Cannabis — also known as marijuana, ganja or “weed” — is, without a doubt, the most controversial herb on the planet. Whether you love it or hate it, the scientific community has long agreed that cannabinoids — the active compounds of the cannabis plant — have incredible medicinal value as they regulate several mechanisms in the body, including pain, mood, inflammation and appetite. In the first half of the article, we deal with Cannabis-specific memory impairment and strategies to deal with it. The second part of the article will focus on ways to enhance Cannabis, including commonly reputed techniques of donating blood, taking fish oil, and eating mango.
Introduction
The first point to make is that when one is spending thirty or more dollars per week on a recreational substance, and it is interfering with performance, there is a clear problem. Rather than abstain from cannabis, many users would continue to justify its use, in part by the addition of designer supplements to their regimen. These substances are supposed to cancel out the negatives. As proponents might argue, they tone down the noxious side effects of an otherwise lifesaving medicine.
These supplements, however, are unlikely to restore mental performance as effectively as abstinence, and may occasionally carry health risks of their own. They may prove especially worthless for the heaviest users of Cannabis, offering the widest scope of benefits to light users. The larger the mental deficit, the harder it is to correct. Those with non-addictive personalities often find cannabis easy to manage, and rarely progress to daily use. Others are not as lucky. Some of us do best to completely avoid recreational substances.
Besides, those who consume cannabis for recreational purposes are also more likely to indulge in other unhealthy habits — like smoking tobacco or using other recreational drugs, going to sleep late and eating foods rich in salt, sugar, and fats — that supplements alone cannot fix. Therefore, recreational cannabis smokers should — as far as possible — try to improve their diet and stop the consumption of tobacco and other recreational drugs.
While these supplements may not be terribly effective against heavy cannabis use, they may help restore function after quitting or reducing consumption. They could even be used by people who have quit cannabis years ago, but who feel they have still not yet recovered all of their mental faculties to baseline. These same supplements, owing in part to their regenerative and modulatory effects on dopamine-containing cells, may eventually find a place in treating the persistent deficits seen with abuse of more toxic drugs, such as cocaine and methamphetamine, and also with Parkinson’s or Huntington’s disease.
Besides abstinence and a healthy lifestyle, another piece of advice, which will become more pertinent as laboratories widen Cannabinoid testing profiles, is to choose strains with a higher ratio of CBD to THC. A recent human study[1], compared the effects of cannabis with CBD to cannabis without CBD to see if the presence of this cannabinoid has any effect on the Cannabis-induced “amotivational syndrome”, as evidenced by “a lower likelihood of making a high-effort choice to earn monetary reward”. The cannabis without CBD led to an overall reduction in motivation compared to the cannabis with CBD.
The cannabis can also be consumed raw, which if the reader isn’t already aware, cannabis which has not been dried delivers the drug in the form “THCA”. This form of the drug is non-psychoactive, but it enjoys some of the same medicinal properties of THC, including a stronger anti-inflammatory activity.[2] Because THCA is not psychoactive, many patients (including cases of pediatric cancer and multiple sclerosis) have chosen to consume it raw, by juicing or tossing it in with their salad. This way, children are able to consume ounces per day and maximize the medicinal qualities without any cognitive side effects. However, it is extremely difficult to find cannabis that has not been dried.
CBD, which is used in epilepsy, has an analogous form in raw cannabis: CBDA. It too is antiepileptic, anti-inflammatory, and exhibits less activity on neurotransmitters than CBD (its active form which requires heat to “decarboxylate” into). Again, to get the benefits of this compound you will need to find fresh cannabis.
Cannabis Memory Impairment
Generally, low glutamate and acetylcholine correlate with memory impairment, while low dopamine correlates with depressive anhedonia (dopamine is also involved in and may explain cannabis’ effect on higher order cognitive functions). At the same time, however, excessive glutamate is toxic to neurons, and having high levels of acetylcholine may cause depression, muscle tension, increased sweating and impairment of memory consolidation during sleep.[3]
Cannabinoids regulate many functions in our brain and body and chronic abuse of cannabis results in neuroadaptations. Let’s have a look at those neuroadaptations based on the latest scientific discoveries.
Dopamine
Dopamine release is blunted in chronic cannabis consumption[4] as a result of the body trying to adapt to the increased levels of dopamine (homeostasis).
This effect is significant in the striatum[5], a region of the brain involved in attention, memory[6], and impulsive behavior. This makes cannabis users more vulnerable to attention and memory deficits, as well as anhedonia and depression.[7]
Cannabinoid receptors
There are two type of cannabinoid receptors: type 1 (CB1) and type 2 (CB2).
CB1 receptors are expressed in the brain and the lungs, the liver and the kidneys, whereas CB2 receptors are primarily expressed in the immune system.
Tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, is primarily a CB1 agonist, though it also has some activity at the CB2 receptor. CB1 mediates the recreational effects of marijuana, as well as other effects such as analgesia, increased appetite, and antiemesis. However, being a partial agonist, THC can both increase or decrease the activity of this receptor[8], and this explains why, based on an individual’s personal body chemistry, the effects of cannabis can range from relaxation and euphoria to stimulation, paranoia and anxiety.
After chronic exposure to THC and synthetic cannabinoids, CB1 receptors will downregulate[9] and internalize[10]. This process mediates tolerance to the effects of cannabis, but may also have further implications as far as brain health and memory goes, which takes us to…
5-HT2A receptor
The 5-HT2A receptor is the primary excitatory neurotransmitter of the serotonin family. It is famously known to mediate the effects of psychedelics drugs, that are in turn known as 5-HT2A agonists.
Individuals suffering from depression are known to have more postsynaptic 5-HT2A receptors compared to non-depressed patients, and downregulation of postsynaptic 5-HT2A receptor is an adaptive process provoked by chronic administration of SSRI antidepressants and may mediate some of their beneficial effects.[11]
CB1 is essential for the correct functioning of 5-HT2A receptors (5-HT2AR) and CB1 agonists like cannabis and synthetic cannabinoids upregulate these receptors.[12] This process is thought to mediate some of the negative effects associated with the use of cannabinoids, particularly anxiety-like behavior[13] and memory impairment.
To test this, scientists injected THC to a group of normal mice and another group of 5-HT2A knockout mice (mice which have been genetically modified to not express the 5-HT2A receptor). When researchers administered THC to normal mice, their memory worsened as predicted. However, when they repeated the experiment on the 5-HT2A knockout mice, this effect was significantly reduced.[14] According to the researchers, “these data suggest that specific effects of THC such as memory deficits, anxiolytic-like effects, social interaction, and DR neuronal activity are under the control of 5-HT2AR.”[15]
5-HT2A receptors, however, did not mediate the analgesic and anxiogenic effects of THC.[16]
The explanation for marijuana-induced memory deficits, according to the researchers, is as follows: 5-HT2A and CB1 receptors are closely interrelated, and CB1 agonists like THC promote the oligomerization of CB1 and 5-HT2A receptors. In simple terms, these receptors “fuse” together to form a larger complex, called heteromers (CB1R-5-HT2AR heteromers, to be precise). As reported by the research team, “CB1R-5-HT2AR heteromers are thus good targets to dissociate the cognitive deficits induced by THC from its beneficial antinociceptive properties.” However, no pharmaceutical drug or nootropic with this target exists on the market, yet.
AMPA, BDNF, mTOR and more
Cannabinoids also lower the activity of the AMPA receptor subunits GluR1 and GluR2/3[17], and may thus impair synaptic plasticity.
Acute use of cannabis in drug-naive subjects increases the levels of BDNF[18], a neurotrophin that promotes neurogenesis (though it also has a role in drug addiction[19]). Chronic users of cannabis, however, have actually lower BDNF levels.[20] It is hard to say if this is a consequence of chronic cannabis use, as maybe the patients had lower BDNF, to begin with.
THC also increases cortisol in drug-naive subjects, but not in chronic users, whom also had lower prolactin levels than the control (but, again, it is impossible to say if it is a consequence of cannabis use or not).[21]
The mTOR kinase may also be involved in marijuana’s detrimental effect on memory, particularly long-term memory.[22]
According to this research, rapamycin (an mTOR blocker) completely abolished cannabis-induced memory impairment, as did NMDA antagonists (though they reduced, — but not abolished —, the memory impairment).[23] However, an earlier study showed that mTOR is important for long-term memory and rapamycin actually hindered the consolidation of long-term memories.[24] Because of the strong immunosuppressant effect of mTOR blockers — as well as their poor safety profile — we strongly oppose their use.
These negative effects are especially magnified when the drug is discontinued and, as a result, withdrawal symptoms of psychological nature can manifest.
Reducing Memory Impairment
In addressing cannabis-specific mental impairments, there are many avenues to pursue. Besides the subtitles below, other supplements which did not earn a subsection or even an honorary mention may nevertheless prove useful. Many popular supplements have the potential to be very effective against cannabis-induced cognitive or emotional deficits. To name a few, galantamine, huperzine-A and centrophenoxine.
A 2013 study compared the cognitive performance of rats who consumed either cannabis or cannabis plus a nootropic drug (Piracetam, Donepezil, Vinpocetine or Ginkgo biloba). The most effective nootropic was Piracetam, though it decreased dopamine and increased noradrenaline — possibly worsening the demotivational effect of cannabis — while Donepezil improved memory while further increasing dopamine (likely due to its sigma agonism). Vinpocetine was also effective, though it may significantly reduce the recreational effects of cannabis due of its mechanism of action.
In another, more recent human study, CDP-Choline reduced impulsivity, improved cognitive performance, and normalized the activity of some regions of the brain (like the ACC) in chronic marijuana smokers.[25]
Green tea, a low-caffeine [26] neurotrophin inducer and serotonin modulator. The L-theanine enhances effects while curbing cravings and reducing cannabis anxiogenic effects.
NAC, a glutamate regulator with a proven efficacy in treating cannabis dependence[27][28][29], may also be neuroprotective, though it will probably reduce the recreational effects of marijuana due to its mechanism of action.
CB1 antagonists
CB1 antagonists occur alongside THC in cannabis — though in much smaller quantities — in the form of CBD and THCV. In high doses, they counteract the recreational effects of marijuana, though small quantities of CBD actually enhance the positive effects while reducing the adverse effects. CB1 antagonists are known, for instance, to improve spatial memory[30] in healthy volunteers and this may in part explain the nootropic qualities of CBD.
Rimonabant was initially studied for obesity, dementia, and cannabis dependence, but withdrawn due to psychiatric effects. Falcarinol is found in carrots, although in such low amounts it would require the reader to consume a kilo per day. Voacanga africana, an uncommon supplement, is the only other potent CB1 antagonist known in the plant kingdom.[31]
Since they act by opposing cannabis at its primary site of action, they have potential in easing withdrawal and addiction, but also in restoring cognitive function more quickly. It’s important to keep in mind these compounds (CB1 antagonists) are very selective and potent, often with downstream effects, as seen in Rimonabant.
The easiest way — and also beneficial in regards to analgesia and inflammation — is to buy an electronic cigarette and some CBD e-liquid and vape it whenever you one feels the need to reduce the effects of THC.
Another substance that indirectly abolishes cannabis intoxication is pregnenolone. According to a 2014 study[32] pregnenolone “acting as a signaling-specific inhibitor of the CB1 receptor, reduces several effects of THC. This negative feedback mediated by pregnenolone reveals a previously unknown paracrine/autocrine loop protecting the brain from CB1 receptor overactivation that could open an unforeseen approach for the treatment of cannabis intoxication and addiction.”[33] It may be a good option to sober up quickly before an interview or an exam.
Lastly, CB1 antagonists upregulate receptors (including downstream dopamine) and may make for speedier tolerance breaks. Luckily, a recent study showed that downregulation of CB1 receptors starts to reverse as fast as 2 days into cannabis withdrawal.[34]
COX-2 inhibitors
The COX-2 pathway appears to be more relevant for glutamate than dopamine. Glutamate is the chief excitatory neurotransmitter, responsible for learning, memory, and many higher order processes. As depicted in the above diagram, COX-2 occurs as roughly the ‘midway’ step in the ladder. Nevertheless, multiple studies have confirmed it is a critical step, mediating much of cannabis’ cognitive side effects.
Cyclooxygenase 1 and 2 are enzymes that participate in the synthesis of prostaglandins from arachidonic acid. Prostaglandins are hormone-like molecules in the body that have a wide range of functions, some of which lead to inflammation and fever.
The reason for using selective COX-2 inhibitors instead of the cheaper unselective NSAIDs, like ibuprofen and aspirin, is that COX-2 is specific to inflamed tissues, whereas inhibition of COX-1 stops the production of prostaglandins all over the body, like the gastrointestinal tract, where they have a (positive) role in protecting the gastric mucosa.
The most potent natural COX-2 inhibitors are (ordered by COX-2 affinity, when the information was available):
- Eugenol[35][36][37] (found in clove, nutmeg, and cinnamon oils)
- Sophoricoside[38] (from Sophora japonica)
- Rutaecarpine[39][40] (from Evodia rutaecarpa)
- Xanthorrhizol[41][42] (from Curcuma xanthorrhiza)
- alpha-Viniferin[43] (from Caragana chamlagu)
- Schisandrin[44] (from Schisandra chinensis)
- Nexrutine®[45] (a patented extract of Phellodendron amurense)
- Bromelain[46] (from pineapple)
- Tribulus terrestris[47]
- Rehmannia glutinosa[48]
Note: C. xanthorrhiza is a different herb from turmeric (aka C. lunga, which is less effective as a COX-2 inhibitor). There is also some conflicting evidence about bromelain being a direct COX-2 inhibitor. Some of these compounds are not bioavailable in isolation (like rutaecarpine), so an extract should be used rather than the isolated compounds.
Other, like eugenol, should never be used as an isolated compound, but only in minute quantities using an essential oil, as they have a bi-phasic action (with low doses being protective, and high doses toxic — particularly to the gastrointestinal mucosa). Eugenol is also a MAO inhibitor and may cause serotonin syndrome when taken alongside SSRIs, SNRI, and TCA antidepressants.
alpha-Viniferin (in the form of C. chamlagu extract) is one of the most interesting compounds, as it also an acetylcholinesterase inhibitor (it increases the levels of acetylcholine), so it has two nootropic mechanisms and may be the perfect candidate to reduce memory impairment caused by THC. However, stilbenoids like resveratrol and pterostilbene have famously poor bioavailability, so either a liposomal solution or the addition of piperine may be necessary to fully benefit from it (though piperine failed to increase plasma concentrations of resveratrol[49]).
Common poorly selective (or indirect) COX inhibitors include fish oil, resveratrol, and three root supplements: ginger, turmeric, and ginseng. To combat fatigue and demotivation, about 10 g of ginger, 2 g of turmeric, and/or 1600 mg ginseng extract can be taken daily, and the user will likely notice an array of other healthful benefits.
Misc
Ampakines are substances that activate the AMPA receptor. This receptor is involved in synaptic plasticity and drugs that target this receptor are currently being researched as treatments for Alzheimer’s disease and dementia. Cannabis and synthetic cannabinoids cause deficits in AMPA transmission, and ampakines may counteract this effect. Some of the most famous and commonly used ampakines are Aniracetam, Sunifiram, and IDRA-21.
Fasoracetam and Coluracetam, two recently discovered racetams, are also anecdotally known to reduce the detrimental effect of cannabis and enhance the “high”.
Minor compounds in cannabis besides THC may be responsible for the depressive and memory-impairing effects, especially when using low-quality hash or weed: citral, pinene, limonene and myrcene perhaps the most well-known. At the CNS myrcene acts as both a depressant and a vasodilator, and it is thought by some to explain the stone or couch-lock of indica strains [50]. According to another study, “… citral, limonene and myrcene presented sedative as well as motor relaxant effects.” The vasodilatory effects lead nicely into our next section, which explains that opening the blood vessel (a method of enhancing desirable effects) enhances drug delivery to the brain.
Forskolin promotes cAMP activity, dopamine transmission, and memory. It also increases oxytocin, which is downregulated in chronic cannabis users[51], and may help reduce emotional blunting.
Memantine, amantadine and other specific alpha-7 nicotinic receptor antagonists may offer a novel approach to treating dependence and cognitive dysfunction[52]. However, memantine is known to significantly potentiate cannabis (as well as synthetic cannabinoids and other psychotropic drugs like caffeine and amphetamine) and reduce the tolerance to its effects. This effect is particularly pronounced at doses higher than 5 mg and can make the experience particularly intense and unpleasant. It also has a long half-life, so it is important that you start low and work your way up to avoid a dangerous 24h-long dissociative trip.
Flavonoids and natural phytochemicals that reduce stress or improve memory in mice studies may also find use. As said before, adopting a healthier diet is only going to improve performance.
Enhancing Desirable Effects
There are many folk remedies for someone seeking to enhance their high. Exercising in a fasted state, giving blood, taking a tolerance break, mixing with alcohol or LSD, and switching to a high-efficiency vaporizer are among the most effective methods of conserving one’s stash and enhancing one’s high.
Vasodilators
As far as supplements go, mango, fish oil and dark chocolate are repeatedly mentioned, although their effectiveness is dubious and difficult to replicate in self-experiments.
Mango is supposed to work through myrcene[53], a vasodilator also found in cannabis, hops and especially passionflower. Funnily enough, mango is also a COX-2 inhibitor.[54] The reader is invited, so long as he is a medical patient, to try cannabis with mango or passionflower and gauge himself whether there has been an appreciable enhancement.
Fish oil and dark chocolate are both said to work by enhancing the endocannabinoid system and also (like mango) by dilating blood vessels, which is supposed to let more blood and more drug into the brain. The dark chocolate is probably a better vasodilator than mango. An English team has even filed a patent for including vasodilators in topical formulas, with the same idea that wider blood vessels enhance drug delivery[55].
Ginkgo and ginger may also be used, as both are potent vasodilators. But like the other supplemental vasodilators, they are not as effective as fasting or giving blood. Giving blood is often reported to be the most effective technique.
Dopamine and Glutamate Modulators
The weak antidepressant nootropic property seen with low dose cannabis can be augmented by many things mentioned in this article: exercise, good diet, and ginseng. Though not limited to dopamine or glutamate, here is a brief overview of supplements that would enhance the desirable effects,
Ginkgo biloba, a vasodilator, GABA-A antagonist and weak dopaminergic herb, though it may increase the anxiogenic effect of cannabis.
Forskolin, Uridine, and Fish Oil will enhance dopamine release, thus increasing the rewarding effects. Uridine has the additional effect of increasing expression of dopamine receptors, especially when paired with fish oil and CDP-Choline
Noopept and Tianeptine are anecdotally known to enhance the high, but the latter can cause memory impairment at higher doses, as well as presenting addictive properties of its own. Noopept, on the other hand, may increase marijuana’s demotivational effects in some individuals.
Agmatine appears to enhance effects, at least ones related to painkilling, perhaps by direct modulation of the CB1 receptor. Glycine has also been reported to enhance the analgesic activity.
ALCAR and Piracetam are more active on acetylcholine, but both work to restore memory. ALCAR, in particular, offers a host of other benefits (such as helping energy production) and is strongly recommended for the reader to try if he has not.
Conclusion
More research needs to be carried out on the treatment options (both natural and synthetic) for cannabis withdrawal and for cannabis-specific mental impairments. Alongside this, we will gain an understanding of which compounds have a synergy with cannabis to enhance its effects (or allow for the same effect at a lower dose).
In the coming decades before the research culminates, we will need to take a closer look at cannabis itself and gain a clearer picture of how it works on the mind. Until then, moderation, a healthy diet and meditation may be the best choices to compliment the use of a potent psychoactive drug.
References