- Thread starter
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Great article SweetSue! Thanks for posting it
You’re welcome Shed.
I’ve posted it before, but not with notes. I learn something new every time I read it.
SweetSue's Class Notes
- Thread starter SweetSue
- Start date
You’re welcome Shed.
I’ve posted it before, but not with notes. I learn something new every time I read it.
Derbybud
Well-Known Member
So do I. Thanks Sue for the added notes.
- Thread starter
- #443
Abbreviations: 5-HT1A, serotonin 1A receptor; AE, adverse events; AIDS, acquired immunodeficiency syndrome; CB1, cannabinoid-one receptor; CB2, cannabinoid-two receptor; CBD, cannabidiol; CBDA, cannabidiolic acid; CRISP-R, Clustered Regularly Interspaced Short Palindromic Repeats; ECS, endocannabinoid system; GAP, Good Agricultural Practice; GCP, Good Clinical Practice; GMP, Good Manufacturing Practice; HIV, human immunodeficiency virus; MS, multiple sclerosis; PAH, polycyclic aromatic hydrocarbon; RCT, randomised controlled trial; THC, Δ9-tetrahydrocannabinol; THCA, tetrahydrocannabinolic acid; TRPV1, transient receptor potential cation channel vanilloid subfamily receptor 1; USAN, United States Adopted Name
⁎ Corresponding author.
E-mail addresses: info@drcarolinemaccallum.com (C.A. MacCallum), ethan.russo@icci.science (E.B. Russo).
Received 27 October 2017; Accepted 1 January 2018
0953-6205/ © 2018 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
Please cite this article as: MacCallum, C.A., European Journal of Internal Medicine (2018), Redirecting
Practical considerations in medical cannabis administration and dosing
Caroline A. MacCallum a,⁎, Ethan B. Russo b
Practical considerations in medical cannabis administration and dosing
a Faculty of Medicine, University of British Columbia, BC, Canada
b International Cannabis and Cannabinoids Institute, Prague, Czech Republic
ARTICLE INFO
Keywords:
Cannabis Cannabinoids Marijuana
Drug abuse Psychopharmacology Adverse events
ABSTRACT
Cannabis has been employed medicinally throughout history, but its recent legal prohibition, biochemical complexity and variability, quality control issues, previous dearth of appropriately powered randomised con- trolled trials, and lack of pertinent education have conspired to leave clinicians in the dark as to how to advise patients pursuing such treatment. With the advent of pharmaceutical cannabis-based medicines (Sativex/na- biximols and Epidiolex), and liberalisation of access in certain nations, this ignorance of cannabis pharmacology and therapeutics has become untenable. In this article, the authors endeavour to present concise data on can- nabis pharmacology related to tetrahydrocannabinol (THC), cannabidiol (CBD) et al., methods of administration (smoking, vaporisation, oral), and dosing recommendations. Adverse events of cannabis medicine pertain primarily to THC, whose total daily dose-equivalent should generally be limited to 30 mg/day or less, preferably in conjunction with CBD, to avoid psychoactive sequelae and development of tolerance. CBD, in contrast to THC, is less potent, and may require much higher doses for its adjunctive benefits on pain, inflammation, and attenuation of THC-associated anxiety and tachycardia. Dose initiation should commence at modest levels, and titration of any cannabis preparation should be undertaken slowly over a period of as much as two weeks. Suggestions are offered on cannabis-drug interactions, patient monitoring, and standards of care, while special cases for cannabis therapeutics are addressed: epilepsy, cancer palliation and primary treatment, chronic pain, use in the elderly, Parkinson disease, paediatrics, with concomitant opioids, and in relation to driving and hazardous activities.
1. Introduction
Cannabis has a history of medical application likely exceeding that of the written word, including mainstream usage in Europe and North America for a century between 1840 and 1940 [1,2]. It is only in the last century that quality control issues, the lack of a defined chemistry, and above all, politically and ideologically motivated prohibition relegated it planta non grata. The discovery and elucidation of the endocannabinoid system [3], coupled with a popular tidal wave of anecdotal accounts and renaissance of therapeutic clinical trials renders that status quo ante untenable.
One preparation, Sativex® (USAN: nabiximols), an oromucosal cannabis-based medicine with 2.7 mg of THC and 2.5 mg CBD plus terpenoids per spray has attained regulatory approval in 29 countries for treatment of spasticity in multiple sclerosis, having met the standards of safety, efficacy and consistency required of any pharmaceutical. The problem for physicians with respect to treatment with herbal cannabis remains acute, however: How does the responsible healer and medical scientist approach the desperate patient for whom conventional medicine has failed and wishes to avail themselves of a purportedly healing herb that has been an international societal outlaw for decades? The answer is simple: educational and scientific standards apply to the cannabis controversy equally with that of any other putative therapy.
Unfortunately, physicians of the world remain profoundly un- educated with respect to cannabis and the endocannabinoid system (ECS) that underlies much of its activity. A recent USA study [4] documented that 89.5% of surveyed residents and fellows felt un- prepared to prescribe, while only 35.3% even felt ready to answer cannabis questions. Additionally, documented pertinent clinical cannabis content in their curricula. While it remains a common complaint that cannabis therapeutics lacks adequate documentation, according to a recent publication [5], scientist and clinicians are recognising the limitations of randomised controlled studies in their generalisability to populations vs. customisation of best evidence based practices for individual patients. Individualized evidence based medicine may be delivered to a patient using an N-of-1, or single clinical trial, whereby the patient is the sole unit of observation for efficacy and side effects of various interventions. This method can be applied to a medical cannabis patient to find an optimal intervention or “sweet spot” combination of plant varieties and dosage forms that provide superior symptom control.[/B][/B]
In this article, two experienced clinicians, internist and neurologist, respectively, offer their review of the literature and personal observa- tions that might serve as an initial guide to suggested Good Clinical Practice (GCP) as applied to cannabis. These include our opinion that cannabis medicines, whether prescription or over-the-counter, should be ideally cultivated organically according to Mendelian selective breeding techniques without the necessity of genetic modification or CRISPR technology according to Good Agricultural Practice (GAP), be extracted and processed under Good Manufacturing Practice (GMP) [6], and be made available to consumers with full information as to cannabinoid and terpenoid profiles, and certification that the material is free of pesticide [7], microbial or heavy metal contamination.
2. Cannabis pharmacology in brief
Cannabis produces phytocannabinoids (plant cannabinoids) in greatest abundance in the unfertilised female flowers in acid form, most abundantly tetrahydrocannabinolic acid-A (THCA-A) and cannabidiolic acid (CBDA), which are most frequently utilised after heating either by smoking, vaporisation, or baking in confections to produce decarbox- ylation of the more familiar neutral cannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD) (see graphical abstract) [8].
THC is the primary psychoactive component of cannabis, working primarily as a weak partial agonist on CB1 and CB2 receptors with well-known effects on pain, appetite, digestion, emotions and thought processes mediated through the endocannabinoid system, a homeostatic regulator of myriad physiological functions [9], found in all chordates. THC can cause psychoactive adverse events depending on dose and patient previous tolerance. Its use is applicable for many symptoms and conditions including; pain, nausea, spasticity/spasms, appetite stimu- lation, anxiety, depression, post-traumatic stress disorder (PTSD), insomnia et al.
CBD, in contrast, has little affinity for these receptors directly, but rather is a negative allosteric modulator of CB1 [10], with protean pharmacological effects on various other receptor systems including TRPV1, 5-HT1A, adenosine A2A and non-receptor mechanisms (re- viewed [11]), productive of analgesic, anti-inflammatory, anti-anxiety, and anti-psychotic effects among many others. CBD is non-intoxicating, and has been shown to help with similar symptoms, with added benefit as an anticonvulsant, anti-psychotic, neuroprotectant, and anti-inflammatory (including autoimmune conditions). Cannabis is a multi-modal treatment. It can be used to treat multiple symptoms and conditions concurrently, which can therefore help to reduce polypharmacy burden.
There are thousands of individual cannabis types, which patients and purveyors may erroneously refer to as ‘strains’, whereas the preferred term is chemical variety or ‘chemovar’ [12]. Each chemovar contains varying concentrations of cannabinoids and other components with important pharmacological and modulatory effects include the monoterpenoids [8,11] myrcene (analgesic, sedating), limonene (anti- depressant and immune-stimulating), pinene (acetylcholinesterase inhibitor alleviating short-term memory impairment from THC) and the sesquiterpenoid beta-caryophyllene (anti-inflammatory analgesic and selective full agonist at the CB2 receptor). The relative proportions of these and other components are the primary determinants of the pharmacological effects and adverse events associated with a particular cannabis chemovar, and is critical information that should be available to patients and physicians recommending such treatment. Until recent years, the vast majority of chemovars in Europe [13] and North America [14] were THC-predominant (Type I cannabis). Con- temporaneously, there has been greater interest in mixed THC:CBD (Type II) and CBD-predominant (Type III cannabis) chemovars with broader mechanisms of action and improved therapeutic indexes [12].
The acid cannabinoids have received much less research interest, but possess fascinating pharmacological properties. THCA has been noted to produce anti-inflammatory effects via antagonism of tumour necrosis factor-alpha (TNF-α) [15], to be a strong anti-emetic [16] and was recently demonstrated to be an agonist of the PPAR-γ nuclear receptor with neuroprotective effects [17], as well as anticonvulsant efficacy [18]. CBDA is also a powerful anti-emetic [19] and anti-anxiety agent [20] in rodents, and both acid cannabinoids have prominent anecdotal reports of benefit on skin and other tumors.
3. Pharmacokinetic considerations
Absorption, distribution, and metabolism determine the onset and duration of action of each dosage form. Absorption has the most variability, and is affected by product lipophilicity, bioavailability as well as the inherent organ tissue differences (i.e., alveolar, dermal vs. gastric). Cannabinoids are lipophilic and have low water solubility. Therefore, for topical or oral routes, they are best absorbed in the presence of fat, oils or polar solvents, such as ethanol. There is suggestion that newer technology such as using nano- or ionized particles or the use omega fats in carrier oil can enhance absorption; or for topicals preparations, using ingredients to mildly disrupt the skin barrier may allow greater absorption of active ingredient. Factors such as recent meals, depth of inhalation, duration of breath holding, temperature of vaporizer all affect cannabis absorption, which can vary from 20%–30% orally, up to 10–60% for inhalation [21]. Clinicians will benefit from an understanding of these factors to prescribe or recommend cannabis to enable estimation of a target quantity of dried product for their patients. See Dosing strategies and clinical pearls section for more details.
4. Modes of administration
This information is summarised (Table 1, Table 2) [7,21–27]. 5. Therapeutic uses
Cannabis can be a useful tool in the treatment of many complex diseases or rare conditions which lack effective conventional therapeutic options, or where the side effects burden of such treatments outweigh the benefits, for example, central sensitivity syndromes (fibromyalgia, chronic fatigue syndrome, migraines, irritable bowel), or multiple sclerosis, neuropathic pain, and refractory nausea. An assessment of current evidence in various indications is summarised (Table 3) [28–33].
6. Dosing strategies and clinical pearls
7. Tactics in titration
Oral THC preparation effects are usually easier to judge vs inhala- tion as the concentrations should be available from the producer. Vaporisation is subject to more variables which can influence estimated dose: size of chamber, depth of inhalation, breath holding, strength of THC in the chemovar, etc. Ideally, the patient would start using a THC- predominant preparation at bedtime to limit adverse events and encourage development of tolerance. However, this is not a must.
* Days 1-2: 2.5 mg THC-equivalent at bedtime. (May start at 1.25 mg if young, elderly, or other concerns.)
* Days 3-4: if previous dose tolerated, increase by 1.25 mg - 2.5 mg THC at bedtime.
* Days 5-6: continue to increase by 1.25 - 2.5 mg THC at bedtime every 2 days until desired effect is obtained. In event if side effects, reduce to previous, best-tolerated dose.
Some patients require THC for daytime use depending on their symptoms. Consider use of a more stimulating chemovar unless sedation is a desired result. Most patients dose orally two to three times per day.
Consider the following regimen:
*Days 1-2: 25 mg THC once a day
* Days 3-4: 2.5 mg THC twice a day
* Increase as needed and as tolerated to 15 mg THC-equivalent divided BID-TID
* Doses exceeding 20-30 mg/day may increase adverse events or induce tolerance without improving efficacy.
Use of high doses of THC-predominant cannabis above 5 g per day are probably unjustified, except in the case of primary cancer treatment (vide infra), and suggest possible tolerance or misuse. THC tolerance may be readily abrogated via a drug vacation of at least 48 h, and
• Most patients require 6–8 sprays of nabiximols per day for symp- tomatic relief with a limit of 12. Above this dose, adverse events are increased without improved efficacy.
• Cannabis medicine doses must be individually determined, as this depends on underlying endocannabinoid tone.
• Use of homemade oral oils or topicals may require much higher dried cannabis than utilised for inhalation.
• CBD-predominant preparations have fewer untoward psychotropic effects, and may require higher dosing.
CBD-predominant chemovars produce fewer adverse events, but there are no established dosing guidelines or maximum doses estab- lished except in psychosis (800 mg) [30]and seizure disorders (2500 mg or 25–50 mg/kg) [29]. For other indications, many patients obtain benefits with much lower doses, starting with 5–20 mg per day of oral preparations divided BID-TID, which may reduce attendant expense.
8. Contraindications
Cannabis is generally contraindicated in pregnancy and lactation, despite a long history of usage [36], and foetal/neonatal sequelae re- main controversial [37,38]. It is also contraindicated in psychosis (except CBD-predominant preparations [30]). Cannabis should be utilised with caution in unstable cardiac conditions, such as angina, due to tachycardia and possible hypotension due to THC, but produces no QTc issues [39]. Use in children and teens remains the subject of debate (see below), as does its use in addiction and dependency. Smoking should be avoided in COPD and asthma.
9. Adverse events
Cannabis has a superior safety profile in comparison to many other medications, with no reported deaths due to overdose, due to a lack of CB1 receptors in brainstem cardiorespiratory centres [40].
THC-mediated side effects are most pertinent and rate-limiting, and are dose-dependent. Using a ‘start low and go slow’ dosing strategy mitigates most adverse events of THC. Also, combining CBD with THC can further reduce those effects (Fig. 1). Patients develop tolerance to psychoactive effects of cannabis quickly over period of days, without concomitant tolerance to the benefits, and therefore maintain the same daily dose of many years [34,35], in stark contrast to opioids. A recent large review of herbal cannabis in Canada revealed no increase in serious adverse events in chronic administration, no harm on cognitive function, pulmonary function tests, biochemistry (creatinine, liver function test, and CBC) [34], confirming patterns seen in decades-long usage in the USA [35].
Common AEs are listed (Table 4) [34,41,42], and their reduction with lower doses and slow titration with nabiximols [42,43] are documented (Fig. 1).
The critical nature of dose and preparation are additionally ex- emplified (Fig. 2), demonstrating that whereas even 10–15 mg of pure oral THC may induce toxic psychosis in the naïve or susceptible in- dividual [44], such reactions were only identified in 4 of 260 exposures to high dose nabiximols for a Phase I RCT containing 48.6 mg of THC by virtue of its CBD and terpenoid profile [39]. Extrapolation of data in Figs. 1 and 2 suggest that other Type II oral preparations may produce similar results with slow titration.
10. Drug interactions
Most drug interactions are associated with concurrent use of other CNS depressants with cannabis. Clinically, significant drug interactions have proven rare [7], and there is no drug that cannot be used with cannabis, if necessary. THC is oxidised by (CYP) 2C9, 2C19, and 3A4. Therefore, serum levels may increase with inhibitors, or decrease with enzyme inducers. Pertinent drug interaction studies are few [45,46]. Existing studies have not demonstrated toxicity/ loss of effect of con- comitant medications, but still theoretically possible [47]. One excep- tion is high dose CBD with clobazam, wherein high levels of a sedating metabolite, N-desmethyl clobazam will require a dose reduction for that drug [29].
11. Monitoring
Depending on the patient, they may need to be seen in follow up every 1–6 months depending on several factors such as; their familiarity with cannabis, comorbid medical conditions, ability to adhere to treatment plan instructions and keep an inventory of cannabis efficacy on individual symptoms/conditions. This should involve appropriate monitoring for efficacy (consider changing dosage routes, dose, and/or plant varieties if needed), side effects of THC, review of concomitant medication changes, and when it is appropriate to initiate a gentle drug taper to minimise withdrawal symptoms, which are rarely problematic in medicinal cannabis patients [48–50]. Finally, consider implementing validated questionnaires and quality of life assessments to allow for documentation of objective measures to capture improvement in symptoms and function.
12. Special cases
12.1. Epilepsy
Cannabis has a long traditional use in treatment of seizures [51], but has frequently been contraindicated in that context in RCTs due to the observed association of THC with proconvulsant effects in rodents at high doses. In contrast, CBD displays only anticonvulsant properties and as Epidiolex® cannabis extract, has been proven safe and effective in a variety of intractable epilepsies, such as Dravet and Lennox-Gastaut syndromes in both observational settings [52] and Phase III clinical trials [29]. Regulatory approval in the USA is expected in 2018. CBD in the latter settings has often required very high doses, as much as 2500 mg/d., whereas some clinicians have claimed similar efficacy at much lower doses when CBD is utilised in preparations containing concomitant low dose THC, THCA and even the anticonvulsant terpenoid, linalool [18].
12.2. Cancer
The anti-emetic effects of THC in association with cancer che- motherapy have long been known and a synthetic form was approved for such use in the USA in 1985. Benefits as a palliative for sleep [53], and particularly for opioid-resistant cancer pain have also been de- monstrated in two Phase II clinical trials of nabiximols [54,55], but unfortunately were not proven definitively in subsequent Phase III studies. Cancer pain remains an indication in Canada under a Notice of Compliance with conditions.
Cannabis has also been an historical primary treatment for cancer [2], with extensive basic science documentation of its cytotoxic effects with cytopreservative effects on normal cells. Initial trials and case reports support the acute need for more formal investigation [56–59]. Thousands of patients worldwide are pursuing such treatment, most often without benefit of appropriate medical monitoring. Both basic science [60,61] and anecdotal clinical reports suggest that cannabis- based treatment is most effective in conjunction with conventional approaches, whether chemotherapy or radiation. High doses (up to 1000 mg/d), preferably of mixed phytocannabinoids (as in cannabis extracts), for up to 3 months may be required to eradicate some ma- lignancies, but emphasis is required that this approach remains anecdotal without benefit of large published RCTs. High doses of THC- containing preparations require slow titration over 2 weeks to induce tolerance to psychoactive sequelae. There is some anecdotal evidence supporting use of acid cannabinoids in much lower doses, and CBDA may improve the pharmacokinetics of CBD [47]. Prolonged main- tenance of cannabis therapy, at some lower dosage may be similarly required to prevent recurrences. It should be borne in mind that ‘cure’ of cancer can only be claimed after a 5-year interval without evidence of tumour. Further objective evidence is needed to support adjunctive cannabis-based medicine treatment of cancer.
12.3. Pain
Cannabis treatment has not generally been useful in relation to treatment of acute pain [62]. In contrast, both THC and CBD-pre- dominant cannabis preparations have proven safe and effective in numerous RCTs of chronic non-cancer pain, whether somatic or neuropathic, peripheral or central (reviewed [22]) and examination in national programs, as in Canada [34].
12.4. The elderly
Whereas vigilance toward adverse events, particularly attributable to polypharmacy are necessary in the elderly patient, monitoring of adverse events with nabiximols reveal no specific increased susceptibility to problems in this age group [42]. THC has been used to advantage to treat agitation in dementia [32], and the neuroprotective effects of it and CBD portend to offer possible advantages in this, and related pathologies [63]. Slow titration is required to avoid AEs, including falls and orthostatic hypotension.
12.5. Parkinson disease
CB1 receptors are densely expressed in the basal ganglia, and can- nabis has shown variable efficacy in various clinical studies [64]. Ad- ditional investigation is required, however, to establish the optimal composition of components. Anecdotal surveys suggest that acid can- nabinoids given orally over prolonged intervals (3 months) may be necessary to achieve clinical improvement [65]. Slow titration is required.
12.6. Paediatrics
Use of cannabis as medicine in children remains another forbidden territory [1], but as in any other context, the relative risks and benefits must be weighed. Recent review has supported efficacy in nausea secondary to chemotherapy and in seizures [66]. It should be stated emphatically that there is a world of difference scientifically and ethically between judicious administration of low doses of cannabinoids for therapeutic purposes as compared to chronic use of high-dose THC for recreational purposes by teenagers. Even synthetic THC has been used to advantage in children with severe static encephalopathies with spasticity and seizures in Germany where warranted [67,68]. Historical data [1] and modern experience in treatment of nausea secondary to chemotherapy [69] support the fact that children under the age of 10 are remarkably resistant to psychoactive sequelae of THC, and are able to tolerate doses, when necessary, that might be more problematic in the adult patient.
In those at risk, younger age of first cannabis use is associated with earlier onset of schizophrenia and bipolar disorder and worse outcomes [70,71]. CBD-predominant preparations, and even THCA, may be a useful therapy for children (or adults) with severe developmental/self- harm, schizophrenia, seizures, brain tumors, refractory or rare diseases. In these conditions, CBD (with low or no THC) may be more efficacious with fewer AEs than traditional therapies. (i.e., opioids, antiepileptic etc). Risks and benefits need to be considered.
12.7. Opioid and other addictions
Nineteenth century observations of the use of cannabis with opioids [72,73] attested to its additive analgesic benefits, reduction of adverse events and even benefit to withdrawal symptoms. This has been sup- ported by basic science investigation [74], and a variety of observa- tional studies [75–77] and epidemiological evidence of decreased opioid overdose mortality in US states with medical cannabis access [78], as well as lowered costs for analgesics including opioids in such states in the Medicare (elderly) [79] and Medicaid (low-income) [80] populations. An intriguing finding from a long-term safety study of nabiximols in survivors of a Phase IIA trial of cancer pain non-responsive to optimised opioids showed no increase in cannabis dosing requirements over ensuing months, without the expected escalation of opioid requirements with continued disease progression and eventual demise [81]. Studies do not report an increase in opioid serum levels when used with cannabis [82].
12.8. Driving and safety sensitive occupations
It is important to include evaluation of social and occupational history during a medical cannabis consultation. This may include determining if a patient works outside the home, has a safety sensitive occupation, drives a motor vehicle, engages in childcare, etc. A reasonable and conservative cannabis regimen for this patient population would be CBD-predominant preparations during working hours, and THC-predominant ones after work or before sleeping.
Patients should not drive or utilise power tools or heavy equipment until accustomed to the effects of the medicine [7]. It is recommended that driving should be avoided for 4 h after inhaled cannabis use, 6 h after ingested cannabis use, or 8 h if euphoria was experienced. If a patient feels impaired, regardless of cause, they should not be driving or working safety sensitive jobs.
In clinical practice we have observed that medical cannabis pa- tients, using daily, appropriate low doses of THC develop tolerance and experience minimal if any impairment, as has been documented for multiple sclerosis patients [83]. There are no serum assays that enable measurement of impairment due to THC accurately. Urine toxicology tests metabolites of THC which merely indicate THC ingestion sometime in the past two to three weeks. The authors believe a combination of neurocognitive testing, along with physical examination or perfor- mance specific activities to capture reaction time, coordination, balance, decision making et al. will prove more valuable in comparison to bodily fluid THC levels.
12.9. Standard of care
The authors believe that the standard of care for cannabis is no different than that for any speciality in the practice of medicine. The requirements are: examination of prior medical records whenever available, a comprehensive history and physical, a thorough discussion of the pros and cons of cannabis, plans for appropriate follow-up care, proper documentation of the consultation, and appropriate commu- nication with other caregivers.
13. Conclusions
As cannabis-based medicines return to mainstream usage, it is essential that clinicians gain a greater understanding of their pharmacology, dosing and administration to maximise therapeutic potential and minimise associated problems. With standardised modern products, and educated caregivers, these are worthy and attainable goals.
Acknowledgements Funding
This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Eventually I’ll get all the links done, but for the time being the photos’ll do.
⁎ Corresponding author.
E-mail addresses: info@drcarolinemaccallum.com (C.A. MacCallum), ethan.russo@icci.science (E.B. Russo).
Received 27 October 2017; Accepted 1 January 2018
0953-6205/ © 2018 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
Please cite this article as: MacCallum, C.A., European Journal of Internal Medicine (2018), Redirecting
Practical considerations in medical cannabis administration and dosing
Caroline A. MacCallum a,⁎, Ethan B. Russo b
Practical considerations in medical cannabis administration and dosing
a Faculty of Medicine, University of British Columbia, BC, Canada
b International Cannabis and Cannabinoids Institute, Prague, Czech Republic
ARTICLE INFO
Keywords:
Cannabis Cannabinoids Marijuana
Drug abuse Psychopharmacology Adverse events
ABSTRACT
Cannabis has been employed medicinally throughout history, but its recent legal prohibition, biochemical complexity and variability, quality control issues, previous dearth of appropriately powered randomised con- trolled trials, and lack of pertinent education have conspired to leave clinicians in the dark as to how to advise patients pursuing such treatment. With the advent of pharmaceutical cannabis-based medicines (Sativex/na- biximols and Epidiolex), and liberalisation of access in certain nations, this ignorance of cannabis pharmacology and therapeutics has become untenable. In this article, the authors endeavour to present concise data on can- nabis pharmacology related to tetrahydrocannabinol (THC), cannabidiol (CBD) et al., methods of administration (smoking, vaporisation, oral), and dosing recommendations. Adverse events of cannabis medicine pertain primarily to THC, whose total daily dose-equivalent should generally be limited to 30 mg/day or less, preferably in conjunction with CBD, to avoid psychoactive sequelae and development of tolerance. CBD, in contrast to THC, is less potent, and may require much higher doses for its adjunctive benefits on pain, inflammation, and attenuation of THC-associated anxiety and tachycardia. Dose initiation should commence at modest levels, and titration of any cannabis preparation should be undertaken slowly over a period of as much as two weeks. Suggestions are offered on cannabis-drug interactions, patient monitoring, and standards of care, while special cases for cannabis therapeutics are addressed: epilepsy, cancer palliation and primary treatment, chronic pain, use in the elderly, Parkinson disease, paediatrics, with concomitant opioids, and in relation to driving and hazardous activities.
1. Introduction
Cannabis has a history of medical application likely exceeding that of the written word, including mainstream usage in Europe and North America for a century between 1840 and 1940 [1,2]. It is only in the last century that quality control issues, the lack of a defined chemistry, and above all, politically and ideologically motivated prohibition relegated it planta non grata. The discovery and elucidation of the endocannabinoid system [3], coupled with a popular tidal wave of anecdotal accounts and renaissance of therapeutic clinical trials renders that status quo ante untenable.
One preparation, Sativex® (USAN: nabiximols), an oromucosal cannabis-based medicine with 2.7 mg of THC and 2.5 mg CBD plus terpenoids per spray has attained regulatory approval in 29 countries for treatment of spasticity in multiple sclerosis, having met the standards of safety, efficacy and consistency required of any pharmaceutical. The problem for physicians with respect to treatment with herbal cannabis remains acute, however: How does the responsible healer and medical scientist approach the desperate patient for whom conventional medicine has failed and wishes to avail themselves of a purportedly healing herb that has been an international societal outlaw for decades? The answer is simple: educational and scientific standards apply to the cannabis controversy equally with that of any other putative therapy.
Unfortunately, physicians of the world remain profoundly un- educated with respect to cannabis and the endocannabinoid system (ECS) that underlies much of its activity. A recent USA study [4] documented that 89.5% of surveyed residents and fellows felt un- prepared to prescribe, while only 35.3% even felt ready to answer cannabis questions. Additionally, documented pertinent clinical cannabis content in their curricula. While it remains a common complaint that cannabis therapeutics lacks adequate documentation, according to a recent publication [5], scientist and clinicians are recognising the limitations of randomised controlled studies in their generalisability to populations vs. customisation of best evidence based practices for individual patients. Individualized evidence based medicine may be delivered to a patient using an N-of-1, or single clinical trial, whereby the patient is the sole unit of observation for efficacy and side effects of various interventions. This method can be applied to a medical cannabis patient to find an optimal intervention or “sweet spot” combination of plant varieties and dosage forms that provide superior symptom control.[/B][/B]
In this article, two experienced clinicians, internist and neurologist, respectively, offer their review of the literature and personal observa- tions that might serve as an initial guide to suggested Good Clinical Practice (GCP) as applied to cannabis. These include our opinion that cannabis medicines, whether prescription or over-the-counter, should be ideally cultivated organically according to Mendelian selective breeding techniques without the necessity of genetic modification or CRISPR technology according to Good Agricultural Practice (GAP), be extracted and processed under Good Manufacturing Practice (GMP) [6], and be made available to consumers with full information as to cannabinoid and terpenoid profiles, and certification that the material is free of pesticide [7], microbial or heavy metal contamination.
2. Cannabis pharmacology in brief
Cannabis produces phytocannabinoids (plant cannabinoids) in greatest abundance in the unfertilised female flowers in acid form, most abundantly tetrahydrocannabinolic acid-A (THCA-A) and cannabidiolic acid (CBDA), which are most frequently utilised after heating either by smoking, vaporisation, or baking in confections to produce decarbox- ylation of the more familiar neutral cannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD) (see graphical abstract) [8].
THC is the primary psychoactive component of cannabis, working primarily as a weak partial agonist on CB1 and CB2 receptors with well-known effects on pain, appetite, digestion, emotions and thought processes mediated through the endocannabinoid system, a homeostatic regulator of myriad physiological functions [9], found in all chordates. THC can cause psychoactive adverse events depending on dose and patient previous tolerance. Its use is applicable for many symptoms and conditions including; pain, nausea, spasticity/spasms, appetite stimu- lation, anxiety, depression, post-traumatic stress disorder (PTSD), insomnia et al.
CBD, in contrast, has little affinity for these receptors directly, but rather is a negative allosteric modulator of CB1 [10], with protean pharmacological effects on various other receptor systems including TRPV1, 5-HT1A, adenosine A2A and non-receptor mechanisms (re- viewed [11]), productive of analgesic, anti-inflammatory, anti-anxiety, and anti-psychotic effects among many others. CBD is non-intoxicating, and has been shown to help with similar symptoms, with added benefit as an anticonvulsant, anti-psychotic, neuroprotectant, and anti-inflammatory (including autoimmune conditions). Cannabis is a multi-modal treatment. It can be used to treat multiple symptoms and conditions concurrently, which can therefore help to reduce polypharmacy burden.
There are thousands of individual cannabis types, which patients and purveyors may erroneously refer to as ‘strains’, whereas the preferred term is chemical variety or ‘chemovar’ [12]. Each chemovar contains varying concentrations of cannabinoids and other components with important pharmacological and modulatory effects include the monoterpenoids [8,11] myrcene (analgesic, sedating), limonene (anti- depressant and immune-stimulating), pinene (acetylcholinesterase inhibitor alleviating short-term memory impairment from THC) and the sesquiterpenoid beta-caryophyllene (anti-inflammatory analgesic and selective full agonist at the CB2 receptor). The relative proportions of these and other components are the primary determinants of the pharmacological effects and adverse events associated with a particular cannabis chemovar, and is critical information that should be available to patients and physicians recommending such treatment. Until recent years, the vast majority of chemovars in Europe [13] and North America [14] were THC-predominant (Type I cannabis). Con- temporaneously, there has been greater interest in mixed THC:CBD (Type II) and CBD-predominant (Type III cannabis) chemovars with broader mechanisms of action and improved therapeutic indexes [12].
The acid cannabinoids have received much less research interest, but possess fascinating pharmacological properties. THCA has been noted to produce anti-inflammatory effects via antagonism of tumour necrosis factor-alpha (TNF-α) [15], to be a strong anti-emetic [16] and was recently demonstrated to be an agonist of the PPAR-γ nuclear receptor with neuroprotective effects [17], as well as anticonvulsant efficacy [18]. CBDA is also a powerful anti-emetic [19] and anti-anxiety agent [20] in rodents, and both acid cannabinoids have prominent anecdotal reports of benefit on skin and other tumors.
3. Pharmacokinetic considerations
Absorption, distribution, and metabolism determine the onset and duration of action of each dosage form. Absorption has the most variability, and is affected by product lipophilicity, bioavailability as well as the inherent organ tissue differences (i.e., alveolar, dermal vs. gastric). Cannabinoids are lipophilic and have low water solubility. Therefore, for topical or oral routes, they are best absorbed in the presence of fat, oils or polar solvents, such as ethanol. There is suggestion that newer technology such as using nano- or ionized particles or the use omega fats in carrier oil can enhance absorption; or for topicals preparations, using ingredients to mildly disrupt the skin barrier may allow greater absorption of active ingredient. Factors such as recent meals, depth of inhalation, duration of breath holding, temperature of vaporizer all affect cannabis absorption, which can vary from 20%–30% orally, up to 10–60% for inhalation [21]. Clinicians will benefit from an understanding of these factors to prescribe or recommend cannabis to enable estimation of a target quantity of dried product for their patients. See Dosing strategies and clinical pearls section for more details.
4. Modes of administration
This information is summarised (Table 1, Table 2) [7,21–27]. 5. Therapeutic uses
Cannabis can be a useful tool in the treatment of many complex diseases or rare conditions which lack effective conventional therapeutic options, or where the side effects burden of such treatments outweigh the benefits, for example, central sensitivity syndromes (fibromyalgia, chronic fatigue syndrome, migraines, irritable bowel), or multiple sclerosis, neuropathic pain, and refractory nausea. An assessment of current evidence in various indications is summarised (Table 3) [28–33].
6. Dosing strategies and clinical pearls
- There is insufficient evidence to support the necessity of a trial of synthetic cannabinoids prior to initiating cannabis-based medicine treatment, unless legal availability is not an option.
- General approach to cannabis initiation is ‘start low, go slow, and stay low’.
- For cannabis inhalation, patients should start with 1 inhalation and wait 15min. Then, they may increase by 1 inhalation every 15–30 min until desired symptom control has been achieved.
- Higher THC concentrations of herbal cannabis may allow utilization of lower amounts. Patients should titrate accordingly to avoid adverse events.
- THC-mediated side effects such as fatigue, tachycardia and dizziness are avoidable when starting dose is low and titration is slow.
- Slow upward dose titration promotes tolerance to psychoactive sequelae of THC, which is especially important for naïve users.
- Medical cannabis patients, in contrast to recreational users, frequently use CBD-predominant chemovars with the smallest amount of THC to get the greatest improvement in symptom control, function, and quality of life, with fewest adverse events.
- Attainment of euphoric effects is not required to attain symptom control.
- For chronic conditions and symptoms, long acting oral preparatiions are the mainstay of treatment.
- Vaporisation can be utilised as an add-on prn technique for episodic exacerbations of symptoms.
- CBD can balance THC side effects, especially in daytime use, or when driving is required.
- Cannabis should be stored in a safe place, or lock box in the home.
- Physicians must clearly communicate the potential risks and safety of cannabis, no differently than with any psychoactive medication. We suggest documentation in a standard ‘treatment agreement’ form for medical-legal purposes. (See https://www.drcarolinemaccallum. com/cannabis-resources/.)
- Patients should keep a ‘symptom inventory’ chart indicating re- sponse or efficacy for each cannabis product for each symptom as and aid for physicians in determining treatment response to cannabis in follow up visits. (See https://www.drcarolinemaccallum. com/cannabis-resources/.)
- Most patients use 1–3 g of herbal cannabis per day. < 5% of patients use > 5 g per day [34]. Tolerance does not develop to the benefits. Over time dose escalation is not generally observed [22,34,35]. Additional needs require reassessment.
- Most patients require 6–8 sprays of nabiximols per day for symp- tomatic relief with a limit of 12. Above this dose, adverse events are increased without improved efficacy.
- Cannabis medicine doses must be individually determined, as this depends on underlying endocannabinoid tone.
- Use of homemade oral oils or topicals may require much higher dried cannabis than utilised for inhalation.
- CBD-predominant preparations have fewer untoward psychotropic effects, and may require higher dosing.
7. Tactics in titration
Oral THC preparation effects are usually easier to judge vs inhala- tion as the concentrations should be available from the producer. Vaporisation is subject to more variables which can influence estimated dose: size of chamber, depth of inhalation, breath holding, strength of THC in the chemovar, etc. Ideally, the patient would start using a THC- predominant preparation at bedtime to limit adverse events and encourage development of tolerance. However, this is not a must.
* Days 1-2: 2.5 mg THC-equivalent at bedtime. (May start at 1.25 mg if young, elderly, or other concerns.)
* Days 3-4: if previous dose tolerated, increase by 1.25 mg - 2.5 mg THC at bedtime.
* Days 5-6: continue to increase by 1.25 - 2.5 mg THC at bedtime every 2 days until desired effect is obtained. In event if side effects, reduce to previous, best-tolerated dose.
Some patients require THC for daytime use depending on their symptoms. Consider use of a more stimulating chemovar unless sedation is a desired result. Most patients dose orally two to three times per day.
Consider the following regimen:
*Days 1-2: 25 mg THC once a day
* Days 3-4: 2.5 mg THC twice a day
* Increase as needed and as tolerated to 15 mg THC-equivalent divided BID-TID
* Doses exceeding 20-30 mg/day may increase adverse events or induce tolerance without improving efficacy.
Use of high doses of THC-predominant cannabis above 5 g per day are probably unjustified, except in the case of primary cancer treatment (vide infra), and suggest possible tolerance or misuse. THC tolerance may be readily abrogated via a drug vacation of at least 48 h, and
• Most patients require 6–8 sprays of nabiximols per day for symp- tomatic relief with a limit of 12. Above this dose, adverse events are increased without improved efficacy.
• Cannabis medicine doses must be individually determined, as this depends on underlying endocannabinoid tone.
• Use of homemade oral oils or topicals may require much higher dried cannabis than utilised for inhalation.
• CBD-predominant preparations have fewer untoward psychotropic effects, and may require higher dosing.
CBD-predominant chemovars produce fewer adverse events, but there are no established dosing guidelines or maximum doses estab- lished except in psychosis (800 mg) [30]and seizure disorders (2500 mg or 25–50 mg/kg) [29]. For other indications, many patients obtain benefits with much lower doses, starting with 5–20 mg per day of oral preparations divided BID-TID, which may reduce attendant expense.
8. Contraindications
Cannabis is generally contraindicated in pregnancy and lactation, despite a long history of usage [36], and foetal/neonatal sequelae re- main controversial [37,38]. It is also contraindicated in psychosis (except CBD-predominant preparations [30]). Cannabis should be utilised with caution in unstable cardiac conditions, such as angina, due to tachycardia and possible hypotension due to THC, but produces no QTc issues [39]. Use in children and teens remains the subject of debate (see below), as does its use in addiction and dependency. Smoking should be avoided in COPD and asthma.
9. Adverse events
Cannabis has a superior safety profile in comparison to many other medications, with no reported deaths due to overdose, due to a lack of CB1 receptors in brainstem cardiorespiratory centres [40].
THC-mediated side effects are most pertinent and rate-limiting, and are dose-dependent. Using a ‘start low and go slow’ dosing strategy mitigates most adverse events of THC. Also, combining CBD with THC can further reduce those effects (Fig. 1). Patients develop tolerance to psychoactive effects of cannabis quickly over period of days, without concomitant tolerance to the benefits, and therefore maintain the same daily dose of many years [34,35], in stark contrast to opioids. A recent large review of herbal cannabis in Canada revealed no increase in serious adverse events in chronic administration, no harm on cognitive function, pulmonary function tests, biochemistry (creatinine, liver function test, and CBC) [34], confirming patterns seen in decades-long usage in the USA [35].
Common AEs are listed (Table 4) [34,41,42], and their reduction with lower doses and slow titration with nabiximols [42,43] are documented (Fig. 1).
The critical nature of dose and preparation are additionally ex- emplified (Fig. 2), demonstrating that whereas even 10–15 mg of pure oral THC may induce toxic psychosis in the naïve or susceptible in- dividual [44], such reactions were only identified in 4 of 260 exposures to high dose nabiximols for a Phase I RCT containing 48.6 mg of THC by virtue of its CBD and terpenoid profile [39]. Extrapolation of data in Figs. 1 and 2 suggest that other Type II oral preparations may produce similar results with slow titration.
10. Drug interactions
Most drug interactions are associated with concurrent use of other CNS depressants with cannabis. Clinically, significant drug interactions have proven rare [7], and there is no drug that cannot be used with cannabis, if necessary. THC is oxidised by (CYP) 2C9, 2C19, and 3A4. Therefore, serum levels may increase with inhibitors, or decrease with enzyme inducers. Pertinent drug interaction studies are few [45,46]. Existing studies have not demonstrated toxicity/ loss of effect of con- comitant medications, but still theoretically possible [47]. One excep- tion is high dose CBD with clobazam, wherein high levels of a sedating metabolite, N-desmethyl clobazam will require a dose reduction for that drug [29].
11. Monitoring
Depending on the patient, they may need to be seen in follow up every 1–6 months depending on several factors such as; their familiarity with cannabis, comorbid medical conditions, ability to adhere to treatment plan instructions and keep an inventory of cannabis efficacy on individual symptoms/conditions. This should involve appropriate monitoring for efficacy (consider changing dosage routes, dose, and/or plant varieties if needed), side effects of THC, review of concomitant medication changes, and when it is appropriate to initiate a gentle drug taper to minimise withdrawal symptoms, which are rarely problematic in medicinal cannabis patients [48–50]. Finally, consider implementing validated questionnaires and quality of life assessments to allow for documentation of objective measures to capture improvement in symptoms and function.
12. Special cases
12.1. Epilepsy
Cannabis has a long traditional use in treatment of seizures [51], but has frequently been contraindicated in that context in RCTs due to the observed association of THC with proconvulsant effects in rodents at high doses. In contrast, CBD displays only anticonvulsant properties and as Epidiolex® cannabis extract, has been proven safe and effective in a variety of intractable epilepsies, such as Dravet and Lennox-Gastaut syndromes in both observational settings [52] and Phase III clinical trials [29]. Regulatory approval in the USA is expected in 2018. CBD in the latter settings has often required very high doses, as much as 2500 mg/d., whereas some clinicians have claimed similar efficacy at much lower doses when CBD is utilised in preparations containing concomitant low dose THC, THCA and even the anticonvulsant terpenoid, linalool [18].
12.2. Cancer
The anti-emetic effects of THC in association with cancer che- motherapy have long been known and a synthetic form was approved for such use in the USA in 1985. Benefits as a palliative for sleep [53], and particularly for opioid-resistant cancer pain have also been de- monstrated in two Phase II clinical trials of nabiximols [54,55], but unfortunately were not proven definitively in subsequent Phase III studies. Cancer pain remains an indication in Canada under a Notice of Compliance with conditions.
Cannabis has also been an historical primary treatment for cancer [2], with extensive basic science documentation of its cytotoxic effects with cytopreservative effects on normal cells. Initial trials and case reports support the acute need for more formal investigation [56–59]. Thousands of patients worldwide are pursuing such treatment, most often without benefit of appropriate medical monitoring. Both basic science [60,61] and anecdotal clinical reports suggest that cannabis- based treatment is most effective in conjunction with conventional approaches, whether chemotherapy or radiation. High doses (up to 1000 mg/d), preferably of mixed phytocannabinoids (as in cannabis extracts), for up to 3 months may be required to eradicate some ma- lignancies, but emphasis is required that this approach remains anecdotal without benefit of large published RCTs. High doses of THC- containing preparations require slow titration over 2 weeks to induce tolerance to psychoactive sequelae. There is some anecdotal evidence supporting use of acid cannabinoids in much lower doses, and CBDA may improve the pharmacokinetics of CBD [47]. Prolonged main- tenance of cannabis therapy, at some lower dosage may be similarly required to prevent recurrences. It should be borne in mind that ‘cure’ of cancer can only be claimed after a 5-year interval without evidence of tumour. Further objective evidence is needed to support adjunctive cannabis-based medicine treatment of cancer.
12.3. Pain
Cannabis treatment has not generally been useful in relation to treatment of acute pain [62]. In contrast, both THC and CBD-pre- dominant cannabis preparations have proven safe and effective in numerous RCTs of chronic non-cancer pain, whether somatic or neuropathic, peripheral or central (reviewed [22]) and examination in national programs, as in Canada [34].
12.4. The elderly
Whereas vigilance toward adverse events, particularly attributable to polypharmacy are necessary in the elderly patient, monitoring of adverse events with nabiximols reveal no specific increased susceptibility to problems in this age group [42]. THC has been used to advantage to treat agitation in dementia [32], and the neuroprotective effects of it and CBD portend to offer possible advantages in this, and related pathologies [63]. Slow titration is required to avoid AEs, including falls and orthostatic hypotension.
12.5. Parkinson disease
CB1 receptors are densely expressed in the basal ganglia, and can- nabis has shown variable efficacy in various clinical studies [64]. Ad- ditional investigation is required, however, to establish the optimal composition of components. Anecdotal surveys suggest that acid can- nabinoids given orally over prolonged intervals (3 months) may be necessary to achieve clinical improvement [65]. Slow titration is required.
12.6. Paediatrics
Use of cannabis as medicine in children remains another forbidden territory [1], but as in any other context, the relative risks and benefits must be weighed. Recent review has supported efficacy in nausea secondary to chemotherapy and in seizures [66]. It should be stated emphatically that there is a world of difference scientifically and ethically between judicious administration of low doses of cannabinoids for therapeutic purposes as compared to chronic use of high-dose THC for recreational purposes by teenagers. Even synthetic THC has been used to advantage in children with severe static encephalopathies with spasticity and seizures in Germany where warranted [67,68]. Historical data [1] and modern experience in treatment of nausea secondary to chemotherapy [69] support the fact that children under the age of 10 are remarkably resistant to psychoactive sequelae of THC, and are able to tolerate doses, when necessary, that might be more problematic in the adult patient.
In those at risk, younger age of first cannabis use is associated with earlier onset of schizophrenia and bipolar disorder and worse outcomes [70,71]. CBD-predominant preparations, and even THCA, may be a useful therapy for children (or adults) with severe developmental/self- harm, schizophrenia, seizures, brain tumors, refractory or rare diseases. In these conditions, CBD (with low or no THC) may be more efficacious with fewer AEs than traditional therapies. (i.e., opioids, antiepileptic etc). Risks and benefits need to be considered.
12.7. Opioid and other addictions
Nineteenth century observations of the use of cannabis with opioids [72,73] attested to its additive analgesic benefits, reduction of adverse events and even benefit to withdrawal symptoms. This has been sup- ported by basic science investigation [74], and a variety of observa- tional studies [75–77] and epidemiological evidence of decreased opioid overdose mortality in US states with medical cannabis access [78], as well as lowered costs for analgesics including opioids in such states in the Medicare (elderly) [79] and Medicaid (low-income) [80] populations. An intriguing finding from a long-term safety study of nabiximols in survivors of a Phase IIA trial of cancer pain non-responsive to optimised opioids showed no increase in cannabis dosing requirements over ensuing months, without the expected escalation of opioid requirements with continued disease progression and eventual demise [81]. Studies do not report an increase in opioid serum levels when used with cannabis [82].
12.8. Driving and safety sensitive occupations
It is important to include evaluation of social and occupational history during a medical cannabis consultation. This may include determining if a patient works outside the home, has a safety sensitive occupation, drives a motor vehicle, engages in childcare, etc. A reasonable and conservative cannabis regimen for this patient population would be CBD-predominant preparations during working hours, and THC-predominant ones after work or before sleeping.
Patients should not drive or utilise power tools or heavy equipment until accustomed to the effects of the medicine [7]. It is recommended that driving should be avoided for 4 h after inhaled cannabis use, 6 h after ingested cannabis use, or 8 h if euphoria was experienced. If a patient feels impaired, regardless of cause, they should not be driving or working safety sensitive jobs.
In clinical practice we have observed that medical cannabis pa- tients, using daily, appropriate low doses of THC develop tolerance and experience minimal if any impairment, as has been documented for multiple sclerosis patients [83]. There are no serum assays that enable measurement of impairment due to THC accurately. Urine toxicology tests metabolites of THC which merely indicate THC ingestion sometime in the past two to three weeks. The authors believe a combination of neurocognitive testing, along with physical examination or perfor- mance specific activities to capture reaction time, coordination, balance, decision making et al. will prove more valuable in comparison to bodily fluid THC levels.
12.9. Standard of care
The authors believe that the standard of care for cannabis is no different than that for any speciality in the practice of medicine. The requirements are: examination of prior medical records whenever available, a comprehensive history and physical, a thorough discussion of the pros and cons of cannabis, plans for appropriate follow-up care, proper documentation of the consultation, and appropriate commu- nication with other caregivers.
13. Conclusions
As cannabis-based medicines return to mainstream usage, it is essential that clinicians gain a greater understanding of their pharmacology, dosing and administration to maximise therapeutic potential and minimise associated problems. With standardised modern products, and educated caregivers, these are worthy and attainable goals.
Acknowledgements Funding
This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Eventually I’ll get all the links done, but for the time being the photos’ll do.
- Thread starter
- #444
I feel like I struck gold with this article. It also pleased me to see we already have a pretty good handle in this community on the particulars of dosing and administration. 
Nice article.
- Thread starter
- #446
I’ve been wandering through Green Flower Media’s Beginner’s series, and this is what I picked up:
Cannabis and Breast Cancer: Mara Gordon
3 primary types of breast cancer
* ERPR positive: responds to 1:2 THC:CBD ratio
- ex: 40-yr old woman might take 50-100 mg/day of THC and 100-200 mg/day of CBD
- if that doesn’t work increase THC to 1:1
Higher CBD is called for to cancel out the translation of the ID-1 gene that fuels metastasis
* HER2 positive: responds well to 1:1
* Triple negative: responds well to 1:1
Whole plant medicine is far superior to isolates
Cannabis and Brain Cancer: Mara Gordon
Cancer is a chronic, systemic disease and must be treated as such.
- If you overcome cancer you’ll be on a maintenance dose indefinitely. Clinical data suggests that discontinuing the maintenance dose pretty much ends your life.
Start with a 3:1 THC:CBD ratio
- get the dose up as high as you can as quickly as you can (think Biobomb suppositories)
- quality of life is the goal, so not so high as the patient can’t function comfortably
If 3:1 doesn’t work FLIP IT to 1:3.
With seizure expression due to either tumor placement or radiation side effects look to THCa instead of increasing CBD.
- You want THC to target the receptors most prevalent in the brain and signal apoptosis.
DIPG is a form that rests in the brain stem, where no eCB1Rs exist
* I’d think this’d call for some powerful topicals applied to the neck and shoulders.
- Mara’s seen longevity and increased quality of life with combination therapies.
- TMZ and THC work synergistically, improving the efficacy of each more than 50% over what either could achieve alone.
Conventional treatment is typically debilitating and offers little in the way of longevity, so many patients opt out.
Cannabis and Diabetes: Jessica Peters, Mara Gordon
THC to increase sleep balance
CBD to reduce inflammation and increase mobility
International data is suggesting CBD can prevent the onset of diabetes
Specific suggestions:
- CBD shows promise to regulate insulin production
- Start with 2-3 doses a day, and continue that for 2-3 weeks before evaluating for change.
Diabetes comes with a myriad of complications and symptoms
- 1:1 works well for pain management
- THC or CBN will promote better sleep patterns
Benefits will be both immediate (sleep, pain mgt) and long-term (inflammation and insulin control).
You treat the whole person.
- Without dietary control you’re paddling upstream and wasting the effort.
THCV shows great promise for blood glucose control.
Somewhere there’s a doctor that said right out loud “50mg of THCV every 8 hours to control Type 2 diabetes.” Someday I’ll find it again. :laugh2;
To find the sweet spot for you, keep a log of all doses and any pertinent data so you can dial in the dose that works for you.
Cannabis and Breast Cancer: Mara Gordon
3 primary types of breast cancer
* ERPR positive: responds to 1:2 THC:CBD ratio
- ex: 40-yr old woman might take 50-100 mg/day of THC and 100-200 mg/day of CBD
- if that doesn’t work increase THC to 1:1
Higher CBD is called for to cancel out the translation of the ID-1 gene that fuels metastasis
* HER2 positive: responds well to 1:1
* Triple negative: responds well to 1:1
Whole plant medicine is far superior to isolates
Cannabis and Brain Cancer: Mara Gordon
Cancer is a chronic, systemic disease and must be treated as such.
- If you overcome cancer you’ll be on a maintenance dose indefinitely. Clinical data suggests that discontinuing the maintenance dose pretty much ends your life.
Start with a 3:1 THC:CBD ratio
- get the dose up as high as you can as quickly as you can (think Biobomb suppositories)
- quality of life is the goal, so not so high as the patient can’t function comfortably
If 3:1 doesn’t work FLIP IT to 1:3.
With seizure expression due to either tumor placement or radiation side effects look to THCa instead of increasing CBD.
- You want THC to target the receptors most prevalent in the brain and signal apoptosis.
DIPG is a form that rests in the brain stem, where no eCB1Rs exist
* I’d think this’d call for some powerful topicals applied to the neck and shoulders.
- Mara’s seen longevity and increased quality of life with combination therapies.
- TMZ and THC work synergistically, improving the efficacy of each more than 50% over what either could achieve alone.
Conventional treatment is typically debilitating and offers little in the way of longevity, so many patients opt out.
Cannabis and Diabetes: Jessica Peters, Mara Gordon
THC to increase sleep balance
CBD to reduce inflammation and increase mobility
International data is suggesting CBD can prevent the onset of diabetes
Specific suggestions:
- CBD shows promise to regulate insulin production
- Start with 2-3 doses a day, and continue that for 2-3 weeks before evaluating for change.
Diabetes comes with a myriad of complications and symptoms
- 1:1 works well for pain management
- THC or CBN will promote better sleep patterns
Benefits will be both immediate (sleep, pain mgt) and long-term (inflammation and insulin control).
You treat the whole person.
- Without dietary control you’re paddling upstream and wasting the effort.
THCV shows great promise for blood glucose control.
Somewhere there’s a doctor that said right out loud “50mg of THCV every 8 hours to control Type 2 diabetes.” Someday I’ll find it again. :laugh2;
To find the sweet spot for you, keep a log of all doses and any pertinent data so you can dial in the dose that works for you.
I'm still plodding my way through the previous article you posted. Luckily this one was an easy read! Thanks for all your research. 
Same here
- Thread starter
- #449
You are both more than welcome.
I dig it up, digest it, do my best to pick out the pertinent data needed at the moment and then walk around for a couple days re-reading over and over again while it percolates in the brain.
Eventually it all falls smoothly into place. Lol! Bit by bit we come into better understanding.
I dig it up, digest it, do my best to pick out the pertinent data needed at the moment and then walk around for a couple days re-reading over and over again while it percolates in the brain.
Eventually it all falls smoothly into place. Lol! Bit by bit we come into better understanding.
- Thread starter
- #450
Cannabis and pain - from a 2012 Oxford study, reported in Smithsonian Magazine:
To determine exactly how cannabis relieves pain, a group of Oxford researchers used healthy volunteers, an MRI machine and doses of THC, the active ingredient in marijuana. Their findings, published today in the journal Pain, suggest something counterintuitive: that the drug doesn’t so much reduce pain as make the same level of pain more bearable.
“Cannabis does not seem to act like a conventional pain medicine,” Michael Lee, an Oxford neuroscientist and lead author of the paper, said in a statement. “Brain imaging shows little reduction in the brain regions that code for the sensation of pain, which is what we tend to see with drugs like opiates. Instead, cannabis appears to mainly affect the emotional reaction to pain in a highly variable way.”
Read more: Cannabis isn't a pain killer, it's a pain distractor
Cannabis and Lupus: from Kaleidoscope Fighting Lupus Can We Talk About Cannabis?
One of the reasons some rheumatologists are hesitant to endorse the use of cannabis is due to other drug interactions. The FDA has reported drug interactions with cannabis among people who took Neurontin (Gabapentin), a pretty common lupus and fibromyalgia drug. Other common lupus medications that might interact are: barbiturates, sedative medications (ambien, klonopin, ativan), antidepressants (prozac), muscle relaxants (flexeril), opioids and even warfarin (coumadin) which is used for the common lupus overlap disease Antiphospholipid syndrome.
Another reason why your rheumatologist may not be on board with you trying medical marijuana is due to the fact that the American College of Rheumatology published a five year study at the University of New Mexico in 2014, that indicated marijuana use in SLE was not associated with was not associated with reduced pain, use of steroids, use of narcotics or disease activity. In fact, the study showed that narcotic use went up, as well as, an increase in end stage renal disease and neuropsychiatric SLE. Sadly, the data they collected was not medically supportive of cannabis being used as a treatment method for SLE.
I think I want to see this report and see where they f*d up. Why am I not surprised? New Mexico is the state that held up the study on PTSD for veterans for years because the governor was a raving anti-cannabis proponent, likely getting kickbacks from somewhere.
Another report to chase down. This one should be done by now:
Dr. Jason McDougall, a professor in the department of pharmacology and anesthesia at Halifax University in Nova Scotia is using a three-year grant from the Arthritis Society to study how cannabis compounds can manage arthritis pain. Dr. McDougall is hopeful that by administering the cannabis like molecules to the painful arthritic areas, they will see improvement not only with dampening the pain levels in the brain but with the actual reduction of inflammation in the joint as well.
To determine exactly how cannabis relieves pain, a group of Oxford researchers used healthy volunteers, an MRI machine and doses of THC, the active ingredient in marijuana. Their findings, published today in the journal Pain, suggest something counterintuitive: that the drug doesn’t so much reduce pain as make the same level of pain more bearable.
“Cannabis does not seem to act like a conventional pain medicine,” Michael Lee, an Oxford neuroscientist and lead author of the paper, said in a statement. “Brain imaging shows little reduction in the brain regions that code for the sensation of pain, which is what we tend to see with drugs like opiates. Instead, cannabis appears to mainly affect the emotional reaction to pain in a highly variable way.”
Read more: Cannabis isn't a pain killer, it's a pain distractor
Cannabis and Lupus: from Kaleidoscope Fighting Lupus Can We Talk About Cannabis?
One of the reasons some rheumatologists are hesitant to endorse the use of cannabis is due to other drug interactions. The FDA has reported drug interactions with cannabis among people who took Neurontin (Gabapentin), a pretty common lupus and fibromyalgia drug. Other common lupus medications that might interact are: barbiturates, sedative medications (ambien, klonopin, ativan), antidepressants (prozac), muscle relaxants (flexeril), opioids and even warfarin (coumadin) which is used for the common lupus overlap disease Antiphospholipid syndrome.
Another reason why your rheumatologist may not be on board with you trying medical marijuana is due to the fact that the American College of Rheumatology published a five year study at the University of New Mexico in 2014, that indicated marijuana use in SLE was not associated with was not associated with reduced pain, use of steroids, use of narcotics or disease activity. In fact, the study showed that narcotic use went up, as well as, an increase in end stage renal disease and neuropsychiatric SLE. Sadly, the data they collected was not medically supportive of cannabis being used as a treatment method for SLE.
I think I want to see this report and see where they f*d up. Why am I not surprised? New Mexico is the state that held up the study on PTSD for veterans for years because the governor was a raving anti-cannabis proponent, likely getting kickbacks from somewhere.
Another report to chase down. This one should be done by now:
Dr. Jason McDougall, a professor in the department of pharmacology and anesthesia at Halifax University in Nova Scotia is using a three-year grant from the Arthritis Society to study how cannabis compounds can manage arthritis pain. Dr. McDougall is hopeful that by administering the cannabis like molecules to the painful arthritic areas, they will see improvement not only with dampening the pain levels in the brain but with the actual reduction of inflammation in the joint as well.
- Thread starter
- #451
Cannabis 101 Summit: Green Flower Media
Cannabis Therapeutics for Seniors - Eloise Theisen, cofounder of Radicle Health
Radicle health has treated over 4000 geriatric patients, with an average age of 76
- 90% were new to cannabi
- 85% were female
- 45% chose cannabis for chronic pain
- 45% chose cannabis for sleep issues
- most of their patients didn't want to smoke
- many patients were initially resistant to using cannabis
In 2010 Eloise was in a traffic accident that changed her life dramatically. Eventually, and very reluctantly she found cannabis, a healing modality that allowed her to finally return to her work and regain her balance in her social world of family and friends.
The demographic of seniors using cannabis is the fastest growing of all
- age 65 and over has increased use by 250%
- Ages 50-65 saw an increase of 60%
Seniors often have special access concerns
- product choices can be overwhelming and confusing
- information and advice is often untrustworthy and incomplete
- without proper guidance and information success rates can be low
- bud tenders know more than doctors, but bud tenders aren't trained to do patient intake or develop treatment plans
- many seniors are taking a shitload of other meds
Senior populations are different
- bioavailability decreases are often the norm (less responsive receptors and poor gut health can mean poor absorbtion and activation)
- filtering organs work less efficiently, holding back metabolism and elimination (can't clear toxins or metabolize consumables in the same ways other populations can)
- problems crop up with balance, sight, and hearing
- many seniors have a lifetime of poor lifestyle and nutritional choices catch up to them as they age (poor diet, lack of exercise, too much alcohol, too much smoking)
Seniors typically take more prescription drugs than the rest of the population
- 65 and older make up only 13% of the population, but put out more than 1/3 of the total national outlay for prescription drugs
- seniors take more drugs long term
- seniors have more incidents of polypharmacology
- over 25% of all ER visits are seniors, many with "adverse drug events"
Polypharmacology
- taking 5 or more meds at one time, not counting vitamins and supplements
- when you take one drug you have a 10% chance of an adverse drug event
- 40% of seniors are victims of polypharmacology
- in assisted living or nursing homes the patients are more often getting 20+ different meds a day
At one drug the chances of complications is only 10%. With each new drug that chance increases. At the level of 10 + meds you're 100% guaranteed to have an "adverse drug event"
- With each additional drug introduced, prescription medicine compliance falters and complications increase.
- Polypharmacology can be fatal with black box medications in a population with failing memory, Alzheimer's, or dementia.
Special concerns for seniors using cannabis that often get overlooked
- RA patients may struggle with "child-proof packaging" (Many simply cut it open)
- may lack the dexterity to manipulate small tools, packages, or bottles (spillage happens)
- may lack strength to depress plungers or open vacuum-sealed packaging
- may find new terms and devices incomprehensible
- may lack charging support for the devices needed
- labels are often rediculously tiny and lack enough information to help increase safe use
- you can get conflicting information from your bud tenders and you PC physican
Cannabis use for seniors can improve the quality of their lives and cut back dramatically on polypharmacology and the side effects that come with it.
Steps to maximize success with cannabis in a senior population
1. Work with a qualified health care provider (insurance doesn't cover cannabis doctors, so patients eschew them).
- You'll save time and money by having a trained provider guide you to specific products and methods of administration.
- A good treatment plan saves you lots of frustration in the experimentation stage of cannabis therapeutics.
- You'll have fewer false starts with someone with experience beside you.
2. Select a route of administration
Topicals
- topicals provide local pain relief
- hands, neck, ankles, and feet all benefit from topical use
Ingestion
- for sleep issues, mood imbalance, and pain management
- Dosing is critical
- a wide variable of onset (1-3 hours)
- depending on metabolism effects can last 5 hours or longer, especially with a a new consumer
- work with HCP to set dosing schedule and find an effective starting dose
Inhalation
- offers best immediate control of dose
- fastest onset and relief for breakthrough pain, anxiety, depression, nausea, muscle spasm
3. Select a cannabinoid
Cannabis will relieve pain, improve your sleep, reduce stress, and improve your mood, if you make wise choices in the ratios.
THC reduces pain and inflammation
- low doses can treat mild pain and inflammation without overwhelming euphoria or impairment
CBD treats inflammatory response
- effective for mild pain, anxiety, inflammatory pain
- will mitigate the effects of THC some find bothersome (lethargy, dysphoria, short-term memory loss)
- CBD alone may not be enough to ease your pain
CBDa can treat mild pain and fatigue
4. Pick a product
- safety and clean.iness are of primary concern
- Testing is still not where we'd be most comfortable. Read the labels. Ask questions.
- seek out small dose products (some now go down to 1 mg dose)
- Look for clear and honest labeling that includes the cannabinoid dose in mg.
Optimal meds tell you the terpene profile as well.
- There are now over 200 different terpenes identified in cannabis, and almost every one of them has a medicinal value all its own that's improved with synergy.
- Myrcene and linalool for evening/night meds
- Pinene, limonene for alerting daytime meds
5. Formulate a plan and stick to it
- Start low, go slow, stay low to minimize unwanted side effects and reduce the chance of tolerance becoming an issue.
- A typical senior dose is between 1-3 mg (some need more, some less)
- Treat one thing at a time and determine how much you'll need for each administration pathway.
Ex: Pain of RA will respond to
- topical for local pain relief
- ingestion to manage pain with a base line
- inhalation for breakthrough pain
Your treatment plan will include
- How much of a medicine to take.
- Frequency of dosing.
- When and how to increase or decrease doses.
Make the plan completely individual.
- experiment with cannabinoid and terpene ratios, doses, timing of doses, etc until you find the sweet spot.
Patience and persistence often pays off.
Cannabis Therapeutics for Seniors - Eloise Theisen, cofounder of Radicle Health
Radicle health has treated over 4000 geriatric patients, with an average age of 76
- 90% were new to cannabi
- 85% were female
- 45% chose cannabis for chronic pain
- 45% chose cannabis for sleep issues
- most of their patients didn't want to smoke
- many patients were initially resistant to using cannabis
In 2010 Eloise was in a traffic accident that changed her life dramatically. Eventually, and very reluctantly she found cannabis, a healing modality that allowed her to finally return to her work and regain her balance in her social world of family and friends.
The demographic of seniors using cannabis is the fastest growing of all
- age 65 and over has increased use by 250%
- Ages 50-65 saw an increase of 60%
Seniors often have special access concerns
- product choices can be overwhelming and confusing
- information and advice is often untrustworthy and incomplete
- without proper guidance and information success rates can be low
- bud tenders know more than doctors, but bud tenders aren't trained to do patient intake or develop treatment plans
- many seniors are taking a shitload of other meds
Senior populations are different
- bioavailability decreases are often the norm (less responsive receptors and poor gut health can mean poor absorbtion and activation)
- filtering organs work less efficiently, holding back metabolism and elimination (can't clear toxins or metabolize consumables in the same ways other populations can)
- problems crop up with balance, sight, and hearing
- many seniors have a lifetime of poor lifestyle and nutritional choices catch up to them as they age (poor diet, lack of exercise, too much alcohol, too much smoking)
Seniors typically take more prescription drugs than the rest of the population
- 65 and older make up only 13% of the population, but put out more than 1/3 of the total national outlay for prescription drugs
- seniors take more drugs long term
- seniors have more incidents of polypharmacology
- over 25% of all ER visits are seniors, many with "adverse drug events"
Polypharmacology
- taking 5 or more meds at one time, not counting vitamins and supplements
- when you take one drug you have a 10% chance of an adverse drug event
- 40% of seniors are victims of polypharmacology
- in assisted living or nursing homes the patients are more often getting 20+ different meds a day
At one drug the chances of complications is only 10%. With each new drug that chance increases. At the level of 10 + meds you're 100% guaranteed to have an "adverse drug event"
- With each additional drug introduced, prescription medicine compliance falters and complications increase.
- Polypharmacology can be fatal with black box medications in a population with failing memory, Alzheimer's, or dementia.
Special concerns for seniors using cannabis that often get overlooked
- RA patients may struggle with "child-proof packaging" (Many simply cut it open)
- may lack the dexterity to manipulate small tools, packages, or bottles (spillage happens)
- may lack strength to depress plungers or open vacuum-sealed packaging
- may find new terms and devices incomprehensible
- may lack charging support for the devices needed
- labels are often rediculously tiny and lack enough information to help increase safe use
- you can get conflicting information from your bud tenders and you PC physican
Cannabis use for seniors can improve the quality of their lives and cut back dramatically on polypharmacology and the side effects that come with it.
Steps to maximize success with cannabis in a senior population
1. Work with a qualified health care provider (insurance doesn't cover cannabis doctors, so patients eschew them).
- You'll save time and money by having a trained provider guide you to specific products and methods of administration.
- A good treatment plan saves you lots of frustration in the experimentation stage of cannabis therapeutics.
- You'll have fewer false starts with someone with experience beside you.
2. Select a route of administration
Topicals
- topicals provide local pain relief
- hands, neck, ankles, and feet all benefit from topical use
Ingestion
- for sleep issues, mood imbalance, and pain management
- Dosing is critical
- a wide variable of onset (1-3 hours)
- depending on metabolism effects can last 5 hours or longer, especially with a a new consumer
- work with HCP to set dosing schedule and find an effective starting dose
Inhalation
- offers best immediate control of dose
- fastest onset and relief for breakthrough pain, anxiety, depression, nausea, muscle spasm
3. Select a cannabinoid
Cannabis will relieve pain, improve your sleep, reduce stress, and improve your mood, if you make wise choices in the ratios.
THC reduces pain and inflammation
- low doses can treat mild pain and inflammation without overwhelming euphoria or impairment
CBD treats inflammatory response
- effective for mild pain, anxiety, inflammatory pain
- will mitigate the effects of THC some find bothersome (lethargy, dysphoria, short-term memory loss)
- CBD alone may not be enough to ease your pain
CBDa can treat mild pain and fatigue
4. Pick a product
- safety and clean.iness are of primary concern
- Testing is still not where we'd be most comfortable. Read the labels. Ask questions.
- seek out small dose products (some now go down to 1 mg dose)
- Look for clear and honest labeling that includes the cannabinoid dose in mg.
Optimal meds tell you the terpene profile as well.
- There are now over 200 different terpenes identified in cannabis, and almost every one of them has a medicinal value all its own that's improved with synergy.
- Myrcene and linalool for evening/night meds
- Pinene, limonene for alerting daytime meds
5. Formulate a plan and stick to it
- Start low, go slow, stay low to minimize unwanted side effects and reduce the chance of tolerance becoming an issue.
- A typical senior dose is between 1-3 mg (some need more, some less)
- Treat one thing at a time and determine how much you'll need for each administration pathway.
Ex: Pain of RA will respond to
- topical for local pain relief
- ingestion to manage pain with a base line
- inhalation for breakthrough pain
Your treatment plan will include
- How much of a medicine to take.
- Frequency of dosing.
- When and how to increase or decrease doses.
Make the plan completely individual.
- experiment with cannabinoid and terpene ratios, doses, timing of doses, etc until you find the sweet spot.
Patience and persistence often pays off.
Great info Sue! I'm so glad you keep posting these articles and summaries because I keep reading then and gleaning more and more info from them.
Glad they got the terminology straight!
Tennessee Tim
Well-Known Member
I went from Methtrexate and other RX"s and being disabled from hip, hand and other joints pain, to returning to work a couple years ago, after dropping the Prescription meds and using Cannabis oral, dermal and inhalation! I even have been testing below the "RA" threshold for over a year now, when my PCP test me every six months! I still have pain, but less, much less and I cope with it better when I inhale some good bud! Joint swelling has gone! It may only be a temporary remission but I'll take it! The chronic pain from osteo type and old injuries is endured better, and as an old landscaper/laborer/farmer I have earned a bunch of pain from my efforts to support a family. It is twisted, blind, ignorance (for some "researchers") to continue to tell people like me, a senior citizen RA victim, cannabis does not help manage RA, pain,swelling and inflammation , when it has helped me with all! Then on top of restoring me to work, it also helps me deal with anxiety and rest better! I feel good! Is it evil or abusing a substance because it makes me feel good while curing/managing my medical issues? I would like to reset some of these experts titles. Perhaps, Professional Hack Researcher (for hire!) for disregarding patient welfare and comfort, would be a better title for the like of these "Experts"?
- Thread starter
- #454
It can make you red with rage, eh Tim? Part of me thinks that plays into their game of repressing cannabis, so I've studiously avoided going there, although I'll admit that I can't bear to watch or read anything on cannabis and diabetes, knowing the medical professionals and prohibition were in part responsible for my husband's early demise.
All things work for good, even this rediculous lack of emperical evidence on the efficacy of cannabis as a healing modality. No one figured on the educational reaches of the Internet as pertains to cannabis, did they? That's where we come in, learning to make our own medicine and sharing with loved ones. We change the world one patient at a time, and we do a damned good job of that in this neighborhood.
We're coming into a glorious age of discovery with cannabis sativa. I, for one, am thrilled to be out here on the cutting edge with the likes of you.
Tennessee Tim
Well-Known Member
Sweet Sue! Following your threads continue to be a joy for me! I get a little pissed off from some of the things I read from "experts/researchers", but I learn more and more from your post, and get comforted by the enlightenment I see happening in society growing faster. Fast is good now! I want to live to see free gardens across America. You Sue are helping that to happen,as a cannabis educator and ambassador to the uninformed, from us who are healing without big corporate medicine! We who are not experts are showing the world what many governments have banned as harmful, can actually heal and enhance life! I know that properly researched cannabis can be tuned into efficient medications, but it is more important to me, to see freely garden grown herbal medicines, that are available to the poor because freedom has been extended to their homes and gardens and the tyranny and hypocrisy of prohibition ended! Kitchen made ,homegrown medicines don't have to make wealthy people richer so that the poor can be healed! I am always more about peace and love when I am stoned ,a good thing, some of these control freaks we are up against could use some of that.
- Thread starter
- #456
My ultimate dream is everyone free to grow unimpeded. A return to kitchen alchemy that heals the body and the soul. That's where I put my focus when political malarkey starts to disrupt my joyful center.
We get what we focus on. I choose freedom.
We get what we focus on. I choose freedom.
Derbybud
Well-Known Member
Like Shed said. Please keep up the posts if you have the time. I'm a much more educated man because of them and am more confident to discuss with others on the benefits of this great plant.
- Thread starter
- #458
I’m glad this resource is being found useful. Sometimes - most times I’m in free fall when I’m searching, so you never know where I’ll end up. Lol!
Sometimes - most times I’m in free fall when I’m searching, so you never know where I’ll end up. Lol!
It is a free fall. None of this has ever had the billion dollar research contract and zillions of tests done.
We are testing and researching based on experience and the lab tests done.
I was watching a documentary from Israel on cbd/THC and healing, and basically, they just confirmed what members here have been saying for years.
Nothing new.
We are testing and researching based on experience and the lab tests done.
I was watching a documentary from Israel on cbd/THC and healing, and basically, they just confirmed what members here have been saying for years.
Nothing new.
Hi @Tennessee Tim long time no see
long time no see