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Epilepsy, Endocannabinoids and Phytocannabinoids

There's promise in the use of cannabis to manage epilepsy

Cannabidiol and several other cannabis components can help patients with seizure disorders, and sometimes it’s best to combine CBD with conventional anti-epileptic meds.
By Stacey Kerr, M.D. On November 25, 2017

Highlights:

• More than 5 million Americans suffer from epilepsy.
CBD is helping many patients, including children with seizure disorders.
THCA, the unheated form of THC, and linalool, an aromatic terpene present in many varieties of cannabis, are potent anticonvulsant compounds.
• Oftentimes, patients must experiment with different cannabis products to find the best remedy for their condition.

“David,” a 10 year old boy, had his first seizure at 2 months of age. The convulsions were photosensitive generalized tonic-clonic seizures that occurred 1-4 times each day. These events were occurring daily, even though he was being treated with two anti-seizure medications – lamotrigine (Lamictal) and valproic acid. But they had already tried carbamazepine, phenobarbital, zonisamide and levetiracetam (Keppra) without success.

On the recommendation of his physician, THCA was added to his medication at 0.05mg/kg/day and his parents immediately noticed a reduction in seizure frequency. They then increased the THCA dosage to 2.2mg/kg/day, and even though there was no benefit noted to this increased dosage, the parents continued at this higher amount. After three months of THCA treatment, his parents reported to his physician a 40% reduction in seizure activity, shorter seizures, and the ability to discontinue the anti-seizure medication Diastat, which they had been using for seizure rescue. Hoping for even more control, they began a formula that contained THC at a THCA:THC ratio of 4:1. This caused transient side effects of somnolence but did nothing to improve the frequency of seizures.

Even if it did not completely resolve his seizure disorder, the phytocannabinoid THCA was able to make a significant difference in David’s quality of life. He is not alone. Cannabis holds hope for many, like David, who suffer from seizure disorders.

Epilepsy is a complex medical, economic, and social issue that affects at least 5.1 million of the US population by 2013 population reports. In Hawaii, there are an estimated 15,000 patients with seizure disorders. The total indirect and direct cost of epilepsy in the United States is estimated to be $15.5 billion yearly. 1, 2 For the individuals and families of those patients with seizure disorders, life can be limited and extremely complicated depending on the type and frequency of seizures and on the effects of anti-seizure medications, both therapeutic and undesirable.

Seizures occur when a part of the brain becomes overly excited or when nerves in the brain begin to fire in an abnormal way. An abrupt imbalance between the triggers of excitatory signals and inhibitory signals causes the excitatory forces to take over. This excitation then spreads to surrounding cells which all start firing in the same abnormal way. Increased excitation of nerve cells, or decreased inhibition of nerve cells due to a variety of potential insults can lead to a seizure. Balance, or homeostasis, is disrupted.

Most epileptics have no known cause for their seizures. The minority have numerous identified causes that include trauma, infections, inborn metabolic errors, drugs (or withdrawal from drugs), and inherited conditions.

Conventional treatment

There are no treatments for the underlying causes of seizures, and no treatments to reliably prevent the development of seizures after head traumas. There are only medications to limit the seizure intensity or frequency, and these medications are not always effective. In fact, a third of epileptic patients fail to become seizure free even after trying and tolerating two or more appropriately prescribed anti-epileptic drugs (AEDs).3

More than 20 new seizure medications have been developed over the past few decades, but the percentage of patients with uncontrolled seizures has not changed as much as we would hope or expect. Patients who are resistant to AEDs have a higher risk of complications and sudden death due to epilepsy. The need for multiple AEDs also increases the occurrence of significant side effects. The need for better, safer, and more effective treatment is clear.

Safety profile

Cannabis is a safe medication with no incidence of fatalities due to the lack of cannabinoid receptors in the brainstem. The most common side effects reported among patients using cannabis for seizure control are fatigue, decreased appetite, and somnolence, all of which resolve when cannabis is discontinued. AEDs can have significant side effects, and contrary to cannabis some of these can be fatal.

It is important to note that there are some drug-drug interactions when using cannabis with AEDs because cannabinoids are primarily metabolized by the Cytochrome P-450 system in the liver. Competition for these enzymes can affect the serum levels of AEDs, so patients using cannabis in addition to prescribed AEDs should be monitored, and dosage adjustments may be needed.

The endocannabinoid system in epilepsy

The job of the endocannabinoid system is to maintain homeostasis, so it is no surprise that cannabis has been used to help control seizures for centuries. Well-designed studies on rats have shown that the endocannabinoid system is a significant part of the brain’s response to seizure disorders.

We know that cannabinoid receptors are particularly dense in the central nervous system, and while we do not yet completely understand all the mechanisms that explain the anti-seizure effects of cannabis, we do have theories.

There are cannabinoid receptors in the hippocampus, that part of the brain that handles emotions and memory encoding. Abnormal changes in cells in the hippocampus are a cause of medial temporal lobe epilepsy, which is one of the most common forms. In this type of epilepsy, hippocampal cells create an excitatory feedback loop that causes seizures. Animal and human studies show that cannabinoids seem to be protective of the normal hippocampal cells, and may make the abnormal cells less active.4

In acutely seizing animals, the endocannabinoid 2-AG was significantly increased compared to controls. By testing the levels of both anandamide and 2-AG we have seen that both are synthesized on demand when seizures occur, thus activating the CB1 receptors. It also appears that there is a significant increase in CB1 receptor expression in epileptic animals, a receptor increase that is prolonged and probably permanent.

In studies done on rats with refractory seizures, it was noted that THC completely terminated those seizures without causing sedation, while maximal levels of phenobarbital or phenytoin were unable to do the same. This indicates that phytocannabinoids may offer advantages in treating refractory seizures compared to currently prescribed anti-convulsants.5

In more recent years research on animal models and human clinical observations have rekindled interest in using cannabis to control epilepsy. Cannabinoids decrease glutamate synthesis throughout the central nervous system, which in turn decreases inflammation and seizure activity.6 Regardless of the mechanism, human clinical observations are promising for the use of cannabis as an anti-epileptic medication, either alone or as adjunctive therapy.

Specific cannabinoids as medicine

The evidence continues to indicate that whole-plant usage is more effective than any single isolated constituent, perhaps due to the entourage effect. Cannabis contains many cannabinoids, THC and CBD being only two of over 80 possibles. In addition, the plant contains terpenes which are medically active chemicals that give the plant its fragrance. Combining these constituents can decrease side effects from any single cannabinoid and together, and may be more effective in controlling seizures. 7 We do not yet know what the best combination is for any specific type of seizure but the evidence is strong enough to encourage more research efforts for answers.

CBD: Is CBD the primary cannabinoid that treats seizure disorders? It seems so if you consider the recent reports of use in severely affected children. CBD is certainly a major player, but not the only one. CBD has been clinically proven as an anticonvulsant for many and at worst, for a minority of patients with epilepsy, it gave no benefit. Its anti-convulsive effects are probably due to a combination of beneficial activities. CBD blocks NMDA receptors (similar to the AED Felbamate) and enhances GABA receptors (similar to phenobarbital and Depakote). It stabilizes ion channels (similar to Dilantin and Keppra), acts as an anti-inflammatory, and also as a neuroprotectant.8

THC: In some study models, THC reduced seizure frequency and intensity, but in others there was no effect. Some patients treated with THC had increased seizure activity.6

THCA: THCA, the acidic raw form of THC is non-psychoactive and also appears to have anti-seizure qualities.9

CBDV: Cannabidivarin or CBDV, is a non-intoxicating cannabinoid that also has significant anti-convulsant properties which were even more effective when combined with CBD.6,10

Alpha-linalool: The terpene alpha-linalool has been shown to have anti-seizure activity in pre-clinical models, especially when combined with cannabinoids.7,9

Dosing

Cannabis has a biphasic dose-response, meaning that more is not always better or more effective. This is more prevalent in THC than in CBD but patients and clinicians are cautioned to avoid the assumption that if a dose is not working, it should be increased. It very well may need to be decreased, especially if THC is part of the preparation.

Dosing for adults has been noted at amounts as small as .02 mg cannabinoids/kg/day, but the clinical trials done on Epidiolex (a purified CBD product made by GW Pharmaceuticals) tested a range of 2-50mg/kg/day. While dosing cannabis for seizures is still an evolving science, an experienced physician treating children for intractable seizures shares the following guidelines. First, an EEG is recorded prior to starting CBD oil and then repeated at 1-3 months if the child is showing improvement. Oral or sublingual dosing of a quality-controlled, lab-analyzed CBD oil with a ratio of at least 10:1 CBD:THC is started at 1mg/kg/day divided into every 8 hour doses. These doses are increased every 1-2 weeks depending on the child’s results. She notes that the therapeutic range for many patients appears to be between 4-9 mg/kg/day. As the seizures decrease in frequency, it is possible that the AEDs can be slowly weaned.10

The latest publication on the use of cannabis for the treatment of epilepsy comes from three physicians with experience in the states of Maine, Washington, and California. Of their 272 combined patients, fourteen percent found cannabis to be ineffective at reducing seizures, fifteen percent experienced a 1-25% reduction in seizures, twenty-eight percent experienced a 76-99% reduction, and ten percent had a complete clinical response.

CBD made the difference

When Sam was 4, he had his first myoclonic seizure, and those progressed to myoclonic absence seizures. Sam did not fall to the floor and twitch. Instead, sometimes 100 times a day, he lost consciousness for 20-30 seconds at a time. He stopped, stared vacantly, his head bobbed rhythmically and then it would all be over. He didn’t even notice these seizures, only that when he would come to, everything around him had shifted slightly. But it kept him from a normal life: having full conversations, from learning in school, and from participating in sports.

Sam had tried almost two-dozen treatments including intravenous immunoglobulin and a ketogenic diet. Few of these were effective, and those that were either had worrisome side effects (hand tremors, hives, zombie consciousness, etc.) or they quit working after a short while. By the time he was 11, he was on massive doses of corticosteroids – the only thing they’d found that made any difference – but the side effects were devastating. He’d been hospitalized twice and seen six neurologists in three states.

Then, as a last resort, his parents decided to try CBD. The effects were profound, but the road was “not a straight line,” to quote his father. CBD had immediately helped – dropping the seizure rate from 68 on a Thursday to 6 on the following Monday. A few years after starting the CBD, Sam was down to between 0 and 5 seizures a day on 1000mg of CBD and taking no other seizure medications. Then, he had his first-ever generalized tonic-clonic seizure. Three weeks later he had another, so Depakote was added to his regimen. The Depakote worked.

Sam is now 15 years old and has had 15 months without a seizure. To his parents, this is a relief and a miracle. He is taking 875mg of Depakote a day, and 250mg of CBD twice a day. Now active in sports, fly fishing and rock climbing, Sam gets to be a normal boy.

Clearly, there is promise in the use of cannabis to manage epilepsy and still much to learn.

Stacey Kerr MD is a teacher, physician, and author living and working in Northern California. Dr. Kerr was in private practice until she decided to write and educate full-time. After several years working with the Society of Cannabis Clinicians, and co-developing the first comprehensive online course in cannabinoid medicine, she is now serving as the Medical Director for Hawaiian Ethos, an evidence-based cannabis company on the Big Island of Hawaii.

This article was reprinted by Project CBD with permission. It may not be reproduced in any form without approval from the source.


1. (cdc.gov/epilepsy)

2. (http://www.epilepsy.com/hawaii)

3. Kwan P. Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342(5):314-9

4. Gloss, Vickrey. Cannabinoids for Epilepsy. The Cochrane Library, 2012

5. Wallace M.J. et al. The Endogenous Cannabinoid System Regulates Seizure Frequency and Duration in a Model of Temporal Lobe Epilepsy, Journal of Pharmacology and Experimental Therapeutics, Vol. 307:129–137, 2003

6. Devinsky et al. Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia, 55(6):791–802, 2014

7. Rosenberg EC, Tsien RW, Whalley BJ, Devinsky O. Cannabinoids and epilepsy. Neurotherapeutics. 2015;12:747–768

8. Jones NA, et al. 2010. Cannabidiol displays anti-epileptiform and anti-seizure properties in vitro and in vivo. Journal of Pharmacology and Experimental Therapeutics 332(2):569-577

9. Sulak D, et al. The current status of artisanal cannabis for the treatment of epilepsy in the United States, Epilepsy Behav (2017), http://dx.doi.org/10.1016/j.yebeh.2016.12.032

10. Hill et al, Cannabidivarin is Anticonvulsant in Mouse and Rat, Br J Pharmacol. 2012 Dec;167(8):1629-42. doi: 10.1111/j.1476-5381.2012.02207.x.

11. Elisabetsky E, Brum LS, Souza DO. Anticonvulsant properties of linalool in glutamate related seizure models. Phytomedicine 1999;6(2):107-13

12. Bonnie Goldstein MD. https://www.theroc.us/goldstein.pdf

Read More

Epilepsy, Endocannabinoids and Phytocannabinoids

There's promise in the use of cannabis to manage epilepsy

Cannabidiol and several other cannabis components can help patients with seizure disorders, and sometimes it’s best to combine CBD with conventional anti-epileptic meds.
By Stacey Kerr, M.D. On November 25, 2017

Highlights:

• More than 5 million Americans suffer from epilepsy.
CBD is helping many patients, including children with seizure disorders.
THCA, the unheated form of THC, and linalool, an aromatic terpene present in many varieties of cannabis, are potent anticonvulsant compounds.
• Oftentimes, patients must experiment with different cannabis products to find the best remedy for their condition.

“David,” a 10 year old boy, had his first seizure at 2 months of age. The convulsions were photosensitive generalized tonic-clonic seizures that occurred 1-4 times each day. These events were occurring daily, even though he was being treated with two anti-seizure medications – lamotrigine (Lamictal) and valproic acid. But they had already tried carbamazepine, phenobarbital, zonisamide and levetiracetam (Keppra) without success.

On the recommendation of his physician, THCA was added to his medication at 0.05mg/kg/day and his parents immediately noticed a reduction in seizure frequency. They then increased the THCA dosage to 2.2mg/kg/day, and even though there was no benefit noted to this increased dosage, the parents continued at this higher amount. After three months of THCA treatment, his parents reported to his physician a 40% reduction in seizure activity, shorter seizures, and the ability to discontinue the anti-seizure medication Diastat, which they had been using for seizure rescue. Hoping for even more control, they began a formula that contained THC at a THCA:THC ratio of 4:1. This caused transient side effects of somnolence but did nothing to improve the frequency of seizures.

Even if it did not completely resolve his seizure disorder, the phytocannabinoid THCA was able to make a significant difference in David’s quality of life. He is not alone. Cannabis holds hope for many, like David, who suffer from seizure disorders.

Epilepsy is a complex medical, economic, and social issue that affects at least 5.1 million of the US population by 2013 population reports. In Hawaii, there are an estimated 15,000 patients with seizure disorders. The total indirect and direct cost of epilepsy in the United States is estimated to be $15.5 billion yearly. 1, 2 For the individuals and families of those patients with seizure disorders, life can be limited and extremely complicated depending on the type and frequency of seizures and on the effects of anti-seizure medications, both therapeutic and undesirable.

Seizures occur when a part of the brain becomes overly excited or when nerves in the brain begin to fire in an abnormal way. An abrupt imbalance between the triggers of excitatory signals and inhibitory signals causes the excitatory forces to take over. This excitation then spreads to surrounding cells which all start firing in the same abnormal way. Increased excitation of nerve cells, or decreased inhibition of nerve cells due to a variety of potential insults can lead to a seizure. Balance, or homeostasis, is disrupted.

Most epileptics have no known cause for their seizures. The minority have numerous identified causes that include trauma, infections, inborn metabolic errors, drugs (or withdrawal from drugs), and inherited conditions.

Conventional treatment

There are no treatments for the underlying causes of seizures, and no treatments to reliably prevent the development of seizures after head traumas. There are only medications to limit the seizure intensity or frequency, and these medications are not always effective. In fact, a third of epileptic patients fail to become seizure free even after trying and tolerating two or more appropriately prescribed anti-epileptic drugs (AEDs).3

More than 20 new seizure medications have been developed over the past few decades, but the percentage of patients with uncontrolled seizures has not changed as much as we would hope or expect. Patients who are resistant to AEDs have a higher risk of complications and sudden death due to epilepsy. The need for multiple AEDs also increases the occurrence of significant side effects. The need for better, safer, and more effective treatment is clear.

Safety profile

Cannabis is a safe medication with no incidence of fatalities due to the lack of cannabinoid receptors in the brainstem. The most common side effects reported among patients using cannabis for seizure control are fatigue, decreased appetite, and somnolence, all of which resolve when cannabis is discontinued. AEDs can have significant side effects, and contrary to cannabis some of these can be fatal.

It is important to note that there are some drug-drug interactions when using cannabis with AEDs because cannabinoids are primarily metabolized by the Cytochrome P-450 system in the liver. Competition for these enzymes can affect the serum levels of AEDs, so patients using cannabis in addition to prescribed AEDs should be monitored, and dosage adjustments may be needed.

The endocannabinoid system in epilepsy

The job of the endocannabinoid system is to maintain homeostasis, so it is no surprise that cannabis has been used to help control seizures for centuries. Well-designed studies on rats have shown that the endocannabinoid system is a significant part of the brain’s response to seizure disorders.

We know that cannabinoid receptors are particularly dense in the central nervous system, and while we do not yet completely understand all the mechanisms that explain the anti-seizure effects of cannabis, we do have theories.

There are cannabinoid receptors in the hippocampus, that part of the brain that handles emotions and memory encoding. Abnormal changes in cells in the hippocampus are a cause of medial temporal lobe epilepsy, which is one of the most common forms. In this type of epilepsy, hippocampal cells create an excitatory feedback loop that causes seizures. Animal and human studies show that cannabinoids seem to be protective of the normal hippocampal cells, and may make the abnormal cells less active.4

In acutely seizing animals, the endocannabinoid 2-AG was significantly increased compared to controls. By testing the levels of both anandamide and 2-AG we have seen that both are synthesized on demand when seizures occur, thus activating the CB1 receptors. It also appears that there is a significant increase in CB1 receptor expression in epileptic animals, a receptor increase that is prolonged and probably permanent.

In studies done on rats with refractory seizures, it was noted that THC completely terminated those seizures without causing sedation, while maximal levels of phenobarbital or phenytoin were unable to do the same. This indicates that phytocannabinoids may offer advantages in treating refractory seizures compared to currently prescribed anti-convulsants.5

In more recent years research on animal models and human clinical observations have rekindled interest in using cannabis to control epilepsy. Cannabinoids decrease glutamate synthesis throughout the central nervous system, which in turn decreases inflammation and seizure activity.6 Regardless of the mechanism, human clinical observations are promising for the use of cannabis as an anti-epileptic medication, either alone or as adjunctive therapy.

Specific cannabinoids as medicine

The evidence continues to indicate that whole-plant usage is more effective than any single isolated constituent, perhaps due to the entourage effect. Cannabis contains many cannabinoids, THC and CBD being only two of over 80 possibles. In addition, the plant contains terpenes which are medically active chemicals that give the plant its fragrance. Combining these constituents can decrease side effects from any single cannabinoid and together, and may be more effective in controlling seizures. 7 We do not yet know what the best combination is for any specific type of seizure but the evidence is strong enough to encourage more research efforts for answers.

CBD: Is CBD the primary cannabinoid that treats seizure disorders? It seems so if you consider the recent reports of use in severely affected children. CBD is certainly a major player, but not the only one. CBD has been clinically proven as an anticonvulsant for many and at worst, for a minority of patients with epilepsy, it gave no benefit. Its anti-convulsive effects are probably due to a combination of beneficial activities. CBD blocks NMDA receptors (similar to the AED Felbamate) and enhances GABA receptors (similar to phenobarbital and Depakote). It stabilizes ion channels (similar to Dilantin and Keppra), acts as an anti-inflammatory, and also as a neuroprotectant.8

THC: In some study models, THC reduced seizure frequency and intensity, but in others there was no effect. Some patients treated with THC had increased seizure activity.6

THCA: THCA, the acidic raw form of THC is non-psychoactive and also appears to have anti-seizure qualities.9

CBDV: Cannabidivarin or CBDV, is a non-intoxicating cannabinoid that also has significant anti-convulsant properties which were even more effective when combined with CBD.6,10

Alpha-linalool: The terpene alpha-linalool has been shown to have anti-seizure activity in pre-clinical models, especially when combined with cannabinoids.7,9

Dosing

Cannabis has a biphasic dose-response, meaning that more is not always better or more effective. This is more prevalent in THC than in CBD but patients and clinicians are cautioned to avoid the assumption that if a dose is not working, it should be increased. It very well may need to be decreased, especially if THC is part of the preparation.

Dosing for adults has been noted at amounts as small as .02 mg cannabinoids/kg/day, but the clinical trials done on Epidiolex (a purified CBD product made by GW Pharmaceuticals) tested a range of 2-50mg/kg/day. While dosing cannabis for seizures is still an evolving science, an experienced physician treating children for intractable seizures shares the following guidelines. First, an EEG is recorded prior to starting CBD oil and then repeated at 1-3 months if the child is showing improvement. Oral or sublingual dosing of a quality-controlled, lab-analyzed CBD oil with a ratio of at least 10:1 CBD:THC is started at 1mg/kg/day divided into every 8 hour doses. These doses are increased every 1-2 weeks depending on the child’s results. She notes that the therapeutic range for many patients appears to be between 4-9 mg/kg/day. As the seizures decrease in frequency, it is possible that the AEDs can be slowly weaned.10

The latest publication on the use of cannabis for the treatment of epilepsy comes from three physicians with experience in the states of Maine, Washington, and California. Of their 272 combined patients, fourteen percent found cannabis to be ineffective at reducing seizures, fifteen percent experienced a 1-25% reduction in seizures, twenty-eight percent experienced a 76-99% reduction, and ten percent had a complete clinical response.

CBD made the difference

When Sam was 4, he had his first myoclonic seizure, and those progressed to myoclonic absence seizures. Sam did not fall to the floor and twitch. Instead, sometimes 100 times a day, he lost consciousness for 20-30 seconds at a time. He stopped, stared vacantly, his head bobbed rhythmically and then it would all be over. He didn’t even notice these seizures, only that when he would come to, everything around him had shifted slightly. But it kept him from a normal life: having full conversations, from learning in school, and from participating in sports.

Sam had tried almost two-dozen treatments including intravenous immunoglobulin and a ketogenic diet. Few of these were effective, and those that were either had worrisome side effects (hand tremors, hives, zombie consciousness, etc.) or they quit working after a short while. By the time he was 11, he was on massive doses of corticosteroids – the only thing they’d found that made any difference – but the side effects were devastating. He’d been hospitalized twice and seen six neurologists in three states.

Then, as a last resort, his parents decided to try CBD. The effects were profound, but the road was “not a straight line,” to quote his father. CBD had immediately helped – dropping the seizure rate from 68 on a Thursday to 6 on the following Monday. A few years after starting the CBD, Sam was down to between 0 and 5 seizures a day on 1000mg of CBD and taking no other seizure medications. Then, he had his first-ever generalized tonic-clonic seizure. Three weeks later he had another, so Depakote was added to his regimen. The Depakote worked.

Sam is now 15 years old and has had 15 months without a seizure. To his parents, this is a relief and a miracle. He is taking 875mg of Depakote a day, and 250mg of CBD twice a day. Now active in sports, fly fishing and rock climbing, Sam gets to be a normal boy.

Clearly, there is promise in the use of cannabis to manage epilepsy and still much to learn.

Stacey Kerr MD is a teacher, physician, and author living and working in Northern California. Dr. Kerr was in private practice until she decided to write and educate full-time. After several years working with the Society of Cannabis Clinicians, and co-developing the first comprehensive online course in cannabinoid medicine, she is now serving as the Medical Director for Hawaiian Ethos, an evidence-based cannabis company on the Big Island of Hawaii.

This article was reprinted by Project CBD with permission. It may not be reproduced in any form without approval from the source.


1. (cdc.gov/epilepsy)

2. (http://www.epilepsy.com/hawaii)

3. Kwan P. Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342(5):314-9

4. Gloss, Vickrey. Cannabinoids for Epilepsy. The Cochrane Library, 2012

5. Wallace M.J. et al. The Endogenous Cannabinoid System Regulates Seizure Frequency and Duration in a Model of Temporal Lobe Epilepsy, Journal of Pharmacology and Experimental Therapeutics, Vol. 307:129–137, 2003

6. Devinsky et al. Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia, 55(6):791–802, 2014

7. Rosenberg EC, Tsien RW, Whalley BJ, Devinsky O. Cannabinoids and epilepsy. Neurotherapeutics. 2015;12:747–768

8. Jones NA, et al. 2010. Cannabidiol displays anti-epileptiform and anti-seizure properties in vitro and in vivo. Journal of Pharmacology and Experimental Therapeutics 332(2):569-577

9. Sulak D, et al. The current status of artisanal cannabis for the treatment of epilepsy in the United States, Epilepsy Behav (2017), http://dx.doi.org/10.1016/j.yebeh.2016.12.032

10. Hill et al, Cannabidivarin is Anticonvulsant in Mouse and Rat, Br J Pharmacol. 2012 Dec;167(8):1629-42. doi: 10.1111/j.1476-5381.2012.02207.x.

11. Elisabetsky E, Brum LS, Souza DO. Anticonvulsant properties of linalool in glutamate related seizure models. Phytomedicine 1999;6(2):107-13

12. Bonnie Goldstein MD. https://www.theroc.us/goldstein.pdf

Read More

Bugs, Mold and Excrement

New regulations for mold and foreign filth are absurdly loose

Welcome to the Brave New World of California Cannabis with No Plant Limits
By Adrian Devitt-Lee On November 25, 2017

Project CBD critiques the new regulations for America’s largest marijuana market

On November 16, 2017, California officials released a new set of regulations for cannabis manufacturing, testing, and growing. In many respects, these updates are a significant improvement to the initial draft regulations, however, some major problems remain.

Two important issues pertain to regulations on mold and foreign filth, which are absurdly loose. And unlike the initial proposal, no statement as to the rationale behind the new regulations has been released.

Safety requirements

Allowable limits for contaminants including pesticides, solvents, and microbes are described in sections 5718-5723 of the new regulations. These regulations have fixed a major issue in the initial draft where two different units were confused – parts per million by weight (µg/g) and parts per million by volume. Now solvent and pesticide limits are given in µg/g.

Other significant changes:

  • Solvent limits are largely improved. Certain class 2 solvents have been banned, as Project CBD had previously suggested.
  • Pesticide limits have swung from being very strict to being overly lax. The environmental concerns related to pesticide overuse appear more problematic than the health effects for consumers.
  • Many pesticide safety limits are still based on regulations for tobacco, which is entirely inappropriate.
  • Required tests for microbial contamination are minimal.
  • Limits on mold – one of the most common contaminants of cannabis – are nearly nonexistent. A product is deemed to pass regulations if less than 1/4th of it is covered in mold.

Solvents – §5718

Solvents are broken into two categories for the purpose of regulations. Category 1 solvents are banned and are not permissible at any detectable levels in cannabis products. Category 2 solvents are allowed up to set action limits that depend on the solvent in question and whether the product is inhaled or not. Action limits for non-inhaled products were appropriate in the initial draft proposal and have not changed.

The initial proposed regulations allowed for the use of highly dangerous solvents, including benzene, which Project CBD suggested be banned from use in cannabis manufacturing. We also suggested that regulators consider banning “class 2” solvents such as chloroform, since they are unnecessary for producing most kinds of cannabis extracts.1

The new regulations now ban the use of benzene and some class 2 solvents like chloroform, but allow other class 2 solvents, including hexane. (Hexane is rarely used to extract oil from cannabis, but is sometimes used to clean the oil of pesticides or other adulterants.) Although Project CBD hopes that cannabis manufacturers avoid using hexane to extract or clean oil, we believe these regulations are appropriate.

Each permissible solvent has a maximum allowable concentration in inhaled cannabis products (e.g. vape cartridges). In the initial draft proposal, these limits were based on safety data from California’s Occupational Health and Safety Administration (OSHA), although the limits were improperly calculated due to confusion with units. (“Parts per million” can have multiple meanings, as mentioned above. See the previous Project CBD statement for more detail.) The new limits are particularly stringent for some class 2 solvents and are overly lenient for ethanol residues.2 On the whole, the new limits are sensible.

Image

The list of banned pesticides has shrunk dramatically

Pesticides – §5719

Similar to solvents, pesticides are broken into banned pesticides, which are not allowed at any detectable concentration, and allowed pesticides. The action limits for permitted pesticides depend on whether the product is inhaled or not.

The regulations were released with only 5 days for public comments – including the weekend – and were not accompanied by any statement of reasons explaining how new safety limits were determined. As such, Project CBD‘s comments on the new pesticide regulations point out potential problems without necessarily suggesting how these issues could be fixed or their extent.

In the new regulations, the list of banned pesticides has shrunk dramatically, from 42 to 21. One of these now-allowed pesticides is a neonicotinoid (acetamiprid) and four others have “high acute toxicity” to humans, according to the initial statement of reasons (bifenthrin, cyfluthrin, naled, and abamectin). Most of the rest of the now-allowed pesticides, including myclobutanil (often sold Eagle-20), were banned in the original proposal due to environmental concerns.

The initial set of draft regulations on pesticides were very strict in some regards. The limit of detection (LOD) – which is the lowest concentration of a compound that can be detected reliably – was arbitrarily set at 0.01 – 0.02 µg/g. This is lower than the actual LOD of pesticides in cannabis for most labs. This has changed – now labs will determine their LODs scientifically and list these LODs on lab reports.3 This is an important fix.

To reiterate: because no statement of reasons has been released, we do not know the rationale behind the limits for pesticides on non-inhaled products. But we can say with some certainty that it is not based on the relative safety of these pesticides.

Safe limits for pesticide ingestion are given as the acceptable daily intake (ADI) or acute reference dose (ARfD), and are reported by the World Health Organization. The ADI indicates a level of pesticide ingestion that is considered safe for chronic daily use, which makes sense for food or medicine. Converting the ADI into a limit for a pesticide in cannabis products depends on the amount of product that is consumed. If the limits were based on safe ingestion limits, the ratio of the ADI to the action limit would be constant. In the current proposal, this ratio varies from 2.5 to 750, a 300-fold difference. Pesticides like trifloxystrobin, bifenazate, and permethrin have very high action limits compared to their toxicity when ingested.

It appears that the limits were not based on environmental concerns either: Of the seven least regulated pesticides (e.g. those with the highest allowable limits), five were originally banned due to potential ground water contamination.

For inhaled products, the limits still appear to be based on tobacco, as described in the initial statement of reasons. This may be because very little is known about the effects of heating or burning pesticides (an information vacuum attributable to lobbying from the tobacco industry). Some pesticides will, in fact, become safer when burned, while many others will break down to much more toxic compounds.

The EPA has previously stated that it need not study the health effects of burning pesticides at concentrations below 0.1 µg/g in cigarettes because those individuals are already smoking tobacco, a harmful substance. After all, nicotine is the insecticide upon which neonicotinoids are based.

It may be true that inhaling less than 0.1 µg/g of most pesticides is safe. But regulations need to be based on scientific data. If safety data on burning and inhaling pesticides is not available, then the law should include provisions to be updated as new data emerges.

The outcomes of the tobacco industry’s war against science should never be used as the basis of safety regulations for another industry. Tobacco is the leading cause of preventable deaths in the United States, killing roughly half a million people every year. This is precisely because the tobacco industry lobbied to ensure that scientific data on health and safety was not used to inform laws or regulations. That should not be the starting point for any aspect of the emerging cannabis industry.

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A sample could pass with one rodent hair

Foreign material – §5722

The foreign material testing, described in §5722, is beyond the pale. §5722(e) states that:

A sample shall be deemed to have passed the foreign material testing if the presence of foreign material does not exceed:
(1) 1/4 of the total sample area covered by sand, soil, cinders, or dirt;
(2) 1/4 of the total sample area covered by mold;
(3) 1 insect fragment, 1 rodent hair, or 1 count mammalian excreta per 3.0 grams; or
(4) 1/4 of the total sample area covered by an
imbedded foreign material.

A small piece of chocolate weighs about 3.5 grams. Under the new regulations, a 16-piece chocolate bar would be considered acceptable if four pieces were covered in dirt, four more were covered in mold, and each of the 16 pieces had an insect part or rat poop on it.

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Labs are not required to test for mold

Microbes – §5720

There is an unprecedented change in regulations on microbial contamination. Cannabis is not required to be free of mold nor are labs required to test for mold. The only limit on mold is given in (2) of the foreign filth section quoted above, which states that up to 1/4th of a product can be covered in mold.

Under the new proposal, products only need to be screened for three microbes: pathogenic E. coli, salmonella, and in the case of inhaled products, aspergillus. Since no statement of reasons were released with the regulations, it is not clear why California is so loose with microbes.

Giving regulators the benefit of the doubt, it may be that they are trying not to restrict the use of beneficial microbes, an organic growing practice that uses non-harmful microbes as an alternative to pesticides. But mold is one of the most common contaminants on cannabis. It is absolutely essential to test for mold on cannabis, particularly when grown indoors.

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Testing will be phased in over the course of a year

Phase in of safety testing – §5715

The regulations have been released with just over a month before they will be implemented. To ease the burden on labs, testing will be phased in over the course of a year. This gives labs time to develop and validate methods for each kind of product and each kind of test.

On January 1, 2018, all legal products must be tested for cannabinoids, allowed solvents, banned pesticides, microbes, and product homogeneity.4 On July 1, 2018, three additional tests will be required: banned solvents, allowed pesticides, and foreign material. On January 1, 2019, heavy metals, mycotoxins, and possibly terpenes will also be tested before sales.

Project CBD hopes that terpene testing will become mandatory as this will help to illuminate the therapeutic properties of these important plant components.

Other regulations

There are many important aspects of the new regulations that address issues beyond consumer safety. Here are some key points:

  • There is effectively no longer a limit on the size of grows. Each license allows a group or individual to grow up to one acre of cannabis, but there is no limit on the number of licenses a group can get. Project CBD shares the concerns of farmers who are worried that this will allow large-scale agriculture to push out smaller, more sustainable gardens. Privileging wealthy out-of-state investors and big players at the expense of family farmers is bad policy with unhealthy long-term implications for California’s economy and environment.
  • Law enforcement are allowed to copy the materials, records, and books of any employee of any licensed cannabis business. See §5800(a)(4).
  • Recreational products can’t be given away for free. Medical patients can be given free products through a compassionate care program, but this program must be run by a local jurisdiction, not a cannabis business. Moreover, only licensed retailers (e.g. a legal dispensary), not product manufacturers, can provide free products to patients. See §5411.
  • Medical patients under the age of 18 cannot be served at a dispensary. Their caregiver must buy product for them. See §5400(b).
  • Edibles are required to contain no more than 10 mg THC per serving and 100 mg THC per package. Other products must contain less than 1000 mg or 2000 mg THC per package, depending if the product is recreational or medical. See §40306.
  • Edibles cannot contain any other addictive substances, including caffeine, alcohol, and nicotine. Exceptions are made for cannabis chocolate, tea, and coffee. See §40300(b).
  • Labs are required to be certified by one of two (ISO or IEC). This will help ensure the accuracy and consistency of lab tests, which has been problematic in the past.
  • It is now much easier to get a license to do ethanol extraction, since it is considered a “nonvolatile solvent.” See the definition of “nonvolatile solvent” in §40100.

Adrian Devitt-Lee, a Project CBD contributing writer, is a research associate at CannaCraft, Inc., a Northern California-based medical marijuana company.

Copyright, Project CBD. May not be reprinted without permission.


1 Solvents are classified into one of three groups by the FDA. Class 1 solvents like benzene are either very toxic or environmental hazards and should be avoided in manufacturing if at all possible. Class 3 solvents like ethanol and butane are fairly safe at low concentrations. Class 2 solvents like chloroform and dichloromethane are less dangerous than class 1 solvents, but should be avoided if the use of a class 3 solvent is possible.
2 This is not to say that the allowable limits are wrong. But compared to safety data from OSHA, limits are disproportionately lax for ethanol and strict for class 2 solvents.
3 A second number to be listed on lab reports is the limit of quantification (LOQ), which is at least as large as the LOD. The LOQ is the limit at which the concentration of a chemical can be accurately discerned. The range between the LOD and the LOQ is the range of concentrations where a test can show that a chemical is present, but cannot determine its exact concentration.
4 Products with multiple servings (e.g. a chocolate bar) will be tested every 6 months to ensure that every piece has roughly the same amount of cannabinoids in it. Specifically, the relative standard deviation must be less than 10% of the mean amount of each cannabinoid.

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More FDA Warnings, Mislabeled CBD Products & Police Raids

A series of police raids in North Dakota has set the stage for a courtroom showdown regarding the legal status of cannabidiol (CBD), the non-intoxicating cannabis component with significant medical properties. Thus far, it’s not going well for purveyors of the claim that hemp-derived CBD is legal in all 50 U.S. states.
By Martin A. Lee On November 10, 2017

Highlights:
  • The FDA has issued more warning letters to hemp CBD companies for making unsubstantiated medical claims.
  • A study published in the Journal of the American Medical Association indicated that 69 percent of hemp CBD products tested did not contain the amount of cannabidiol indicated on the label.
  • Sporadic police raids continue to target CBD retailers in several states.
  • A legal battle over the status of hemp-derived CBD looms in federal court.

A series of police raids in North Dakota has set the stage for a courtroom showdown regarding the legal status of cannabidiol (CBD), the non-intoxicating cannabis component with significant medical properties. Thus far, it’s not going well for purveyors of the claim that hemp-derived CBD is legal in all 50 U.S. states.

In October 2017, Northwest District Judge Robin Schmidt refused to dismiss drug trafficking charges against Falesteni Abuhamda, the owner of two North Dakota tobacco stores, which allegedly sold products containing CBD with very little or no psychoactive THC [tetrahydrocannabinol]. Abuhamda’s attorney argued that the CBD products were legal because the CBD oil was extracted from the stalk of industrial hemp.

But a forensic scientist with the state’s crime lab easily debunked this argument by stating the obvious: CBD is not found in any appreciable amount in hemp stalk. Rather it exudes from the resinous flowers and leaves of the cannabis plant. And, therefore, CBD is forbidden under the Controlled Substances Act, according to the Drug Enforcement Administration (DEA).

FDA saber-rattling

The Food and Drug Administration (FDA), which defers to the DEA on cannabis-related matters, considers CBD to be an experimental pharmaceutical undergoing evaluation. In early November, the FDA sent letters to several companies selling hemp-derived CBD products warning that they were violating the Federal Food, Drug and Cosmetic Acts.

This was the third time in recent years that the FDA has issued warnings to CBD manufacturers and retailers, which market hemp-derived CBD products as nutraceuticals or food supplements. The most recent round of FDA warning letters did not involve false statements about the source of the CBD extracts. Instead, the agency objected to unsubstantiated medical claims allegedly made by four CBD oil producers: Greenroads Health, Natural Alchemist, That’s Natural! Marketing and Consulting, and last but not least, the Stanley Brothers.

Some of these unsubstantiated claims, according to the FDA, included patient testimonials and assertions that CBD “may be effective in treating tumors from cancer” and other diseases. Thus far, however, there have been no FDA-approved clinical trials that might validate preclinical studies and anecdotal accounts of CBD‘s anti-cancer properties.

Today one can easily purchase unregulated CBD products online and at some supermarkets and storefronts across the nation. For the most part, it’s a crapshoot for consumers: A new study published in the Journal of the American Medical Association disclosed that only 31 percent of 84 lab tested hemp-derived CBD products contained the amount of CBD indicated on the label. And who knows what else was in some of these products.

Sporadic raids

While CBD currently seems to be a low priority for federal law enforcement agencies, in recent months there have been sporadic local police raids against CBD retailers in several states besides North Dakota, including (but not limited to):

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Ongoing polics raids
  • Indiana. In April 2017, Governor Eric Holcomb signed a bill allowing people with treatment-resistant epilepsy who register with the state to possess CBD products that contain less than 0.3 percent THC. Shortly thereafter, a law enforcement crackdown on CBD retailers resulted in the seizure of more than 3000 CBD products from about 60 stores throughout the Hoosier State. In August, Indiana’s Alcohol and Tobacco Commission declared a moratorium on CBD raids “unless the products clearly violate Indiana law.” Since the moratorium announcement, Indiana excise police have continued to issue citations to stores selling CBD.
  • Missouri. Vince Sanders, owner of American Shaman, a Kansas City-based wholesaler, supplied CBD products to several stores in Missouri and Kansas. He says his products are legal because they are made from industrial hemp and contain hardly any THC. But Missouri law only allows for low-THC cannabis oil to be sold by manufacturers that are licensed by the state health department, which is not the case for American Shaman.
  • Kansas. Kansas is a zero tolerance state when it comes to THC – hardly any is too much in Kansas. Eddie Smith, owner of Into The Mystic, was surprised when police officers showed up at his alternative medicine store in Mission, Kansas, in May 2017 and confiscated an array of hemp-derived CBD products. During a previous visit, an undercover cop purchased some CBD from Smith’s store. A 22-year-old U.S. Army veteran, Smith protested that he had been told “with 100 percent certainty that [CBD] is totally legal in all 50 states.”
  • Wisconsin. In May 2017, police raided several gas stations in Oshkosh, Wisconsin, which sold CBD products. A month later, police busted two storefronts in Franklin, Wisconsin, for retailing CBD-infused gummies that contained traces of THC. The store owners said that they had been assured by the wholesale CBD vendor that the products were legal to sell and possess. But Wisconsin law stipulates that CBD can only be dispensed by a pharmacist or physician – not a gas station – to a patient who has been certified to possess cannabidiol for treating a specific medical condition.
  • Ohio. In August 2017, police returned 18 bottles of hemp-derived CBD to Poor Boys Smoke Shop in Marysville, Ohio, after a Union County prosecutor declined to press charges stemming from a law enforcement raid two years earlier. Medical marijuana is technically legal in Ohio, but corrupt licensing procedures have stymied patient access to cannabis and CBD-rich products.
  • Nebraska. In September 2017, Nebraska Attorney General Doug Peterson declared that CBD sales in the Cornhusker State are flat-out illegal. But under state law, the University of Nebraska Medical Center has the authority to distribute CBD to certified patients who participate in an experimental research program. CBD commerce outside of the university program is strictly forbidden. “To date no drug products containing CBD have received FDA approval,” Peterson noted.
  • Massachusetts. Two detectives visited Jay’s Smoke Shop in Taunton, MA, to inform the proprietor that it was not okay to sell CBD products at his store, even though residents in the Bay State had voted to legalize cannabis both for medical and adult use. It’s currently legal to possess and use cannabis, including CBD-rich products, in Massachusetts, but not in public or while driving a vehicle. Storefront sales won’t be authorized until 2018 at the earliest.

Complicated laws

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Source: Wikipedia “Legality of cannabis by U.S. jurisdiction”

Currently eight states plus the District of Columbia have legalized cannabis for both medical and adult use; twenty-one more states allow the therapeutic use of cannabis to some degree, but not recreational use; and 18 states have legalized CBD, but not the whole plant or cannabis products containing higher levels of THC. Only three states consider every part of the cannabis plant, including CBD, to be illegal.

Does this mean that cannabidiol is actually legal in most of the United States?

Yes, sort of … maybe.

Confusion regarding CBD‘s status stems in part from the patchwork of complicated laws that vary from state to state. But the main problem is Uncle Sam’s abject refusal to acknowledge what has been known throughout the world for centuries: cannabis has significant medical value. Cannabis prohibition, a draconian, racist relic, is based on a mountain of lies, and until this anachronistic policy is terminated, attempts to sort out the legal status of CBD will be mired in contradiction and uncertainty.

Most so-called CBD-only states allow possession of very low or no-THC cannabis products, but do not allow licensed dispensaries, production facilities or home cultivation. In other words, one can possess CBD, but one can’t legally buy it or sell it. Overly restrictive laws in CBD-only states often limit the use of CBD products to children with treatment-resistant seizure disorders.

But even in states with legal protections for CBD users, the substance is still technically forbidden under federal law. Several bills are pending in Congress to extricate CBD from the Controlled Substances Act. Such efforts would not be necessary if CBD was federally legal.

No resin, no THC, no CBD

Undaunted, some CBD proponents believe that cannabidiol is already legal by virtue of a 2004 Ninth Circuit U.S. Appeals Court decision (Hemp Industries Association v. DEA) that struck down the DEA‘s attempt to ban hemp food products. But this decision never mentioned CBD and the reasoning behind it undermines the notion that hemp stalk is a viable source of CBD.

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No resin, no THC, no CBD

The Ninth Circuit rejected the DEA‘s argument because hemp food products aren’t made from the resin-bearing parts of the plant – the flower tops and leaves – that contain THC and other proscribed cannabinoids.

Hemp-derived protein powder and nutritional supplements are made from hempseed, which has no resin, no THC and no CBD; thus hemp food, according to the Ninth Circuit ruling, is exempt from the Controlled Substances Act.

The DEA lacked credibility when it argued that hemp food should be banned because it comes from hempseed (which is resin-deficient). And today’s CBD hemp companies lack credibility when they try to skirt the law by arguing that their CBD comes from hemp stalk (which is resin-deficient).

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2014 Farm Bill

The Farm Bill exception

The 2014 Farm Bill also makes no mention of CBD, but it is often cited by domestic hemp producers as the reason why CBD is federally legal. The Farm Bill defines industrial hemp as cannabis that contains 0.3 percent THC or less. Cannabis with more than 0.3 percent THC in any part of the plant is considered marijuana and is therefore illegal under federal law.

Most significantly, the Farm Bill carved out an exception to the Controlled Substances Act for industrial hemp that is cultivated under the auspices of a state-sanctioned agricultural or academic research program. (The Farm Bill doesn’t specify what constitutes “research.”) Thus far, twenty-three states have enacted laws pertaining to industrial hemp. And for the first time since World War II, industrial hemp is being grown – supposedly for research purposes –in many parts of the United States.

The Omnibus Appropriations Act of 2016 gave another boost to the fledgling domestic hemp industry by stipulating that federal funds could not be used “to prohibit the transportation, processing, sale or use of industrial hemp that is grown or cultivated in accordance with [the Farm Bill]” – in other words, neither the DEA nor state law enforcement can prevent interstate commerce involving industrial hemp.

Does this mean that CBD oil extracted from hemp grown in Kentucky or Colorado is legal to process, sell and transport across state lines, as long as it doesn’t have more than 0.3 percent THC?

The Hemp Industries Association says yes. The DEA says no.

Legal battle looming

In December 2016, the DEA issued an administrative tracking code for cannabis oil extracts, including CBD concentrates and isolates derived from hemp biomass as well as from marijuana leaves and flower tops. This tracking code did not ban CBD because CBD has always been illegal under the 1970 Controlled Substances Act, which forbids any preparation made from cannabis resin. All the phytocannabinoids, including CBD and THC, reside in the resinous trichomes of the cannabis plant.

The Hemp Industries Association (HIA) maintains that the DEA failed to recognize the legal distinction between marijuana and hemp, as defined by the Farm Bill, when it announced the new tracking code for cannabis oil extracts. So in January 2017, the HIA filed a judicial review petition that challenged the DEA‘s churlish administrative maneuver.

Until a federal judge weighs in, robust CBD commerce will continue in a confusing legal environment, while sports stars and celebrities sing the praises of CBD and medical patients clamor for quality cannabis oil extracts.

About the Author:

Martin A. Lee is the director of Project CBD and author of Smoke Signals: A Social History of Marijuana – Medical, Recreational and Scientific.


1 Even though 0.3 percent THC is an arbitrary political number with no scientific basis, it has become the current standard that much of the world uses to distinguish hemp from marijuana. The 0.3 percent legal limit for THC is based on the work of Canadian cannabis researcher Ernst Small, who wrote The Species Problem with Cannabis. In this book, Small acknowledged that there isn’t a natural dividing point at which cannabinoid content could be used to distinguish hemp from other kinds of cannabis. Nevertheless, he chose 0.3 percent THC as where to draw the line on the continuum of cannabis types.
2 The 1970 Controlled Substances Act defines “marihuana” as “all parts of the plant Cannabis sativa L. [sic], whether growing or not; the seeds thereof; the resin extracted from any part of such plant; and every compound, manufacture, salt, derivative, mixture, or preparation of such plant, its seeds or resin. Such term does not include the mature stalks of such plant, fiber produced from such stalks, oil or cake made from the seeds of such plant, any other compound, manufacture, salt, derivative, mixture, or preparation of such mature stalks (except the resin extracted therefrom), fiber, oil or cake, or the sterilized seed of such plant which is incapable of germination.”

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