Due both to its common use as a recreational intoxicant and its employment in medicine, cannabis has been widely examined for its therapeutic potential and side effects. Among these side effects is tolerance, the regulation of cannabinoid uptake as a result of over stimulation. Tolerance is indicated by the requirement of larger doses to achieve a consistent desired effect, or when a given dose no longer provides it. Higher doses commonly result in the indication of higher impact of undesirable effects though, as with cannabinoids, tolerance can be achieved for many of these as well. Tolerance to cannabinoid stimulation results in withdrawal, most notably marked at 12 hours after cessation of “heavy” use by inner-unrest, increased activity and irritability. During a flushing period of 4 weeks following a 4 week daily ingestion period of 210 mg smoked THC, determined by Georgotas and Zeidenberg (comprehensive psychology), mild-withdrawal symptoms were reported to last between 5-7 days, with no inflammation or indication of desire for THC in the remaining 3 weeks.
Unlike the mythic ‘street-knowledge’ assay, which implies cannabinoid re-absorption through lipid deposits resulting in ‘occupied’ receptors due to constant stimulation, modern neuroassays have concluded tolerance to be based solely in receptor regulation. The cannabinoid content of endogenous lipid deposits has been shown to be less than active physiologically and psychologically.
A non-tolerant ingestion of smoked marijuana results in peak plasma concentrations of 90-95 ng/ml and peak effects lasting 75-90 minutes at which time plasma levels drop below psychoactive concentrations at 10 ng/ml. Plasma concentrations are unaltered by tolerance, indicating no change in endocannabinoid signaling, however cannabinoid stimulation, especially in ligand activation, decreases as a result of receptor based regulation. As has been widely explained and explored, availability of bonding-sites is reduced by down-tolerance and phosphorylation after prolonged or extreme exposure to cannabinoid agonists, resulting in a notable decrease in efficacy of stimulation and effects.
Various Cannabanoids are active at different receptors, both by their affinity for CB1 or CB2 or their digested distribution. As a result, specific tolerance occurs effecting specific site of action.
-Tolerance to the pharmacological effects of ataxia, analgesia, motor inhibition, and anticonvulsant activity usually occurs within 3-7 days of administration, depending on dose and frequency, as a result of cerebellum based CB1receptor-binding and WIN55,212-2 stimulation.
-Long-term memory inhibition, as well as certain neuroendocrine actions (including neuroprotective), take several weeks to develop tolerance desensitization, the former in part due to anandamide’s relatively high endogenous availability. Anandamide levels in the striatum show reduction after prolonged exposure to cannabinoid receptor agonists, though the availability of the precursors was not diminished, suggesting a superficial alteration of productivity.
-More resistant populations of CB1 receptors, primarily located in the limbic regions responsible for emotional stimulation, were uniquely resilient in prolonging the onset of tolerance regulation. Tolerance to immunosuppressive effects of CP-55,940 through stimulation of CB2 receptors is largely insignificant even over extended periods of exposure.
-CB1 activation in Hipocampal neuron populations responsible for short-term memory develops down-tolerance within 24 hours of Δ9-THC administration and showed no impact (positive or negative) from increased anadamide availability or administration.
-Cannabinoid analogues WIN55,212-2, CP-55,940 and 11-hydroxy-Δ8-THC, more infinitively specific cannabinoid agonists take 7-9 days to develop normal tolerance shown to take 3-7 days in administration of less-specific agonists. Due to their specific affinity for bonding efficiently with CB1 receptors (predominant site of CNS stimulant and psychoactive activity), tolerance develops more slowly than with less accurately coupled agonists such as Δ9-THC, CBN and CBD.
-In vitro cultures of neuroblastoma cell line (N18TG2) exhibited rapid-tolerance to chronic exposure to cannabinoid agonist stimulation, showing a natural cellular response.
Though tolerance and dependence often develop concomitantly, in the case of cannabinoid stimulation, since the primary actions of tolerance are neuroreceptive as opposed to adaptive endocannabinoid signaling, tolerance and dependence are independently significant. There is no scientific consensus on the implications of cannabinoid dependence and withdrawal. As there is no indication of somatic and/or neurovegetative periods after abrupt cessation of high-dose cannabinoid therapy, the criteria for physical dependence remain unfulfilled as defined by worldwide health ministries. Psychological withdrawal implications failed to appear in any animal study, though have occurred in human and some non-human primates, to a notably lesser degree than opiods. Primary indicated factors of “heavy” marijuana use behavioral withdrawal include irritability, sleep deficits, attentional deficits, and anxiety, and have been shown to noticeably recede within a 3-day period of cessation, dissipating completely within 1 week.
Recreational tolerance is relatively minute, if existent, in occasional users or ‘weekend-smokers’. Daily consumption for medicinal or recreational purposes however, can have greater, though still relatively diminutive, tolerance implications. Allowing receptor recuperation every 90 minutes could greatly decrease the impact of downregulation, and ingestion of appropriate doses rather than the commonly high recreational dose could aid in the resistance of phosphorylation tolerance. A recent study employing capsaicim antagonists and markers during Δ9-THC administration for analgesic property showed a low ceiling of consumption efficiency, followed by a rapid phosphorylation at high doses, implying a ‘sweet-spot’ theory, in which an exact dose is exponentially more efficient than an overdose. Recreational tolerance is relatively minute, if existent, in occasional users or ‘weekend-smokers’, due to the allowed recovery time. Daily consumption for medicinal or recreational purposes however, can have greater, though still relatively diminutive, tolerance implications. Forecasting scientific developments imply that through integration of specific agonists at specific bonding sites could reduce selective tolerance while achieving reasonable effects. The application of esoteric agonists could potentially alleviate tolerance based dosing and the complications it implies. Additionally, dosing with cannabinoid antagonists, such as CBD and CBG, can combat downregulation of receptors and expose increased availability.
The modification of protein residues is one of the most common mechanisms for protein regulation, at the synapse and elsewhere. Amongst the myriad of potential protein-modifications, the addition of functional groups (namely, phosphorylation and methylation) is highly-ubiquitous. The addition of functional groups may alter protein conformational states, thereby altering SARs and the magnitude of potential activation. This form of modification may also enhance or inhibit residue interactions necessary for ligand binding or dissociation- this may result in an increased or decreased affinity or efficacy. Additionally, protein modification may be used as a signaling residue for protein associations (i.e. receptor coupling, enhancement protein locking..etc.) or regulation (i.e. internalization, recycling or degradation). Nearly every protein studied reacts differently to different modifications, and most proteins utilize multiple simple-modifications.
Phosphorylation of CB1 receptors reduces CB1r-ligand binding efficacy in addition to targeting the protein for endosomal recycling. Phosphorylated CB1 receptors are quickly removed from the synapse (this process may begin within minutes of phosphorylation) and stored temporarily in a recycling endosome within the neuron (usually within the synaptic bouton), where it may be trafficked back to the surface or eventually degraded, depending on further signaling from the post-synaptic density.
The added consequence of this downregulation is a reduction in the size and quantity of synaptic protrusions. Just as the upregulation of synaptic proteins results in an increase in the size and overall quantity of synaptic protrusions by the addition of the endosomal liposome-components to the synapse in the process of vesicle fusion, receptor downregulation indicates the removal of synaptic material, resulting in a reduction in the density of synapse (see AMPAR-regulation at medium-spiny neurons in the NAc for a more thorough, well-studied example of this phenomenon). This overall reduction in synaptic connectivity has significant implications for the time-course of tolerance.
The explanation for this is a resistance to increased dosage/frequency. If the individual were to steadily increase his intake, he would most certainly still experience a tolerance. In the previous example, tolerance developed as a result of persistent administration and large doses. If that individual can remember the beginning of this 5 year period, he would likely note that he began with a sensitivity not unlike that which he experiences now. It is highly unlikely that he went from not smoking at all to wake-n-baking and dosing all day (this is called a 'loading-dose' followed by 'maintenance-doses' in pharmacology).
It is not difficult to ward off the development of tolerance with a resistance to the escalation of the frequency or quantity of dosing.
Though many individuals find that they are socially pressured into taking multiple hits off of a joint as it is passed around, most would do best to stay with their single-toke. A naive user, based on the quantity of cannabinoids on average in one modern marijuana cigarette, should take one deep breath and then step back. If the desired effect is not reached within 15-20min, another hit may be administered.
If this user is convinced that they would like a tolerance (I highly suggest that they stick with the method of sparse, small doses that they currently have and avoid doing so), the best method would be to increase the frequency of administration. If an increase in dose makes them uncomfortable, they might want to simply dose more often. This will cause an increase in tolerance, though not as rapidly. In all honesty though, there is nothing wrong with being sensitive to the effects of a drug-- know your body, know yourself- dose accordingly; that is the key.
CB-receptor distribution changes drastically from adolescence through adulthood. Many users find a significant difference between their response to the drug as a teenager and their response to a similar dose as an adult-- contrary to popular myth, this is not usually a product of 'super-potent modern killer-weed' or 'hyper-skunk' or whatever the media-outlets are labeling it these-days. This difference in response is a simple (or not so simple) matter of cannabinoid-receptor expression differences during development.
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