of Choice?

Be honest.  We all have one.  What’s your poison?  Booze, tobacco, prescription drugs… or something a little more exotic?  Cannabis is a controversial plant, regarded by many as a godsend.  If Carlsberg made a ‘erb…

But in all seriousness…  How much do we know about cannabis?  And are the chemical compounds it contains poison or… panacea?

 

Beginnings of Toxicology

The title page of Mathieu Orfila's work "Traité des Poisons", published in 1813.

Until the 19th century, most poisons were undetectable, as well as very common.  This state of affairs meant that poisoners could easily escape detection and punishment.  As a result, poisoning was widespread in places throughout history, such as in Italy and France in the late 1600s.

In 1813, Mateu Orfila compiled his ‘Traité des Poisons‘ – the book divided poisons into several groups and described their effects on the living body, the symptoms of illness they produce, the signs they leave in a dead body, and the ways of identifying them.  It was the beginning of Modern Toxicology.

Many potentially harmful substances are deliberately consumed everyday by average individuals for their mood and mind altering effects.  These particular substances are known in legal terms as drugs of abuse.  There is an extensive array of them, either produced illegally or diverted from licit sources.

 

A photograph assembling some of the most common drugs of abuse, from alcohol and wine to cannabis and spice.
Some of the commonest drugs of abuse may be more common than you might expect… Source: USAMDT

Drugs of Abuse

Depending on how they affect the central nervous system (CNS), drugs of abuse may be categorised into:

  • stimulants

Amphetamines and cocaine stimulate the brain activity.

  • depressants

Alcohol, barbiturates, benzodiazepines, heroin inhibit the brain activity.

  • hallucinogens

Ecstasy and lysergic acid diethylamide (LSD) induce alterations in perception and mood.

 

 

A bar chart focusing on the harm caused by drugs in general, be they legal or illegal. The 2010 Study shows the most harmful drug is legal, and it is alcohol.
Alcohol features at the very top of the table returned from Nutt, D. et al. (2010) study on “Harm Caused by Drugs” in The Lancet.  Cannabis is deemed a lot less likely to cause harm than alcohol.  Source: Wikimedia

What the Law Says about Drugs

 

In the United Kingdom, the Misuse of Drugs Act 1971 is intended at preventing the unauthorised use of specific substances.  Under this legislation, drugs are placed in one of three categories (A, B or C), depending on the harm caused by their misuse.

Category A drugs are deemed the most dangerous, whereas Category C drugs are considered the least harmful.  Any penalty that apply to offences concerning specific drugs is governed by the category to which it belongs.

Cannabis is a Class B Drug under the Misuse of Drugs Act 1971.

 

The Misuse of Drugs Regulations 2001 stipulate the requirements concerning the legitimate distribution, production, record keeping and storage of controlled drugs, as well as whether they can be made available on prescription or not.

A close-up photograph showing a computer keyboard: the large <Enter> key has been replaced by a green key with a little cannabis leaf symbol, spelling the message: "Vote Cannabis".
Many states of the U.S. have legalised the production and sale of cannabis and cannabis-based products. But the federal law still prohibits it…  Source: norml.org

At this time, the United States Drug Enforcement Administration lists marijuana and its cannabinoids as Schedule I controlled substances.  This means that they cannot legally be prescribed, possessed, or sold under federal law.  Whole or crude marijuana (including marijuana oil or hemp oil) is not approved by the US Food and Drug Administration (FDA) for any medical use.  But the use of marijuana to treat some medical conditions is now legal under state laws in many states.  And a change is coming…

Drugs are often derived from organically-produced plant chemical compounds.

Plants are brilliant at organic chemistry.

 

In some countries and U.S. states, cannabis is legal to possess.  These include Portugal, the Netherlands, North Korea, Colorado, Washington, Alaska, and Oregon.

 

A photograph showing a Cannabis field, growing outdoors somewhere in Oregon, United States.
Outdoor Cannabis Growing in Oregon, U.S.A. Source: Inc.com

Cannabis 101

One of those ‘drugs of abuse’ comes from a plant, and has become World-renowned for having the most remarkable positive health benefits – cannabis (or marijuana).

Cannabis goes by many names, including

  • pot,
  • grass,
  • dope,
  • weed,
  • ‘erb,
  • hemp,
  • hash,
  • marihuana,
  • ganja…

 

Marijuana is one the names given to the dried buds and leaves of varieties of the Cannabis sativa plant.  Cannabis is a genus of flowering plants that includes a single species, Cannabis sativa, sometimes divided into two additional species, Cannabis indica and Cannabis ruderalis.  The three taxa are indigenous to Central Asia, and South Asia.  The plants can grow wild in warm and tropical climates throughout the World, and they can be cultivated commercially.

Possibly the most versatile plant on the planet, Cannabis is also possibly the most controversial.  Cannabis is NOT just a great material for making super-capacitors.  Its uses range from a popular recreational drug to a potential medicine for a range of currently incurable conditions.

Cannabis is a mild hallucinogen.

 

A graph showing how the average percentage of THC in samples of seized marijuana has varied between 1988 and 2008. The trend is on the increase. Source: University of Mississippi Potency Monitoring Project.
Average Percentage of THC in Samples of Seized Marijuana, 1988-2008. Source: University of Mississippi Potency Monitoring Project.

A Party Drug

Cannabis is a popular recreational drug around the World, only behind alcohol, caffeine and tobacco.  Cannabis is a mild hallucinogenic drug.

In the United States alone, it is believed that over 100 million Americans have tried cannabis, with up to 25 million Americans using it in the past year, and over 14 million doing so regularly despite harsh laws against its use.

In the United Kingdom, Cannabis remains the most popular illegal drug.

According to NHS’s Cannabis Facts, the proportion of 11-15 year olds in England who had used cannabis in the last year fell from 13.3% in 2003 to 7% in 2013.  The proportion of 16-59 year old using cannabis in the last year has fallen from 10.6% in 2003-04 to 6.6% in 2013-14.

The psychoactive effects of cannabis are known to have a biphasic nature:

  • Primary psychoactive effects include a state of relaxation, and to a lesser degree, euphoria from its main psychoactive compound, THC,
  • Secondary psychoactive effects, such as a facility for philosophical thinkingintrospection and metacognition have been reported.

 

A tertiary psychoactive effects of the drug cannabis, can include an increase in heart rate and increased appetite, believed to be caused by 11-OH-THC, the main psychoactive metabolite of THC produced in the liver.

 

A cartoon caricaturing the effects of consuming cannabis by young people.The Effects of Cannabis

The effects of smoking Cannabis usually begin within 10-20 minutes after absorption, and they may last between two-three hours.  To the novice user in particular, they include a feeling of relaxation, sleepiness and a lack of concentration.

A cartoon showing a red-eyed Spongebob Squarepants holding a joint and commenting: "If it wasn't for weed, I would have never been created in the first place."Seasoned users report enhanced perception and heightened creativity.

‘Normal’ cognition is resumed after approximately three hours for larger doses via a smoking pipe, bong or vaporiser.  However, if a large amount is taken orally, the effects may last much longer.  After 24 hours to a few days, minuscule psychoactive effects may be felt, depending on  the dosage, the frequency and the user’s tolerance to the drug.

As reported on the Urban75.com webpage on Cannabis:

Side effects: For many, smoking dope is as natural and everyday as a brew of hot tea, and they find the drug helps make their life a little less stressful without unduly affecting their judgement or abilities.

A very stoned Bugs Bunny-type cartoon rabbit saying: "Far out, dude." Source: Weed MemesFor others it can have quite the opposite effect, turning ordinary folk into unbearable, spaced out, lazy hippies.  A night of industrial strength spliffing can transform you into a giggling oaf who will burst into laughter at wholly unamusing incidents and find deep intellectual depth in the Spice Girls’ lyrics.

Your trousers and sofa will become riddled with burn marks from dropped spliffs, and you will have to face the regular dilemma of being hit with the munchies at 3 am only to find that you were too out of it to get the shopping in.

This can result in regular users turning into lazy gits whose crap diet turns their body into a most unattractive proposition.

 

The common side-effects of Cannabis can include

  • dizziness,
  • sedation,
  • dry mouth,
  • blurred vision,
  • mental confusion,
  • spatio-temporal disconnection,
  • seizures and
  • memory holes.

 

Cannabis withdrawal symptoms are typically mild and never life-threatening, despite the increasing trend in THC potency of the drug observed in seized marijuana samples over the years.

For this reason, to many users, if Carlsberg made a weed, this would be the one…

For many, smoking dope is as natural and everyday as a brew of hot tea.

 

And when you look closer at our complex human physiological systems, it appears to make very good sense.

 

The Endocannabinoid System and Associated Receptors

An anatomical diagram illustrating the locations of the main receptors in the human endocannabinoid system.
The two main receptors that form the endocannabinoid system are the CB1 and CB2 cannabinoid receptors.  It has been accepted recently that the orphan receptor GPR55 can be considered as the third receptor for cannabinoid activity.  All these receptors are transmembrane proteins capable of sending out a an extracellular signal into the interior of a cell.  Source: Fundación Canna

The Endo-Cannabinoid System is a group of endogenous cannabinoid receptors located in the mammalian brain and throughout the central and peripheral nervous systems, consisting of neuromodulatory lipids and their receptors.  Known as “the body’s own cannabinoid system”, the ECS is involved in a variety of physiological processes including appetite, pain sensation, mood, and memory, and in mediating the psychoactive effects of cannabis.

Two primary endocannabinoid receptors have been identified:

  • CB1 receptor, first cloned in 1990
  • CB2 receptor, cloned in 1993.

 

CB1 receptors are located primarily in the brain, but they also are found in blood vessels and heart cells.  CB2 receptors are primarily located outside of the brain, in the peripheral nervous system and glands.

Since these receptors are so widespread throughout the brain and body, marijuana smoking can have a widespread effect on the brain, heart, cardiovascular system, nervous system, reproductive system, and immune system.

 

An infographic explaining how different cannabinoids work on different cannabinoid receptors in the human body.
Researchers have identified over 70 unique cannabinoids in the human body. Many of these compounds interact with the human endo-cannabinoid system via cannabinoid receptors found throughout the body. Some cannabinoids bind more selectively to certain receptors and can thus be targeted to treat specific symptoms. Source: Cre8 Health

Cannabinoids and the Human Body

The CB1 cannabinoid receptors type 1, are found predominantly in the brain and nervous system, as well as in peripheral organs and tissues, and are the main molecular target of the endocannabinoid ligand (binding molecule), Anandamide, as well as its mimetic phytocannabinoid, THC.

CB1 receptors are metabotropic receptors expressed most abundantly in the brain and their distribution has been widely characterised in humans.  CB1 receptors are highly expressed in the

  • hippocampus,
  • basal ganglia,
  • cortex and
  • cerebellum.

 

They are less expressed in the amygdala, hypothalamus, nucleus accumbens, thalamus, periapeduncular grey matter and the spinal cord, as well as in other brain areas, mainly in the telencephalon and diencephalum.

CB1 receptors are also expressed in several peripheral organs.  Thus, they are present in the:

  • adipocytes,
  • liver,
  • lungs,
  • smooth muscles,
  • gastrointestinal tract,
  • pancreatic b-cells,
  • vascular endothelium,
  • reproductive organs,
  • immune system,
  • sensorial peripheral nerves and
  • sympathetic nerves.

 

Scientific imaging showing the comparison of CB2 expression in neurons microglia and astrocytes.
Comparison of CB2 immunoreactivity in neurons, activated microglia and astrocytes in the mouse brain. Source: Savonenko AV, Melnikova T, Wang Y, Ravert H, Gao Y, Koppel J, et al. (2015) ‘Cannabinoid CB2 Receptors in a Mouse Model of Aβ Amyloidosis: Immunohistochemical Analysis and Suitability as a PET Biomarker of Neuroinflammation’

The CB2 cannabinoid receptor, is a G protein-coupled receptor from the cannabinoid receptor family that is encoded by the CNR2 gene in humans.

The distribution of CB2 receptors is quite different and mainly restricted to the periphery in the immune system cells, such as:

  • macrophages,
  • neutrophils,
  • monocytes,
  • B-lymphocytes,
  • T-lymphocytes and
  • microglial cells.

 

Recently, CB2 receptor expression has also been shown in

  • skin nerve fibres and keratinocytes,
  • bone cells such as osteoblasts, osteocytes and osteoclasts,
  • liver and
  • somatostatin secreting cells in the pancreas.

 

The presence of CB2 receptors has also been demonstrated at the

 

There is evidence of staining with the CB2 antibody of human neurons.  The presence of functional CB2 receptors is still debated.  Recent evidences suggest that the CB2 receptor mediates emotional behaviours, such as schizophrenia, anxiety, depression, memory and nociception, supporting the presence of neuronal CB2 receptors or the involvement of glial cells in emotional behaviours.

Approximately 360 amino acids comprise the human CB2 receptor, making it somewhat shorter than the 473 amino acid-long CB1 receptor.

One other main endocannabinoid is 2-Arachidonoylglycerol (2-AG) which is active at both cannabinoid receptors, along with its own mimetic phytocannabinoidCBD.

2-AG and CBD are involved in the regulation of such crucial metabolic functions as:

 

A set of two annotated photographs showing the differences between the male and female cannabis plants. The male plant has little "balls" at the base of the leaves. The female plant has small "hairs".
The morphological differences between male and female Cannabis plants.  The active components are concentrated in the leaves and flowering tops of the plant.  Source: AllPotSeeds.com

Canna-Chemicals

Cannabis has been used in herbal remedies for centuries.  Scientists have identified many biologically active components in marijuana. These are called cannabinoids.  The classical cannabinoids are concentrated in a viscous resin produced in the plant’s structures, known as glandular trichomes.

To create new hybrid strains of cannabis, male pollen is combined with the flowers of female cannabis plants.  Thousands of combinations can be achieved in this way by cross-pollinating the tall Sativa plants with the fast-flowering Indica plants.  The produced offsprings share the characteristics of both plants, including their content variations in psychoactive and non-psychoactive organic compounds.

 At least 113 different phyto-cannabinoids have been identified from the Cannabis plant.

The three most studied components are the chemicals:

  • \Delta^9-TetraHydroCannabinol (THC),
  • CannaBiDiol (CBD), and
  • CannaBiNol (CBN).

 

A diagram showing a molecule model of the cannabinoid chemical Tetrahydrocannabinol THC.
TetraHydroCannabinol (THC) Molecule Source: Wikipedia

Tetrahydrocannabinol THC is the principal psychoactive constituent (or cannabinoid) of cannabis.  It can be an amber or gold coloured glassy solid when cold, which becomes viscous and sticky if warmed.

A diagram showing a molecule model of the cannabinoid chemical Cannabidiol CBD.
Cannabidiol (CBD) molecule Source: Wikimedia

Cannabidiol CBD is only one of the 113 active cannabinoids identified in Cannabis.  It is a major phytocannabinoid, accounting for up to 40% of the plant’s extract.  CBD is considered to have a wide scope of potential medical applications – due to clinical reports showing the lack of side effects, particularly a lack of psychoactivity (as associated with \Delta^9-THC), and non-interference with several psychomotor learning and psychological functions.

Cannabinol CBN is a weak psychoactive cannabinoid found only in trace amounts in Cannabis.  Pharmacologically, relevant quantities are formed as a metabolite of tetrahydrocannabinol (THC).  CBN acts as a partial agonist at the CB1 receptors, but it has a higher affinity to CB2 receptors, however lower compared to THC.  Cannabinol has been shown to have analgesic properties, but modern production processes aim to minimize the formation of CBN.

11-OH-THC is also a metabolite of THC.  The conversion from THC to 11-OH-THC is relatively high when cannabis is consumed in the form of cannabis edibles and, compared to oral consumption, lower when it is smoked or vaped.  11-OH-THC is more potent than THC and crosses the blood-brain barrier more easily.

Other phytocannabinoids are being studied.

 

A bar chart showing the therapeutic index of several drugs of abuse (including alcohol). Here cannabis or marijuana makes the top of the table with the lowest toxicity.
Ranking psychoactive substances by their ratios of lethal dose to effective dose gives a general picture of how likely each is to precipitate an acute fatal reaction. By this measure, many illicit drugs are considerably safer than alcohol. Source: Gable (2006)

Therapeutic Index

The therapeutic index (TI) is an established clinical indication setting of an approved drug.  It refers to the ratio of the dose of drug that causes adverse effects at an incidence/severity not compatible with the targeted indication (e.g. toxic dose in 50% of subjects, TD50) to the dose that leads to the desired pharmacological effect (e.g. efficacious dose in 50% of subjects, ED50).

\frac {LD_{50}}{ED_{50}}

 

The therapeutic index varies widely from one substance to another.  The most forgiving among the opioid analgesics is Remifentanyl, which offers a therapeutic index of 33,000:1, while Diazepam, a benzodiazepine sedative-hypnotic and skeletal muscle relaxant has a less-forgiving index of 100:1 and morphine, a sedative, antidepressant, and analgesic of herbal origin (genus Papaver) has an index of 70:1 (still considered very safe).

A high therapeutic index means that the margin of safety exists between beneficial and toxic doses is great.

 

An infographic comparing a pint of lager versus a cannabis leaf.Cannabis Safer than Alcohol?

With regards to cannabis and alcohol, the therapeutic index is 1,000 and 10, respectively.  This is the reason why some have advocated the prescription of cannabis as a medicine to combat chronic pain that cannot be treated by ordinary painkillers (eg. morphine).

The properties of cannabis are safer and more predictable compared to alcohol.

Although a plausible solution, simply legalising the use of cannabis for medical purposes will not make it a drug that is devoid of all danger.  Indeed, the favourable therapeutic index of cannabis does not bring out its latent toxicity in case the substance is abused over prolonged periods of time (chronic use).

At high doses, cannabis can even induce panic attacks, mental aberration (paranoia) and hallucinations.

So is Cannabis a poison?

 

Sola Dosis Facit Venenum

“Everything is poison, there is poison in everything.  Only the dose makes a thing not a poison.”  Paracelsus (1493 – 1541)

Since the 1940s, one rule of toxicology is the following:

The adverse effects of a poisonous substance are directly proportional to the dose being absorbed.  Hence more poison, more dire effects… provided the dose is above a safe threshold.  Below this no-effect level, nothing happens.

… Or does it?

This a paradox of toxicology…

The dose is the poison… or perhaps the cure.

 

Is Cannabis a Panacea?

Cannabis is the most commonly used illegal drug throughout the World.

A table showing the different health benefits of different cannabinoids. Source: Wikimedia, Trends in Pharmacological Science (2009).

Research of the cannabinoid system has many similarities with that of the opioid system.  In both instances, studies into drug-producing plants led to the discovery of an endogenous control system with a central role in neurobiology.

Few compounds have had as much positive press from patients as those of the cannabinoid system.  While these claims are investigated in disorders such as multiple sclerosis, spasticity and pain, basic research is discovering interesting members of this family of compounds that have previously unknown qualities, the most notable of which is the capacity for neuroprotection.

Large randomised clinical trials of the better known compounds are in progress.  Even if the results of these studies are not as positive as many expect them to be, that we are only just beginning to appreciate the huge therapeutic potential of this family of compounds is clear.

Baker et al. 2003 ‘The Therapeutic Potential of Cannabis‘, The Lancet

In the meantime, reducing the risk to individuals remains obviously paramount.  The science of toxicology may provide one step in that direction, by helping to teach members of our society what a lot of tribal people already have known for a long time.

Despite the associated health risks and social stigmas, mind-altering chemicals have been used for centuries in almost every cultures.

As such it would be unrealistic to expect that the recreational use of a drug like Cannabis will suddenly cease.