Medical Marijuana: A Triumph of Hope Over Experience

“Medical marijuana” has penetrated the paediatric market with potions for treating autism. Success has been declared on the bases of some observations, without any reference to the clinical effects of acute intoxication, or of chronic exposure on development and function of growing brains. The promotional material fails to mention any preceding studies on the brains of children, which is no surprise: there are none. In reality, doctors are invited to prescribe cannabis in ad hoc participation in unregulated experimentation. It is a matter of Hope over experience.

For example, US-based Zelira Therapeutics Ltd, a self-described “Global Biopharmaceutical Company developing and marketing clinically validated cannabinoid-based medicines” entered the Australian market in October 2020, after securing agreements for local manufacture and marketing of two products, known as HOPE 1 and HOPE 2, which are claimed to help autistic children as young as five.

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The HOPEs contain the two major components of the cannabis plant: psycho-active delta-tetrahydrocannabinol (THC) and neuroprotective cannabidiol (CBD), plus an “entourage” of terpenes that provide taste, smell and mysterious “support” for the main performers. HOPE 1 contains THC and CBD in a ratio of 1:1, each contributing 5 mg/ml. HOPE 2 is largely THC, contributing 8.3 mg/ml to CBD’s 1.7 mg, a ratio of almost 5:1.

Though these products are promoted for the treatment of childhood autism, there has been “mission creep” into the less precise, more common range of autism spectrum disorders (ASD), and beyond, into the imprecise realms of Attention Deficit Hyperactivity Disorder (ADHD).

And business is growing. According to the Therapeutic Goods Administration (TGA), applications for permission to prescribe cannabis for autism spectrum disorder and ADHD have accelerated since 2019, despite Covid restrictions on promotional access to doctors.[1]

Regarding autism spectrum disorder, there has been an all-age total of 1800 applications since 2019: rising from 231 in that year, to 522 in 2020, to 767 in 2021, and to 281 by May 2022. Of these, 739 were for children aged 2 to 11, and 500 for those 12 to 17.

For ADHD, there have been 1420 applications, mostly for those aged 18 to 44, but 101 have been for children aged 2 to 11, increasing from 4 in 2019, to 59 in 2021, to 19 by May 2022.

Given Zelira’s promotional campaign has barely begun, and that 0.6 per cent of all Australian children are reported to have autism, 1.5 per cent to be on the spectrum, and some 8 per cent to be suffering from ADHD[2], a fruitful market beckons.

 

The cannabinoid system

Evaluating the use of cannabis in children and adolescence requires some understanding of biology, and reference to international literature regarding complications.

For centuries, cannabis has been consumed in hope of relief from disease and in expectation of psychological distraction. In the 400s BC, the Greek historian Herodotus described how cannabis caused participants in the funerary customs of the Scythians “to howl with joy”, and in the first century AD the Greek physician Galen noted its promotion of “senseless talk”[3].

But it was only in the 1800s that a cannabis resin was found to contain “a powerful narcotic … which produces complete intoxication”.[4] Identification of components, however, had to wait until the 1940s when the moderating CBD was obtained[5], and the 1960s, when psychoactive THC was discovered[6].

It was originally thought that cannabinoids entered neurons by dissolving through their walls (as do anaesthetics), but their revealed structure seemed too complex for that. Then, in 1988, it was discovered that they worked by stimulating receptors on the surfaces of neurons throughout the brain: from cortex, basal ganglia, limbic system, to cerebellum[7].

Logically, it was asked: Why would the brain invest so much energy on the manufacture and maintenance of so many receptors in so many places, to await stimulation by plants that might never be consumed? The hunt for purpose was on!

In consequence, in 1992, an innate chemical was identified which stimulated receptors in the manner of “external” THC. In deference to its psychogenic effects, it was called “anandamide” after the Sanskrit word ananda, “bliss”.[8] A second receptor was discovered in 1993[9], and another stimulator, 2-AG, in 1995[10].

It appeared there could be a family of stimulators (known as ligands) which acted on various receptors throughout the brain to comprise an “internal” Endocannabinoid System (ECS) which governed much cerebral development and function. Such governance, however, is not centralised. It is more like a federation of many local governments in which ligands are produced, in many and various sites, in accordance with individual and varying local needs. In contrast, “external” THC exerts a totalitarian mass effect, stimulating all receptors, everywhere, at once, regardless of local needs. CBD undergoes a similar process but, in a kind of “yin and yang” co-operation, it modulates if not opposes the effects of THC.

Though much remains unknown, the balanced “tone” of ECS influences the growth of the brain, and then maintains cells and circuitry that underlie cognition, memory, emotion, evaluation of external and internal stimuli, and appropriate decision-making (or executive function), as well as sleep, appetite, balance and movement, and such non-cerebral functions as immunity and reproduction.

 

The clinic impact of THC

The effects of acute exposure to THC reflect its intoxicating, psychoactive powers. In humans, though no lethal dose has been established, its effects include impairment of cognition, attention, memory, behaviour and executive function[11][12], and distortion of mental perceptions, from the desired “high” to, sometimes, hallucinations. Low doses may allay anxiety, while high doses make it worse. Studies on memory and learning in animals have concurred[13].

The effects of chronic exposure are debated because it is difficult to exclude “genetic, mental health and environmental influences”[14], and to quantify dosage. Controlled studies have revealed persistent reduction in learning[15][16] but, fortunately, improvement has been noted after cessation of administration.

The deleterious effects of chronic exposure to THC reflect its dose-related toxicity. It accumulates in neurons, inflicting damage, perhaps by inciting inflammation[17] and provoking apoptosis (natural cell death)[18]. It causes “neuronal shrinkage and degeneration”, as well as inhibition of neuronal connectivity, and it damages chromosomes.[19]

In growing brains, THC disrupts “the temporally ordered sequence of events that occur during neurotransmitter development, in addition to negatively impacting neural cell survival and maturation”[20]. Prini et al imply that, given THC “interacts with all (ECS) receptors throughout the brain” without regard for the subtlety of individual needs, chronic “over-activity” interrupts structural and functional connectivity[21].

Sophisticated imaging has revealed dimensional changes in regions abounding in receptors, for example, in the hippocampus[22] which integrates cognition, memory, emotions and response[23]. These changes have correlated with drug dependency[24]. Functional effects have also been measured. For example, reduced IQ and cognition have been demonstrated in exposed adolescents, as well as “increased motor impulsivity and suboptimal decision making”, all due to “a lasting neurotoxic effect on the brain”[25], and correlating with younger age of initiation and duration of exposure.[26]

Even if cognitive assessment has failed to reveal significant impairment by THC, functional MRI has shown “chronic users … had to mobilise more neuronal resources … to succeed in a given test”[27].[28] As in grey matter, “impairments in structural integrity and coherence” have been found in white matter whose broad tracts may be likened to broadband connections between the controlling centres of a metropolis. It is not surprising that their disruption may “elicit a constellation of behaviours that closely resemble the symptoms of psychosis”.

Whether THC predisposes, on its own, to permanent psychosis is debated. Lowe et al argue that “much of the evidence suggests harmful consequences” in regard to “major depressive disorder”, “significant evidence” for an association with agoraphobia and social anxiety disorder and an increased risk of schizophrenia in a “dose dependent manner”. The authors conclude that “multiple studies” correlate cannabis with earlier onset of psychosis (schizophrenia), increased symptom severity, higher rates of relapse and longer hospitalisation time, as well as overall poorer illness and quality-of-life outcomes.[29]

However, the “two-hit hypothesis” maintains THC is but one component of cumulative forces, including genes and the environment, that lead to psychosis. Regarding children, the point is that no one knows what the effect of chronic administration will be, and autistic brains have already been “hit” once.

 

The effect of CBD

Cannabidiol (CBD) is the other major component of cannabis but, although structurally similar to THC, it does not share its psychoactive properties. A review concludes that there is “evidence suggesting … CBD is neuroprotective, mitigating the neurotoxic effects of THC”. The authors conclude that THC and CBD have “opposing effects on the function and activity and connectivity between (cerebral) regions” and worry about the consumption of recreational cannabis with increasingly high percentages of THC compared to CBD (as in Zelira’s tinctures) [30].

These neuro-modulatory effects of CBD underlie its now established contribution to the management of refractory epilepsy in childhood[31].

 

Autism and ADHD

Autism is a neurodevelopmental disorder of unknown aetiology, influenced by genetics, in which there is impairment in language, communication, social and play skills, associated with stereotypical body movements and a marked need for sameness[32]. Behavioural challenges, ranging from ADHD to rages, are common, as are anxiety and depression, and there is distortion of social reality.

ADHD is characterised by inattention, impulsivity and overactivity. It, too, reflects genetic influence but there is often contribution from family dysfunction. ADHD may also be complicated by anxiety and depression, and almost psychotic rages.[33]

Early childhood behavioural and educational intervention is basic, aiming to enhance cognitive, language and social skills in the child and improve relationships in the family.[34] Psychotherapy is important but mood disorders may require anti-depressant or anti-anxiety medications: paradoxically, hyperactivity may improve with such “stimulants” as methylphenidate; and rages may respond to antipsychotic agents including risperidone.

There are side-effects of these medicines (such as somnolence, agitation, increased or decreased appetite) and the long-term effects remain unclear. Sometimes, however, behavioural challenges appear insurmountable and, given populist belief in cannabis, it is not surprising drug companies are rallying to the cause. But will it help? And at what cost?

 

Will cannabis help?

One of the first published observations on the effects of cannabis on autism was conducted in Israel by Raphael Mechoulam (foundational investigator of the physiology of cannabis) et al, and published in 2019[35]. Of parents of 188 autistic children administered cannabis, 93 responded to questions of their effect: 30 per cent reported significant improvement, 53.7 per cent moderate, 6.4 per cent slight and 8.6 per cent no change. Of 17 respondents from 23 parents who discontinued the trial, 12 reported no effect, and 5 reported side-effects including restlessness, sleepiness and psycho-activity. Of the 55 patients who had been taking antipsychotics (the most prevalent class of medications at the beginning of the trial), after six months of cannabis, the drug had been able to be withdrawn in 11 (20%), but needed to be continued at the original dose in 41 (75%).

Before assuming that reduction in doses of standard therapy suggests treatment by cannabis is more effective, it should be noted that Barchel et al, in a similar study, merely reported “non inferiority” of cannabis (THC:CBD, 1:20) to standard therapy for self-injurious behavioural disruption, anxiety and sleep disorder.[36] Also, ability to reduce the doses of standard therapy in association with cannabis may reflect their competition for metabolism, resulting in elevation of effective dose[37][38].

Furthermore, as to whether standard therapy is associated with structural and functional changes similar to those of THC, while there is concern over the effect of maternal anti-depressants on the brain of the unborn[39], and exposure to risperidone at a later age[40], there is nothing approaching the interruption by THC. To the contrary, some imaging studies have reported “normalisation”. [41][42][43][44][45]

Mechoulam’s study stands almost alone.[46][47][48] As reviewed by Xiong, “literature is sparse and does not recommend cannabis as an evidence based treatment for ASD symptoms and co-morbid conditions”. [49] Agarwal et al agree: “there is currently insufficient evidence for cannabis use in ASD”[50].

Mechoulam et al, themselves, conclude that a CBD-enriched treatment of autism “can potentially lead to an improvement in behavioural symptoms” but warned results “should be interpreted with caution” because they were based on uncontrolled “subjective self report” by parents who had sought the treatment, raising the possibility of “inflated expectations of the novel treatment ‘miracle’”.

Other obstacles to interpretation include the low rate of parental response—only 60 per cent in Mechoulam’s study, suggesting lack of enthusiasm in the rest. Also, the ratios of THC to CBD varied from almost straight THC to 1:1, 1:20, and even 1:75, and the doses of THC from 0.06 to 0.22 mg/kg/ day. Of course, none had untreated, blinded controls.

Mechoulam’s caution contrasts with promotional material from Zelira, in whose “self-reported outcomes survey of 50 participants using Zelira Therapeutics” there are claims of improvements similar to Mechoulam’s but the dosage is unclear.

 

How much cannabis will be administered?

Another Zelira publication reports tinctures of HOPE 1 were taken by 26 per cent, HOPE 2 by 54 per cent, and a combination of both, by 20 per cent [51] but the ultimate dose of THC was not defined. Drug representatives appear hesitant to define upper limits. They suggest one millilitre twice a day might suffice, but that could mean a range from 10 to almost 18 mg a day which, for a five-year-old could be 0.6 to 1.2 mg/kg/day and, for a ten-year-old, 0.3 to 0.6 mg/kg/day, which doses are much higher than in other reports.

Zelira’s most recent publication removes doubts about limitation of doses: it barely exists.[52] Writing only of HOPE 1 (though the stronger HOPE 2 also has TGA approval), Zelira laments, “The optimal dose … has not been established”, and that “without close supervision, parents take several months to [esclalate] their dose”. Zelira proposes a “more structured approach” in which doses are increased every two or three days over a “2 to 4 week period” until “unacceptable tolerability [sic] occurs”.

Initially, Zelira recommends a twice-daily dose but declares this may be increased to four times a day to achieve a “maintenance phase” characterised by “maximal benefits with minimal side effects”. If taken literally, and restricted to just once-daily doses, this extraordinarily open-ended advice could permit escalation from 1 to 14 ml per day with each millilitre containing up to 8.75 mg of psychoactive THC. That is, 122.5 mg could be given every day, in four divided doses of 30 mg, each with effects lasting four to six hours.

To put this in perspective, acute intoxication in an adult may result from 5 to 15 mg of THC. The Mayo Clinic[53] recommends THC doses of 2.1 mg to 8.4 mg twice a day to increase appetite in adults with AIDS. For adults suffering from refractory vomiting of cancer, Mayo advises doses of THC equivalent to 3 to 9 mg four to six times a day in an average five-year-old, and 5 to 14 mg in one aged ten. Expressed differently, 0.18 to 0.5 mg/kg/day should help adults vomiting with cancer: doses similar to Zelira’s initial rate for behavioural problems in children.

The sensitivity of brain cells to THC, and the magnitude of Zelira’s doses, are emphasised by reports that THC “might have potential to protect the brain” from neuro-inflammatory processes incurred in trauma and ageing if given in doses of 0.0002 mg/kg: 100 times lower than those resulting in conventional effect[54].

 

The brains of mice and humans

Zelira justifies minimisation of CBD by reference to research on the effects of THC and CBD on the brains of mice inbred for a genetic deficiency associated with behavioural effects not dissimilar to autism in humans[55]. To assess chronic administration, mice were given concoctions of THC and CBD twice a week, each containing a dose of THC equivalent to 17 mg for a five-year-old human. To assess the effect of acute exposure, another dose was given, after which, one hour later, behaviour was assessed.

Acutely, THC with some CBD reduced repetitive movements, anxiety and hyperactivity (reminiscent of autism) but was less successful than concentrated THC in improving “social defects”, as assessed by time spent sniffing strangers. Thus, it was concluded that CBD was counter-productive.

However, another conclusion is surely possible. The mice were given very large doses of THC with little or no moderating CBD. Could they have been too intoxicated (too stoned?) for repetitive scratching, running around, sniffing “Hello” to strangers, and taking things further if she agreed?

Regarding chronic effects, after six weeks, Zelira “found the long term use of THC did not significantly harm the working memory and motivation compared to the control mice”. They could still traverse a Y-shaped maze, and appeared to suffer no “increased susceptibility to negative mood” after being forced to swim.

Nowhere in its promotional material does Zelira sully its victory over autistic mice with mention of the known effects of THC on the growing brains of humans. Getting through a maze after a nasty swim is suggested to be more convincing of safety than all those functional and structural assessments of the effects of THC on the human brain with their pessimistic conclusions of harm.[56][57][58][59][60][61] Consumers should have faith: no discernible effect of THC on the one-gram brain of a mouse should negate fears of harm to the brain of a child, which is more than a thousand times larger, and infinitely more complex.

In practice, Zelira’s advice to increase doses until “unacceptable tolerability occurs” means increasing doses until the intoxicating power of THC subdues aggression and hyperactivity, or until undesirable side effects emerge. Thus, Zelira’s tinctures are likely to work.

The problem, of course, is the cost. Cognitive and emotional impairment will interfere with early intervention, and cellular toxicity will begin to erode structure and function. Then there is the matter of dependency.

 

What about dependency?

How long it takes a child’s brain to become dependent on THC is unknown. The mechanism includes down-regulation of receptors in order to reduce damage to the cell from sustained over-excitation. But, should that excitation be reduced (as in reduction of THC dosage), the new balance will be disturbed, and the cells will cry out for restitution in concert with the howling child.

Dependency has been reported in up to 37.2 per cent of chronic users, reflecting drug and environmental influences[62]. It has been reported in 20 per cent of those who begin consumption in adolescence, and 50 per cent of daily users, with rates rising with dosage and duration of consumption[63].

The marketing pitch of Zelira may reveal how long that company believes it takes to induce continued consumption of its products. Its representatives are offering free starter packs of one month’s supply of HOPE to the first five patients recruited by doctors. While this generosity saves families $200, one month may be all it takes to incur at least parental dependence on the drug.

As with other effects of THC, there are no regulated studies of dependency on the brains of children. Studies are restricted to the “growing” brains of the unborn and the adolescent in both rodents and humans, apparently neglecting the child. Yet, whereas the brain weight of a child reaches 90 per cent of that of an adult by five years, it adds another 5 per cent by the age of ten. Such growth has been confirmed by MRI studies which also reveal “sculpting” towards maturity.[64][65] Perhaps the very thought of a child being exposed to THC has, up until now, been unthinkable.

 

Where are the ethics?

Doctors are being encouraged to participate in this new unregulated experimentation on the brains of children. All they have to do is apply to the TGA for permission to prescribe cannabis, invoking failure of current therapy[66]. The TGA appears rarely to refuse but, in each case, passes medico-legal responsibility to the doctor by insisting that “fully informed consent” be secured from the parent. Pontius Pilate would be proud.

As to how the task of “fully informing” a parent dedicated to the mysteries of cannabis might be achieved is not answered. Nor is the greater question of who, in the halls of medical and governmental authority, has approved “the ethics” of administering a toxic drug to neuro-developmentally challenged children without regulated pre-clinical or clinical studies in animals or in children, and in the face of consistent, substantial evidence of harm?

Permission to prescribe cannabis to children flies in the face of the Commonwealth Narcotics Amendments Act 2016 which, according to explanatory notes, not only seeks to regulate production and distribution of home-grown cannabis for medicinal use, but to ensure its use is safe and based on scientific evidence. The Bill proclaims commitment to numerous human rights, except those protecting the child from unregulated experimentation. Nuremburg would not be proud.

Dr John Whitehall is a professor of paediatrics at a Sydney University.

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